Current Trends in the Development of Drugs for the Treatment of Alzheimer’s Disease and their Clinical Trials

  • S.O. Bachurin Institute of Physiologically Active Compounds of the Russian Academy of Sciences, 1 Severny proezd, Moscow region, Chernogolovka, 142432 Russia
  • E.V. Bovina Institute of Physiologically Active Compounds of the Russian Academy of Sciences, 1 Severny proezd, Moscow region, Chernogolovka, 142432 Russia
  • A.A. Ustyugov Institute of Physiologically Active Compounds of the Russian Academy of Sciences, 1 Severny proezd, Moscow region, Chernogolovka, 142432 Russia
Keywords: Alzheimer’s disease, neurodegenerative diseases, multitarget compounds, disease-modifying drugs, repositioning of drugs


Intracellular and extracellular accumulation of fibrillary proteins, beta-amyloid and hyperphosphorylated Tau, in patients with Alzheimer’s disease (AD) leads to chronic and progressive neurodegenerative process. Overaccumulation of aggregates results in synaptic dysfunction and inevitable neuronal loss. Although the exact molecular pathways of the AD still require better understanding, it is clear this neuropathology is a multifactorial disorder where the advanced age is the main risk factor. Lately, several dozens of drug candidates have succeeded to phase II clinical trials; however, none has passed phase III. In this review we summarize existing data on anti-AD therapeutic agents currently undergoing clinical trials and included in the public websites and as well as the Thomson Reuters «Integrity» database. We revealed three major trends in AD drug discovery. First, developing of “disease-modifying agents” could potentially slow the progression of structural and functional abnormalities in the central nervous system providing sustainable improvements of cognitive functions, which persist even after drug withdrawal. Secondly, the focused design of multitargeted drugs acting on multiple key molecular pathways. Finally, the repositioning of drugs that are already available on the market for the novel (anti-AD) application provides a promising strategy for finishing clinical trials and re-marketing.


  1. WHO. Dementia. Retrieved December 12, 2017, from:

  2. McDade, E. Bateman, R. J. (2017). Stop Alzheimer's before it starts. Nature, 547(7662), 153-155. DOI

  3. Vademecum. R&D VSEGO SVYATOGO Retrieved March 23, 2016, from:

  4. Kukharsky, M. S., Ovchinnikov, R. K., Bachurin, S. O. (2015). [Molecular aspects of the pathogenesis and current approaches to pharmacological correction of Alzheimer's disease]. Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova, 115(6), 103-114. DOI

  5. Nussbaum, J. M., Seward, M. E., Bloom, G. S. (2014). Alzheimer disease: a tale of two prions. Prion, 7(1), 14-19. DOI

  6. Carreiras, M. C., Mendes, E., Perry, M. J., Francisco, A. P., Marco-Contelles, J. (2013). The multifactorial nature of Alzheimer's disease for developing potential therapeutics. Current Topics in Medicinal Chemistry, 13(15), 1745-1770. DOI

  7. De-Paula, V. J., Radanovic, M., Diniz, B. S., Forlenza, O. V. (2012). Alzheimer's disease. Subcellular Biochemistry, 65, 329-352. DOI

  8. Karran, E., Mercken, M., De Strooper, B. (2011). The amyloid cascade hypothesis for Alzheimer's disease: an appraisal for the development of therapeutics. Nature Reviews Drug Discovery, 10(9), 698-712. DOI

  9. Maccioni, R. B., Farias, G., Morales, I., Navarrete, L. (2010). The revitalized tau hypothesis on Alzheimer's disease. Archives of Medical Research, 41(3), 226-231. DOI

  10. Sorbi, S. (1993). Molecular genetics of Alzheimer's disease. Aging (Milano), 5(6), 417-425. DOI

  11. Scheltens, P., Blennow, K., Breteler, M. M., de Strooper, B., Frisoni, G. B., Salloway, S., Van der Flier, W. M. (2016). Alzheimer's disease. Lancet Neurology, 388(10043), 505-517. DOI

  12. Bradley, W. G. (1990). Alzheimer's disease: theories of causation. Advances in Experimental Medicine and Biology, 282, 31-38. DOI

  13. Borchelt, D. R., Thinakaran, G., Eckman, C. B., Lee, M. K., Davenport, F., Ratovitsky, T., Prada, C. M., Kim, G., Seekins, S., Yager, D., Slunt, H. H., Wang, R., Seeger, M., Levey, A. I., Gandy, S. E., Copeland, N. G., Jenkins, N. A., Price, D. L., Younkin, S. G., Sisodia, S. S. (1996). Familial Alzheimer's disease-linked presenilin 1 variants elevate Abeta1-42/1-40 ratio in vitro and in vivo. Neuron, 17(5), 1005-1013. DOI

  14. Chartier-Harlin, M. C., Crawford, F., Hamandi, K., Mullan, M., Goate, A., Hardy, J., Backhovens, H., Martin, J. J., Broeckhoven, C. V. (1991). Screening for the beta-amyloid precursor protein mutation (APP717: Val----Ile) in extended pedigrees with early onset Alzheimer's disease. Neuroscience Letters, 129(1), 134-135. DOI

  15. Levy-Lahad, E., Wijsman, E. M., Nemens, E., Anderson, L., Goddard, K. A., Weber, J. L., Bird, T. D., Schellenberg, G. D. (1995). A familial Alzheimer's disease locus on chromosome 1. Science, 269(5226), 970-973. PMID: 7638621

  16. Sisodia, S. S., Kim, S. H., Thinakaran, G. (1999). Function and dysfunction of the presenilins. The American Journal of Human Genetics, 65(1), 7-12. DOI

  17. Goedert, M., Wischik, C. M., Crowther, R. A., Walker, J. E., Klug, A. (1988). Cloning and sequencing of the cDNA encoding a core protein of the paired helical filament of Alzheimer disease: identification as the microtubule-associated protein tau. Proceedings of the National Academy of Sciences of the United States of America, 85(11), 4051-4055. DOI

  18. Wischik, C. M., Novak, M., Edwards, P. C., Klug, A., Tichelaar, W., Crowther, R. A. (1988). Structural characterization of the core of the paired helical filament of Alzheimer disease. Proceedings of the National Academy of Sciences of the United States of America, 85(13), 4884-4888. DOI

  19. Olsson, B., Lautner, R., Andreasson, U., Ohrfelt, A., Portelius, E., Bjerke, M., Holtta, M., Rosen, C., Olsson, C., Strobel, G., Wu, E., Dakin, K., Petzold, M., Blennow, K., Zetterberg, H. (2016). CSF and blood biomarkers for the diagnosis of Alzheimer's disease: a systematic review and meta-analysis. The Lancet Neurology, 15(7), 673-684. DOI

  20. Glenner, G. G., Wong, C. W., Quaranta, V., Eanes, E. D. (1984). The amyloid deposits in Alzheimer's disease: their nature and pathogenesis. Applied Pathology, 2(6), 357-369. PMID: 6242724

  21. Selkoe, D. J. (1994). Alzheimer's disease: a central role for amyloid. Journal of Neuropathology and Experimental Neurology, 53(5), 438-447. DOI

  22. Khlistunova, I., Biernat, J., Wang, Y., Pickhardt, M., von Bergen, M., Gazova, Z., Mandelkow, E., Mandelkow, E. M. (2006). Inducible expression of Tau repeat domain in cell models of tauopathy: aggregation is toxic to cells but can be reversed by inhibitor drugs. The Journal of Biological Chemistry, 281(2), 1205-1214. DOI

  23. Walsh, D. M. Selkoe, D. J. (2007). A beta oligomers - a decade of discovery. Journal of Neurochemistry, 101(5), 1172-1184. DOI

  24. Querfurth, H. W. LaFerla, F. M. (2010). Alzheimer's disease. The New England Journal of Medicine, 362(4), 329-344. DOI

  25. Friedland-Leuner, K., Stockburger, C., Denzer, I., Eckert, G. P., Muller, W. E. (2014). Mitochondrial dysfunction: cause and consequence of Alzheimer's disease. Progress in Molecular Biology and Translational Science, 127, 183-210. DOI

  26. Raskin, J., Cummings, J., Hardy, J., Schuh, K., Dean, R. A. (2015). Neurobiology of Alzheimer's Disease: Integrated Molecular, Physiological, Anatomical, Biomarker, and Cognitive Dimensions. Current Alzheimer Research, 12(8), 712-722. DOI

  27. Tipping, K. W., van Oosten-Hawle, P., Hewitt, E. W., Radford, S. E. (2015). Amyloid Fibres: Inert End-Stage Aggregates or Key Players in Disease? Trends in Biochemical Sciences, 40(12), 719-727. DOI

  28. Iqbal, K., Liu, F., Gong, C. X. (2016). Tau and neurodegenerative disease: the story so far. Nature reviews Neurology, 12(1), 15-27. DOI

  29. Gavrilova, S. I., Seleznyova, N. D., Roshchina, I. F., Fedorova, Y. B., Rannaya diagnostika bolezni Alzgeimera na dodementnoistadii i preventivnaja terapiya., in Neirodegenerativnye zabolevaniya, Ugryumov, M. V., Editor. 2014, Nauchny Mir: Moskow. p. 95-123.

  30. Nordberg, A. (2006). Mechanisms behind the neuroprotective actions of cholinesterase inhibitors in Alzheimer disease. Alzheimer Disease and Associated Disorders, 20(2 Suppl 1), S12-18. DOI

  31. Chalmers, K. A., Wilcock, G. K., Vinters, H. V., Perry, E. K., Perry, R., Ballard, C. G., Love, S. (2009). Cholinesterase inhibitors may increase phosphorylated tau in Alzheimer's disease. Journal of neurology, 256(5), 717-720. DOI

  32. Danysz, W., Parsons, C. G., Mobius, H. J., Stoffler, A., Quack, G. (2000). Neuroprotective and symptomatological action of memantine relevant for Alzheimer's disease--a unified glutamatergic hypothesis on the mechanism of action. Neurotoxicity Research, 2(2-3), 85-97. DOI

  33. Danysz, W. Parsons, C. G. (2012). Alzheimer's disease, beta-amyloid, glutamate, NMDA receptors and memantine--searching for the connections. British Journal of Pharmacology, 167(2), 324-352. DOI

  34. Mohandas, E., Rajmohan, V., Raghunath, B. (2009). Neurobiology of Alzheimer's disease. Indian J Psychiatry, 51(1), 55-61. DOI

  35. Hemming, M. L. Selkoe, D. J. (2005). Amyloid beta-protein is degraded by cellular angiotensin-converting enzyme (ACE) and elevated by an ACE inhibitor. The Journal of Biological Chemistry, 280(45), 37644-37650. DOI

  36. Zhang, Y., McLaughlin, R., Goodyer, C., LeBlanc, A. (2002). Selective cytotoxicity of intracellular amyloid beta peptide1-42 through p53 and Bax in cultured primary human neurons. Journal of Cell Biology, 156(3), 519-529. DOI

  37. Laske, C. (2015). Phase 3 trials of solanezumab and bapineuzumab for Alzheimer's disease. The New England Journal of Medicine, 370(15), 1459. DOI

  38. Honig, L. S., Vellas, B., Woodward, M., Boada, M., Bullock, R., Borrie, M., Hager, K., Andreasen, N., Scarpini, E., Liu-Seifert, H., Case, M., Dean, R. A., Hake, A., Sundell, K., Hoffmann, V. P., Carlson, C., Khanna, R., Mintun, M., DeMattos, R., Selzler, K. J., Siemers, E. (2018). Trial of Solanezumab for Mild Dementia Due to Alzheimer's Disease. The New England Journal of Medicine, 378(4), 321-330. DOI

  39. Budd, S. H., O'Gorman, J., Chiao, P., Bussière, T., Tian, Y., Zhu, Y., Gheuens, S., Skordos, L., Chen, T., Sandrock, A. (2017). Clinical Development of Aducanumab, an Anti-Aβ Human Monoclonal Antibody Being Investigated for the Treatment of Early Alzheimer's Disease. The journal of prevention of Alzheimer's disease, 4(4), 255-263. DOI

  40. Jacobsen, H., Ozmen, L., Caruso, A., Narquizian, R., Hilpert, H., Jacobsen, B., Terwel, D., Tanghe, A., Bohrmann, B. (2014). Combined treatment with a BACE inhibitor and anti-Abeta antibody gantenerumab enhances amyloid reduction in APPLondon mice. Journal of Neuroscience, 34(35), 11621-11630. DOI

  41. Relkin, N. (2014). Clinical trials of intravenous immunoglobulin for Alzheimer's disease. Journal of Clinical Immunology, 34 Suppl 1, S74-79. DOI

  42. Relkin, N. R., Szabo, P., Adamiak, B., Burgut, T., Monthe, C., Lent, R. W., Younkin, S., Younkin, L., Schiff, R., Weksler, M. E. (2009). 18-Month study of intravenous immunoglobulin for treatment of mild Alzheimer disease. Neurobiology of Aging, 30(11), 1728-1736. DOI

  43. Baxalta. Phase III Efficacy, Safety, and Tolerability Study of HYQVIA/HyQvia and GAMMAGARD LIQUID/KIOVIG in CIDP. Retrieved May 18, 2018, from:

  44. Liu, E., Schmidt, M. E., Margolin, R., Sperling, R., Koeppe, R., Mason, N. S., Klunk, W. E., Mathis, C. A., Salloway, S., Fox, N. C., Hill, D. L., Les, A. S., Collins, P., Gregg, K. M., Di, J., Lu, Y., Tudor, I. C., Wyman, B. T., Booth, K., Broome, S., Yuen, E., Grundman, M., Brashear, H. R. (2015). Amyloid-beta 11C-PiB-PET imaging results from 2 randomized bapineuzumab phase 3 AD trials. Neurology, 85(8), 692-700. DOI

  45. Hu, C., Adedokun, O., Ito, K., Raje, S., Lu, M. (2015). Confirmatory population pharmacokinetic analysis for bapineuzumab phase 3 studies in patients with mild to moderate Alzheimer's disease. Journal of Clinical Pharmacology, 55(2), 221-229. DOI

  46. Jarvis, L. M. (2015). The Next Chapter In Treating Alzheimer's. Chemical and Engineering News. ACS, 93(22), 11-15.

  47. Schneeberger, A., Mandler, M., Otawa, O., Zauner, W., Mattner, F., Schmidt, W. (2009). Development of AFFITOPE vaccines for Alzheimer's disease (AD)--from concept to clinical testing. The Journal of Nutrition, Health & Aging, 13(3), 264-267. DOI

  48. PRNewswire. Breakthrough in Alzheimer's Disease: AFFiRiS Halted Clinical Progression in Alzheimer Patients Upon Treatment With AD04 in a Phase II Clinical Study. Retrieved June 04, 2014, from:

  49. Schneeberger, A., Hendrix, S., Ellison, N., BГјrger, V., Dubois, B. (2015). Results from a phase II study to assess the clinical and immunological activity, safety and tolerability of AFFITOPE AD02 in patients with early Alzheimer's (Abst. 042). in Alzheimer's & Dementia: The Journal of the Alzheimer's Association. Nice, France.

  50. Hickman, D. T., Lopez-Deber, M. P., Ndao, D. M., Silva, A. B., Nand, D., Pihlgren, M., Giriens, V., Madani, R., St-Pierre, A., Karastaneva, H., Nagel-Steger, L., Willbold, D., Riesner, D., Nicolau, C., Baldus, M., Pfeifer, A., Muhs, A. (2011). Sequence-independent control of peptide conformation in liposomal vaccines for targeting protein misfolding diseases. The Journal of Biological Chemistry, 286(16), 13966-13976. DOI

  51. Tucker, S., Moller, C., Tegerstedt, K., Lord, A., Laudon, H., Sjodahl, J., Soderberg, L., Spens, E., Sahlin, C., Waara, E. R., Satlin, A., Gellerfors, P., Osswald, G., Lannfelt, L. (2015). The murine version of BAN2401 (mAb158) selectively reduces amyloid-beta protofibrils in brain and cerebrospinal fluid of tg-ArcSwe mice. Journal of Alzheimer's Disease, 43(2), 575-588. DOI

  52. Wang, C. Y., Finstad, C. L., Walfield, A. M., Sia, C., Sokoll, K. K., Chang, T. Y., Fang, X. D., Hung, C. H., Hutter-Paier, B., Windisch, M. (2007). Site-specific UBITh amyloid-beta vaccine for immunotherapy of Alzheimer's disease. Vaccine, 25(16), 3041-3052. DOI

  53. UnitedNeuroscienceLtd. Evaluate the Safety, Tolerability, Immunogenicity and Efficacy of UB-311 in Mild Alzheimer's Disease (AD) Patients. Retrieved April 11, 2018, from:

  54. Adolfsson, O., Pihlgren, M., Toni, N., Varisco, Y., Buccarello, A. L., Antoniello, K., Lohmann, S., Piorkowska, K., Gafner, V., Atwal, J. K., Maloney, J., Chen, M., Gogineni, A., Weimer, R. M., Mortensen, D. L., Friesenhahn, M., Ho, C., Paul, R., Pfeifer, A., Muhs, A., Watts, R. J. (2012). An effector-reduced anti-beta-amyloid (Abeta) antibody with unique abeta binding properties promotes neuroprotection and glial engulfment of Abeta. Journal of Neuroscience, 32(28), 9677-9689. DOI

  55. Landen, J. W., Zhao, Q., Cohen, S., Borrie, M., Woodward, M., Billing, C. B., Jr., Bales, K., Alvey, C., McCush, F., Yang, J., Kupiec, J. W., Bednar, M. M. (2013). Safety and pharmacology of a single intravenous dose of ponezumab in subjects with mild-to-moderate Alzheimer disease: a phase I, randomized, placebo-controlled, double-blind, dose-escalation study. Clinical Neuropharmacology, 36(1), 14-23. DOI

  56. Dodel, R., Rominger, A., Blennow, K., Barkhof, F., Wietek, S., Haag, S., Bartenstein, P., Farlow, M., Jessen, F. (2011). A randomized, double-blind, placebo-controlled dose-finding trial of intravenous immunoglobulin (IVIG; Octagam® 10%,Octapharma AG) in patients with mild to moderate Alzheimer's disease (GAM10-04). Alzheimer's & Dementia: The Journal of the Alzheimer's Association, 7(4), e55-e56. DOI

  57. Pradier, L., Cohen, C., Blanchard, V., Debeir, T., Barneoud, P., Canton, T., Menager, J., Bohme, A., Rooney, T., Guillet, M., Cameron, B., Shi, Y., Naimi, S., Ravetch, J., Claudel, S., Alam, J. (2013). SAR228810: An antiprotofibrillar beta-amyloid antibody designed to reduce risk of amyloid-related imaging abnormalities (ARIA). Alzheimer's & Dementia: The Journal of the Alzheimer's Association, 9(4), P808-P809. DOI

  58. Rosen, L., Pomfret, M., Billinton, A., Chessell, I., Chessell, T., Kugler, A., Lindqvist, E., McFarlane, M., Groves, M., Narwal, R., Tan, K., Tatipalli, M., Dudley, A. (2015). Tolerability and preliminary pharmacodynamics after single doses of MEDI1814, a Beta-Amyloid 42 (Aß42)-specific antibody, in mild-moderate Alzheimer's disease. In 8th Clinical Trials Alzheimer's Disease (CTAD) Confernce Abst. #OC25. Barcelona: The Journal of Prevention of Alzheimer's Disease.

  59. KHK Pharma. A Study of Single and Multiple Doses of KHK6640 in Subjects With Prodromal or Mild to Moderate Alzheimer's Disease. Retrieved February 03, 2014, from:

  60. Davtyan, H., Ghochikyan, A., Petrushina, I., Hovakimyan, A., Davtyan, A., Poghosyan, A., Marleau, A. M., Movsesyan, N., Kiyatkin, A., Rasool, S., Larsen, A. K., Madsen, P. J., Wegener, K. M., Ditlevsen, D. K., Cribbs, D. H., Pedersen, L. O., Agadjanyan, M. G. (2013). Immunogenicity, efficacy, safety, and mechanism of action of epitope vaccine (Lu AF20513) for Alzheimer's disease: prelude to a clinical trial. Journal of Neuroscience, 33(11), 4923-4934. DOI

  61. Zhou, B., Rothlein, R., Shen, J., Valcarce, C., Selmer, J., Hanhan, M., Kindy, M., Mjalli, A., Kostura, M. (2013). TTP4000, a soluble fusion protein inhibitor of receptor for advanced glycation end products (RAGE) is an effective therapy in animal models of Alzheimer's disease. in Experimental Biology. Boston, USA.

  62. Yan, R. Vassar, R. (2014). Targeting the beta secretase BACE1 for Alzheimer's disease therapy. The Lancet Neurology, 13(3), 319-329. DOI

  63. Alexander, R., Haeberlein, S., Rosen, L. (2015). AZD3293 a novel BACE1 inhibitor: Pharmacokinetics and effects on plasma and CSF A-beta peptides following multiple-dose administration in Alzheimer's disease patients (Abst. 091). 12th International Conference on Alzheimer's and Parkinson's Disease (AD/PD). Nice, France.

  64. Neumann, U., Rueeger, H., Machauer, R., Veenstra, S. J., Lueoend, R. M., Tintelnot-Blomley, M., Laue, G., Beltz, K., Vogg, B., Schmid, P., Frieauff, W., Shimshek, D. R., Staufenbiel, M., Jacobson, L. H. (2015). A novel BACE inhibitor NB-360 shows a superior pharmacological profile and robust reduction of amyloid-beta and neuroinflammation in APP transgenic mice. Molecular Neurodegeneration, 10, 44. DOI

  65. Matijevic, M., Watanabe, H., Sato, Y., Bernier, F., McGrath, S., Burns, L., Yamamoto, N., Ogo, M., Dezso, Z., Chow, J., Oda, Y., Kaplow, J., Albala, B. (2015). A single dose of the beta-secretase inhibitor, e2609, decreases CSF bace1 enzymatic activity in cynomolgus monkeys. Alzheimer's & Dementia: The Journal of the Alzheimer's Association, 11(7), P841. DOI

  66. Nicolas, L., Kammerer, K.-P., Schaible, J., Link, J., Kleiner, O., Borta, A., Podhorna, J., Scholpp, J. (2015). Pharmacokinetics, pharmacodynamics, and safety of the novel bace inhibitor bi1181181 after oral administration of single ascending doses in healthy subjects. Alzheimer's & Dementia: The Journal of the Alzheimer's Association, 11(7), P740-P741. DOI

  67. FORUMPharmaceuticals. Safety, Tolerability, Pharmacokinetics of EVP-0962 and Effects of EVP-0962 on Cerebral Spinal Fluid Amyloid Concentrations in Healthy Subjects and in Subjects With Mild Cognitive Impairment or Early Alzheimer's Disease. Retrieved January 13, 2014, from:

  68. Navarro, D., Castaner, R., Fernandez-Forner, D. (2015). NME digest. Drugs on the Future, 40(10), 667.

  69. Panza, F., Seripa, D., Solfrizzi, V., Imbimbo, B. P., Lozupone, M., Leo, A., Sardone, R., Gagliardi, G., Lofano, L., Creanza, B. C., Bisceglia, P., Daniele, A., Bellomo, A., Greco, A., Logroscino, G. (2016). Emerging drugs to reduce abnormal beta-amyloid protein in Alzheimer's disease patients. Expert Opinion on Emerging Drugs, 21(4), 377-391. DOI

  70. ShanghaiGreenvalleyPharmaceutical. Safety, Efficacy and Dose Titration of Sodium Oligo-mannurarate Capsule on Mild to Moderate Alzheimer's Disease. Retrieved January 27, 2015, from:

  71. Maccecchini, M. L., Chang, M. Y., Pan, C., John, V., Zetterberg, H., Greig, N. H. (2012). Posiphen as a candidate drug to lower CSF amyloid precursor protein, amyloid-beta peptide and tau levels: target engagement, tolerability and pharmacokinetics in humans. Journal of Neurology, Neurosurgery and Psychiatry, 83(9), 894-902. DOI

  72. Sinha, S., Du, Z., Maiti, P., Klarner, F. G., Schrader, T., Wang, C., Bitan, G. (2012). Comparison of three amyloid assembly inhibitors: the sugar scyllo-inositol, the polyphenol epigallocatechin gallate, and the molecular tweezer CLR01. ACS Chemical Neuroscience, 3(6), 451-458. DOI

  73. Transition Therapeutics. Transition Therapeutics Announces Results of Data Analysis from ELND005 Phase 2/3 Clinical Study in Agitation and Aggression in Alzheimer's Disease Patients. Retrieved May 03, 2018, from:

  74. Pepys, M. B., Herbert, J., Hutchinson, W. L., Tennent, G. A., Lachmann, H. J., Gallimore, J. R., Lovat, L. B., Bartfai, T., Alanine, A., Hertel, C., Hoffmann, T., Jakob-Roetne, R., Norcross, R. D., Kemp, J. A., Yamamura, K., Suzuki, M., Taylor, G. W., Murray, S., Thompson, D., Purvis, A., Kolstoe, S., Wood, S. P., Hawkins, P. N. (2002). Targeted pharmacological depletion of serum amyloid P component for treatment of human amyloidosis. Nature, 417(6886), 254-259. DOI

  75. Suhr, O. B., Lundgren, E., Westermark, P. (2010). Transthyretin amyloidoses: New strategies for therapeutic intervention. Drugs on the Future, 35(4), 325. DOI

  76. BELLUS. BELLUS Health Announces Partnership for the Development of BLU8499. Retrieved September 04, 2012, from:

  77. Vartiainen, N. E., Williams, M., Charles, M. L., Stenius, T., Nurmi, A., Yrjanheikki, J. (2009). SAN-61 protects against Ab1-42, OGD and H2O2 in rat mixed cortical cultures and inhibits GSK-3b (Abst. 336.16/L15). in 39th Society for Neuroscience Meeting. Chicago.

  78. Hu, Q., Cam, J., Lake, T., Cummings, J., Esposito, L., Yadon, M.-C., Snow, A. Identification of Exebryl-1 and other novel small molecules as tau protein aggregation inhibitors. in Alzheimer's & Dementia: The Journal of the Alzheimer's Association. Abst #P2-529. 2011. DOI

  79. Brunden, K. R., Trojanowski, J. Q., Lee, V. M. (2009). Advances in tau-focused drug discovery for Alzheimer's disease and related tauopathies. Nature Reviews Drug Discovery, 8(10), 783-793. DOI

  80. Valera, E., Spencer, B., Masliah, E. (2016). Immunotherapeutic Approaches Targeting Amyloid-beta, alpha-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders. Neurotherapeutics, 13(1), 179-189. DOI

  81. Novak, M. (2009). Tau vaccine: Active immunization with misfolded tau protein attenuates tau pathology in the transgenic rat model of tauopathy. in Alzheimer's Association International Conference on Alzheimer's Disease (Abst S2-01-02). Vienna, Austria: Alzheimer's & Dementia.

  82. Sheridan, C. (2015). Pivotal trials for beta-secretase inhibitors in Alzheimer's. Nature Biotechnology, 33(2), 115-116. DOI

  83. Riedmann, E. M. (2014). Swiss biotech firm starts first trial of a tau-targeting Alzheimer vaccine. Human Vaccines & Immunotherapeutics, 10(3), 531. DOI

  84. Bristol-MyersSquibb. A Randomized, Double-Blind, Placebo-Controlled, Single Ascending Dose Study of Intravenously Administered BMS-986168 in Healthy Subjects. Retrieved November 06, 2017, from:

  85. Wischik, C. M., Edwards, P. C., Lai, R. Y., Roth, M., Harrington, C. R. (1996). Selective inhibition of Alzheimer disease-like tau aggregation by phenothiazines. Proceedings of the National Academy of Sciences of the United States of America, 93(20), 11213-11218. DOI

  86. Wischik, C. M., Staff, R. T., Wischik, D. J., Bentham, P., Murray, A. D., Storey, J. M., Kook, K. A., Harrington, C. R. (2015). Tau aggregation inhibitor therapy: an exploratory phase 2 study in mild or moderate Alzheimer's disease. Journal of Alzheimer's Disease, 44(2), 705-720. DOI

  87. Fox, P. Cognitive and Functional Connectivity Effects of Methylene Blue in Healthy Aging, Mild Cognitive Impairment and Alzheimer's Disease (MB2). Retrieved January 05, 2018, from:

  88. Baddeley, T. C., McCaffrey, J., Storey, J. M., Cheung, J. K., Melis, V., Horsley, D., Harrington, C. R., Wischik, C. M. (2015). Complex disposition of methylthioninium redox forms determines efficacy in tau aggregation inhibitor therapy for Alzheimer's disease. Journal of Pharmacology and Experimental Therapeutics, 352(1), 110-118. DOI

  89. Panza, F., Solfrizzi, V., Seripa, D., Imbimbo, B. P., Lozupone, M., Santamato, A., Zecca, C., Barulli, M. R., Bellomo, A., Pilotto, A., Daniele, A., Greco, A., Logroscino, G. (2016). Tau-Centric Targets and Drugs in Clinical Development for the Treatment of Alzheimer's Disease. BioMed Research International, 2016, 15. DOI

  90. Muggia, F. Kudlowitz, D. (2014). Novel taxanes. Anticancer Drugs, 25(5), 593-598. DOI

  91. Ramirez, M. J., Lai, M. K., Tordera, R. M., Francis, P. T. (2014). Serotonergic therapies for cognitive symptoms in Alzheimer's disease: rationale and current status. Drugs, 74(7), 729-736. DOI

  92. Wilkinson, D., Windfeld, K., Colding-Jorgensen, E. (2014). Safety and efficacy of idalopirdine, a 5-HT6 receptor antagonist, in patients with moderate Alzheimer's disease (LADDER): a randomised, double-blind, placebo-controlled phase 2 trial. The Lancet Neurology, 13(11), 1092-1099. DOI

  93. Maher-Edwards, G., Dixon, R., Hunter, J., Gold, M., Hopton, G., Jacobs, G., Hunter, J., Williams, P. (2011). SB-742457 and donepezil in Alzheimer disease: a randomized, placebo-controlled study. International Journal of Geriatric Psychiatry, 26(5), 536-544. DOI

  94. Daripelli, S., Bhyrapuneni, G., Mudigonda, K., Benade, V., Ayyanki, G., Kamuju, V., Ponnamaneni, R., Manoharan, A., Nirogi, R. (2015). Novel 5-HT6 antagonist, SUVN-502 potentiates the effects of donepezil on neurochemical and electrophysiological activity in rat hippocampus (Abst. 761.11). In 45th Annual Meeting Society for Neuroscience. Chicago, USA.

  95. Tkachenko, S., Ivachtchenko, A., Khvat, A., Okun, I., Lavrovsky, Y., Salimov, R. (2009). Discovery and preclinical studies of AVN-322 highly selective and potent 5HT6 antagonist for cognition enhancement in treating neurodegerative diseases. In 9th International Conference Alzheimer's and Parkinson Disease (AD/PD).

  96. Kwon, S., Rajagopal, L., Huang, M., Michael, E., Meltzer, H. (2015). RP5063 reverses and prevents sub-chronic phencyclidine-induced declarative memory deficits and increased dopamine efflux in the prefrontal cortex region in C57BL/6J mice (Abst/823.04). in 45th Annual Meeting Society for Neuroscience. Chicago, USA.

  97. Thomsen, M. S., Andreasen, J. T., Arvaniti, M., Kohlmeier, K. A. (2016). Nicotinic Acetylcholine Receptors in the Pathophysiology of Al zheimer's Disease: The Role of Protein-Protein Interactions in Current and Future Treatment. Current Pharmaceutical Design, 22(14), 2015-2034. DOI

  98. Lombardo, S. Maskos, U. (2013). Role of the nicotinic acetylcholine receptor in Alzheimer's disease pathology and treatment. Neuropharmacology, 96(Pt B), 255-262. DOI

  99. Othman, A., Meier, A., Ritchie, C. W., Florian, H., Gault, L. M., Tang, Q. (2014). Efficacy and safety of the alpha7 agonist abt-126 as a monotherapy treatment in mild-to-moderate alzheimer's dementia: results of a phase 2b trial. Alzheimer's & Dementia: The Journal of the Alzheimer's Association, 10(4), P137. DOI

  100. Frolich, L., Ashwood, T., Nilsson, J., Eckerwall, G. (2011). Effects of AZD3480 on cognition in patients with mild-to-moderate Alzheimer's disease: a phase IIb dose-finding study. Journal of Alzheimer's Disease, 24(2), 363-374. DOI

  101. Greenamyre, J. T., Maragos, W. F., Albin, R. L., Penney, J. B., Young, A. B. (1988). Glutamate transmission and toxicity in Alzheimer's disease. Progress in Neuro-psychopharmacology & Biological Psychiatry, 12(4), 421-430. DOI

  102. Nakamura, T. Lipton, S. A. (2016). Protein S-Nitrosylation as a Therapeutic Target for Neurodegenerative Diseases. Trends in Pharmacological Sciences, 37(1), 73-84. DOI

  103. Avanir. Avanir Pharmaceuticals Announces Initiation of Phase II Study of AVP-786 for the Adjunctive Treatment of Major Depressive Disorder. Retrieved August 26, 2014, from:

  104. Chumakov, I., Nabirotchkin, S., Cholet, N., Milet, A., Boucard, A., Toulorge, D., Pereira, Y., Graudens, E., Traore, S., Foucquier, J., Guedj, M., Vial, E., Callizot, N., Steinschneider, R., Maurice, T., Bertrand, V., Scart-Gres, C., Hajj, R., Cohen, D. (2015). Combining two repurposed drugs as a promising approach for Alzheimer's disease therapy. Scientific Reports, 5, 7608. DOI

  105. Lin, C. H., Chen, P. K., Chang, Y. C., Chuo, L. J., Chen, Y. S., Tsai, G. E., Lane, H. Y. (2014). Benzoate, a D-amino acid oxidase inhibitor, for the treatment of early-phase Alzheimer disease: a randomized, double-blind, placebo-controlled trial. Biological Psychiatry, 75(9), 678-685. DOI

  106. Grigoriev, V. V., Proshin, A. N., Kinzirsky, A. S., Bachurin, S. (2009). Modern approaches to the design of memory and cognitive function stimulants based on AMPA receptor ligands. Russian Chemical Reviews, 78(5), 485. DOI

  107. Louis, C., Danober, L., Carrié, I., Dumas, N., Albinet, K., Llopis, K., Roger, A., Gandon, M.-H., Hugot, A., Krentner, M., Thomas, J.-Y., Rogez, N., Vandesquille, M., Krazem, A., Béracochéa, D., Bertainaanglade, V., Drieu la rochelle, C., Junges, C., Bertrand, M., Billiald, S., Tordjman, C., Cordi, A., Lestage, P. (2015). In vivo pharmacological profile of S47445, a novel positive allosteric modulator of AMPA-type glutamate receptors (Abst. 365). in 12th International Conference on Alzheimer's and Parkinson's Disease (AD/PD). Nice, France.

  108. Mandavilli, A. (2006). The amyloid code. Nature Medicine, 12(7), 747-751. DOI

  109. Piette, F., Belmin, J., Vincent, H., Schmidt, N., Pariel, S., Verny, M., Marquis, C., Mely, J., Hugonot-Diener, L., Kinet, J. P., Dubreuil, P., Moussy, A., Hermine, O. (2011). Masitinib as an adjunct therapy for mild-to-moderate Alzheimer's disease: a randomised, placebo-controlled phase 2 trial. Alzheimer's research & therapy, 3(2), 16. DOI

  110. Lawlor, B., Kennelly, S., O'Dwyer, S., Cregg, F., Walsh, C., Coen, R., Kenny, R. A., Howard, R., Murphy, C., Adams, J., Daly, L., Segurado, R., Gaynor, S., Crawford, F., Mullan, M., Lucca, U., Banzi, R., Pasquier, F., Breuilh, L., Riepe, M., Kalman, J., Wallin, A., Borjesson, A., Molloy, W., Tsolaki, M., Olde Rikkert, M. (2014). NILVAD protocol: a European multicentre double-blind placebo-controlled trial of nilvadipine in mild-to-moderate Alzheimer's disease. BMJ Open, 4(10). DOI

  111. Ferguson, S., Bishop, A., Mouzon, B., Phillips, J., Crynen, G., Reed, J., Chaytow, H., Mullan, M., Mathura, V., Mullan, M., Crawford, F. (2011). Time course of inflammatory marker response after TBI (Abst #254.07/Z8). in 41th Annual Meeting Society for Neuroscience. Washington, D.C.

  112. Sadek, B., Saad, A., Sadeq, A., Jalal, F., Stark, H. (2016). Histamine H3 receptor as a potential target for cognitive symptoms in neuropsychiatric diseases. Behavioural Brain Research, 312, 415-430. DOI

  113. Panayi, F., Sors, A., Bert, L. (2015). Mechanistic characterization of S 38093, a novel inverse agonist at histamine H3 receptors (Abst. 156). in 12th International Conference on Alzheimer's and Parkinson's Disease (AD/PD). Nice, France.

  114. Benade, V. S., Daripelli, S., Thentu, J. B., Manoharan, A., Medapati, R. B., Subramanian, R., Mekala, V. R., Shinde, A. K., Badange, R. K., Goyal, V. K., Pandey, S. K., Nirogi, R. (2015). SUVN-G3031, a H3 receptor inverse agonist produces procognitive effects without affecting sleep in preclinical models. Alzheimer's & Dementia: The Journal of the Alzheimer's Association, 11(7), P475. DOI

  115. Yao, J., Zhao, L., Mao, Z., Chen, S., Wong, K. C., To, J., Brinton, R. D. (2013). Potentiation of brain mitochondrial function by S-equol and R/S-equol estrogen receptor beta-selective phytoSERM treatments. Brain Research, 1514, 128-141. DOI

  116. Rinne, J. O., Wesnes, K., Hänninen, J., Murphy, M., Riordan, H., Rouru, J., Group, A. S. (2013). Safety and efficacy of ORM-12741 on cognitive and behavioral symptoms in patients with Alzheimer's disease: A randomized, double-blind, proof-of-concept study. Journal of the Neurological Sciences, 333, e322. DOI

  117. Lahmy, V., Meunier, J., Malmstrom, S., Naert, G., Givalois, L., Kim, S. H., Villard, V., Vamvakides, A., Maurice, T. (2013). Blockade of Tau hyperphosphorylation and Abeta(1)(-)(4)(2) generation by the aminotetrahydrofuran derivative ANAVEX2-73, a mixed muscarinic and sigma(1) receptor agonist, in a nontransgenic mouse model of Alzheimer's disease. Neuropsychopharmacology, 38(9), 1706-1723. DOI

  118. Cudkowicz, M., Bozik, M. E., Ingersoll, E. W., Miller, R., Mitsumoto, H., Shefner, J., Moore, D. H., Schoenfeld, D., Mather, J. L., Archibald, D., Sullivan, M., Amburgey, C., Moritz, J., Gribkoff, V. K. (2011). The effects of dexpramipexole (KNS-760704) in individuals with amyotrophic lateral sclerosis. Nature Medicine, 17(12), 1652-1656. DOI

  119. Chiu, W. H., Depboylu, C., Hermanns, G., Maurer, L., Windolph, A., Oertel, W. H., Ries, V., Hoglinger, G. U. (2015). Long-term treatment with L-DOPA or pramipexole affects adult neurogenesis and corresponding non-motor behavior in a mouse model of Parkinson's disease. Neuropharmacology, 95, 367-376. DOI

  120. Sanchez, P. E., Zhu, L., Verret, L., Vossel, K. A., Orr, A. G., Cirrito, J. R., Devidze, N., Ho, K., Yu, G. Q., Palop, J. J., Mucke, L. (2012). Levetiracetam suppresses neuronal network dysfunction and reverses synaptic and cognitive deficits in an Alzheimer's disease model. Proceedings of the National Academy of Sciences of the United States of America, 109(42), E2895-2903. DOI

  121. Xiao, R. (2016). Levetiracetam might act as an efficacious drug to attenuate cognitive deficits of Alzheimer's disease. Current Topics in Medicinal Chemistry, 16(5), 565-573. DOI

  122. Hunsberger, H. C., Weitzner, D. S., Rudy, C. C., Hickman, J. E., Libell, E. M., Speer, R. R., Gerhardt, G. A., Reed, M. N. (2015). Riluzole rescues glutamate alterations, cognitive deficits, and tau pathology associated with P301L tau expression. Journal of Neurochemistry, 135(2), 381-394. DOI

  123. Sugiyama, A., Saitoh, A., Inagaki, M., Oka, J., Yamada, M. (2015). Systemic administration of riluzole enhances recognition memory and facilitates extinction of fear memory in rats. Neuropharmacology, 97, 322-328. DOI

  124. Blasco, H., Mavel, S., Corcia, P., Gordon, P. H. (2014). The glutamate hypothesis in ALS: pathophysiology and drug development. Current Medicinal Chemistry, 21(31), 3551-3575. DOI

  125. Giacobini, E. (1994). Therapy of Alzheimer disease: symptomatic or neuroprotective? Journal of Neural Transmission. Supplementa, 43, 211-217. PMID: 7884402

  126. Knapp, M. J., Knopman, D. S., Solomon, P. R., Pendlebury, W. W., Davis, C. S., Gracon, S. I. (1994). A 30-week randomized controlled trial of high-dose tacrine in patients with Alzheimer's disease. The Tacrine Study Group. Journal of the American Medical Association, 271(13), 985-991. DOI

  127. Lane, R. M. He, Y. (2013). Butyrylcholinesterase genotype and gender influence Alzheimer's disease phenotype. Alzheimer's & Dementia: Translational Research & Clinical Interventions, 9(2), e1-73. DOI

  128. Furukawa-Hibi, Y., Alkam, T., Nitta, A., Matsuyama, A., Mizoguchi, H., Suzuki, K., Moussaoui, S., Yu, Q. S., Greig, N. H., Nagai, T., Yamada, K. (2011). Butyrylcholinesterase inhibitors ameliorate cognitive dysfunction induced by amyloid-beta peptide in mice. Behavioural Brain Research, 225(1), 222-229. DOI

  129. Inestrosa, N. C., Dinamarca, M. C., Alvarez, A. (2008). Amyloid-cholinesterase interactions. Implications for Alzheimer's disease. The FEBS Journal, 275(4), 625-632. DOI

  130. Macdonald, I. R., Rockwood, K., Martin, E., Darvesh, S. (2014). Cholinesterase inhibition in Alzheimer's disease: is specificity the answer? Journal of Alzheimer's Disease, 42(2), 379-384. DOI

  131. Froestl, W., Pfeifer, A., Muhs, A. (2013). Cognitive enhancers (nootropics). Part 3: drugs interacting with targets other than receptors or enzymes. disease-modifying drugs. Journal of Alzheimer's Disease, 34(1), 1-114. DOI

  132. Bhattacharya, S., Maelicke, A., Montag, D. (2015). Nasal Application of the Galantamine Pro-drug Memogain Slows Down Plaque Deposition and Ameliorates Behavior in 5X Familial Alzheimer's Disease Mice. Journal of Alzheimer's Disease, 46(1), 123-136. DOI

  133. Weinreb, O., Amit, T., Bar-Am, O., Youdim, M. B. (2012). Ladostigil: a novel multimodal neuroprotective drug with cholinesterase and brain-selective monoamine oxidase inhibitory activities for Alzheimer's disease treatment. Current Drug Targets, 13(4), 483-494. DOI

  134. Scott, J. S., Goldberg, F, V., Andrew V. Turnbull, A. V. (2014). Medicinal Chemistry of Inhibitors of 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1). Journal of Medicinal Chemistry, 57 (11), 4466–4486. DOI

  135. AstellasPharmaGlobalDevelopment. A Positron Emission Tomography Occupancy Study Using Ligand [11C]AS2471907 and Following Oral Dosing of ASP3662. Retrieved June 28, 2016, from:

  136. Weinreb, O., Badinter, F., Amit, T., Bar-Am, O., Youdim, M. B. (2015). Effect of long-term treatment with rasagiline on cognitive deficits and related molecular cascades in aged mice. Neurobiology of Aging, 36(9), 2628-2636. DOI

  137. Shaddinger, B. C., Xu, Y., Roger, J. H., Macphee, C. H., Handel, M., Baidoo, C. A., Magee, M., Lepore, J. J., Sprecher, D. L. (2014). Platelet aggregation unchanged by lipoprotein-associated phospholipase A(2) inhibition: results from an in vitro study and two randomized phase I trials. PLOS ONE, 9(1), e83094. DOI

  138. GlaxoSmithKline. GSK2647544 RD, DDI in Healthy Young and Elderly Volunteers. Retrieved June 8, 2017, from:

  139. Rosenbrock, H., Marti, A., Koros, E., Runge, F., Fuchs, H., Giovannini, R., Dorner-Ciossek, C. (2015). Improving synaptic plasticity and cognitive function in rodents by the novel phosphodiesterase 9A inhibitor bi409306. Alzheimer's & Dementia: The Journal of the Alzheimer's Association, 11(7), P612. DOI

  140. NIH. New NIH-funded memory drug moves into Phase 1 clinical study. Retrieved December 30, 2015, from:

  141. Sun, M. K., Hongpaisan, J., Lim, C. S., Alkon, D. L. (2014). Bryostatin-1 restores hippocampal synapses and spatial learning and memory in adult fragile x mice. Journal of Pharmacology and Experimental Therapeutics, 349(3), 393-401. DOI

  142. Pradal, J., Zuluaga, M. F., Maudens, P., Waldburger, J. M., Seemayer, C. A., Doelker, E., Gabay, C., Jordan, O., Allemann, E. (2015). Intra-articular bioactivity of a p38 MAPK inhibitor and development of an extended-release system. European Journal of Pharmaceutics and Biopharmaceutics, 93, 110-117. DOI

  143. Alam, J. J. (2015). Selective Brain-Targeted Antagonism of p38 MAPKalpha Reduces Hippocampal IL-1beta Levels and Improves Morris Water Maze Performance in Aged Rats. Journal of Alzheimer's Disease, 48(1), 219-227. DOI

  144. Lues, I., Weber, F., Meyer, A., Bühring, U., Hoffmann, T., Kühn-Wache, K., Manhart, S., Heiser, U., Pokorny, R., Chiesa, J. (2015). A phase 1 study to evaluate the safety and pharmacokinetics of PQ912, a glutaminyl cyclase inhibitor, in healthy subjects. Alzheimer's & Dementia: Translational Research & Clinical Interventions, 1(3), 182-195. DOI

  145. Takamura, Y., Ono, K., Matsumoto, J., Yamada, M., Nishijo, H. (2014). Effects of the neurotrophic agent T-817MA on oligomeric amyloid-beta-induced deficits in long-term potentiation in the hippocampal CA1 subfield. Neurobiology of Aging, 35(3), 532-536. DOI

  146. Boxer, A. L., Lang, A. E., Grossman, M., Knopman, D. S., Miller, B. L., Schneider, L. S., Doody, R. S., Lees, A., Golbe, L. I., Williams, D. R., Corvol, J. C., Ludolph, A., Burn, D., Lorenzl, S., Litvan, I., Roberson, E. D., Hoglinger, G. U., Koestler, M., Jack, C. R., Jr., Van Deerlin, V., Randolph, C., Lobach, I. V., Heuer, H. W., Gozes, I., Parker, L., Whitaker, S., Hirman, J., Stewart, A. J., Gold, M., Morimoto, B. H. (2014). Davunetide in patients with progressive supranuclear palsy: a randomised, double-blind, placebo-controlled phase 2/3 trial. Lancet Neurology, 13(7), 676-685. DOI

  147. Jouroukhin, Y., Ostritsky, R., Assaf, Y., Pelled, G., Giladi, E., Gozes, I. (2013). NAP (davunetide) modifies disease progression in a mouse model of severe neurodegeneration: protection against impairments in axonal transport. Neurobiology of Disease, 56, 79-94. DOI

  148. Martínez-Morales, P.L., Revilla, A., Ocaña, I, González, C., Sainz, P., McGuire, D., Liste, I. (2013). Progress in Stem Cell Therapy for Major Human Neurological Disorders. Stem Cell Reviews and Reports, 9(5), 685-699. DOI

  149. Medipost. The Safety and The Efficacy Evaluation of NEUROSTEM®-AD in Patients With Alzheimer's Disease. Retrieved April 23, 2012, from:

  150. Anand, R., Seiberling, M., Kamtchoua, T., Pokorny, R. (2007). Tolerability, safety and pharmacokinetics of the FGLL peptide, a novel mimetic of neural cell adhesion molecule, following intranasal administration in healthy volunteers. Clinical Pharmacokinetics, 46(4), 351-358. DOI

  151. FGL-L. (2006). Drug Data Reports, 28(11), 1006. from:

  152. Eriksdotter-Jonhagen, M., Linderoth, B., Lind, G., Aladellie, L., Almkvist, O., Andreasen, N., Blennow, K., Bogdanovic, N., Jelic, V., Kadir, A., Nordberg, A., Sundstrom, E., Wahlund, L. O., Wall, A., Wiberg, M., Winblad, B., Seiger, A., Almqvist, P., Wahlberg, L. (2012). Encapsulated cell biodelivery of nerve growth factor to the Basal forebrain in patients with Alzheimer's disease. Dementia and Geriatric Cognitive Disorders, 33(1), 18-28. DOI

  153. Jelinek, G. A., Weiland, T. J., Hadgkiss, E. J., Marck, C. H., Pereira, N., van der Meer, D. M. (2015). Medication use in a large international sample of people with multiple sclerosis: associations with quality of life, relapse rate and disability. Neurological Research, 37(8), 662-673. DOI

  154. Lawson, D. H., Lee, S., Zhao, F., Tarhini, A. A., Margolin, K. A., Ernstoff, M. S., Atkins, M. B., Cohen, G. I., Whiteside, T. L., Butterfield, L. H., Kirkwood, J. M. (2015). Randomized, Placebo-Controlled, Phase III Trial of Yeast-Derived Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) Versus Peptide Vaccination Versus GM-CSF Plus Peptide Vaccination Versus Placebo in Patients With No Evidence of Disease After Complete Surgical Resection of Locally Advanced and/or Stage IV Melanoma: A Trial of the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network Cancer Research Group (E4697). Journal of Clinical Oncology, 33(34), 4066-4076. DOI

  155. Garcia, J. A., Elson, P., Tyler, A., Triozzi, P., Dreicer, R. (2014). Sargramostim (GM-CSF) and lenalidomide in castration-resistant prostate cancer (CRPC): results from a phase I-II clinical trial. Urologic Oncology, 32(1), 33 e11-37. DOI

  156. Marsh, S. E., Abud, E. M., Lakatos, A., Karimzadeh, A., Yeung, S. T., Davtyan, H., Fote, G. M., Lau, L., Weinger, J. G., Lane, T. E., Inlay, M. A., Poon, W. W., Blurton-Jones, M. (2016). The adaptive immune system restrains Alzheimer's disease pathogenesis by modulating microglial function. Proceedings of the National Academy of Sciences of the United States of America, 113(9), E1316-1325. DOI

  157. McGeer, P. L., Akiyama, H., Itagaki, S., McGeer, E. G. (1989). Immune system response in Alzheimer's disease. The Canadian Journal of Neurological Sciences, 16(4 Suppl), 516-527. DOI

  158. Deardorff, W. J. Grossberg, G. T. (2017). Targeting neuroinflammation in Alzheimer's disease: evidence for NSAIDs and novel therapeutics. Expert Review of Neurotherapeutics, 17(1), 17-32. DOI

  159. Shin, J. H., Lee, Y. A., Lee, J. K., Lee, Y. B., Cho, W., Im, D. S., Lee, J. H., Yun, B. S., Springer, J. E., Gwag, B. J. (2012). Concurrent blockade of free radical and microsomal prostaglandin E synthase-1-mediated PGE2 production improves safety and efficacy in a mouse model of amyotrophic lateral sclerosis. Journal of Neurochemistry, 122(5), 952-961. DOI

  160. GliaCure. Safety, Tolerability, and Pharmacokinetic Study of Single Ascending Doses of GC021109 in Healthy Subjects (NCT02254369). Retrieved February 18, 2015, from:

  161. Huang, W. J., Zhang, X., Chen, W. W. (2016). Role of oxidative stress in Alzheimer's disease. Biomedical Reports, 4(5), 519-522. DOI

  162. Butchart, J., Brook, L., Hopkins, V., Teeling, J., Puntener, U., Culliford, D., Sharples, R., Sharif, S., McFarlane, B., Raybould, R., Thomas, R., Passmore, P., Perry, V. H., Holmes, C. (2015). Etanercept in Alzheimer disease: A randomized, placebo-controlled, double-blind, phase 2 trial. Neurology, 84(21), 2161-2168. DOI

  163. Lee, D. S., Choi, J., Kim, S. H., Kim, S. (2014). Ameliorating effects of HX106N, a water-soluble botanical formulation, on Abeta25-35-induced memory impairment and oxidative stress in mice. Biological & Pharmaceutical Bulletin, 37(6), 954-960. DOI

  164. Shen, C., Chen, L., Jiang, L., Lai, T. Y. (2015). Neuroprotective effect of epigallocatechin-3-gallate in a mouse model of chronic glaucoma. Neuroscience Letters, 600, 132-136. DOI

  165. SKChemicals. A Confirmatory Trial of SK-PC-B70M in Mild to Moderate Alzheimer's Disease. Retrieved November 26, 2013, from:

  166. Yang, G., Wang, Y., Sun, J., Zhang, K., Liu, J. (2016). Ginkgo Biloba for Mild Cognitive Impairment and Alzheimer's Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Current Topics in Medicinal Chemistry, 16(5), 520-528. DOI

  167. WhaninPharmaceuticalCompany. An Efficacy and Safety Study of INM-176 for the Treatment of Patients With Alzheimer Type Dementia. Retrieved June 13, 2011, from:

  168. Farias, G. A., Guzman-Martinez, L., Delgado, C., Maccioni, R. B. (2014). Nutraceuticals: a novel concept in prevention and treatment of Alzheimer's disease and related disorders. Journal of Alzheimer's Disease, 42(2), 357-367. DOI

  169. Li, F., Gong, Q., Dong, H., Shi, J. (2012). Resveratrol, a neuroprotective supplement for Alzheimer's disease. Current Pharmaceutical Design, 18(1), 27-33. DOI

  170. Turner, R. S., Thomas, R. G., Craft, S., van Dyck, C. H., Mintzer, J., Reynolds, B. A., Brewer, J. B., Rissman, R. A., Raman, R., Aisen, P. S. (2015). A randomized, double-blind, placebo-controlled trial of resveratrol for Alzheimer disease. Neurology, 85(16), 1383-1391. DOI

  171. Zhai, P., Xia, C. L., Tan, J. H., Li, D., Ou, T. M., Huang, S. L., Gu, L. Q., Huang, Z. S. (2015). Syntheses And Evaluation Of Asymmetric Curcumin Analogues As Potential Multifunctional Agents For The Treatment Of Alzheimer's Disease. Current Alzheimer Research, 12(5), 403-414. DOI

  172. Kume, K., Hanyu, H., Sakurai, H., Takada, Y., Onuma, T., Iwamoto, T. (2012). Effects of telmisartan on cognition and regional cerebral blood flow in hypertensive patients with Alzheimer's disease. Geriatrics & Gerontology International, 12(2), 207-214. DOI

  173. Shindo, T., Takasaki, K., Uchida, K., Onimura, R., Kubota, K., Uchida, N., Irie, K., Katsurabayashi, S., Mishima, K., Nishimura, R., Fujiwara, M., Iwasaki, K. (2012). Ameliorative effects of telmisartan on the inflammatory response and impaired spatial memory in a rat model of Alzheimer's disease incorporating additional cerebrovascular disease factors. Biological & Pharmaceutical Bulletin, 35(12), 2141-2147. DOI

  174. Accera. AC-1204 26-Week Long Term Efficacy Response Trial With Optional Open-label Ext (NOURISH-AD). Retrieved May 17, 2017, from:

  175. Sun, X. J., Zhao, L., Zhao, N., Pan, X. L., Fei, G. Q., Jin, L. R., Zhong, C. J. (2012). Benfotiamine prevents increased beta-amyloid production in HEK cells induced by high glucose. Neuroscience Bulletin, 28(5), 561-566. DOI

  176. O'Hare, E., Jeggo, R., Kim, E. M., Barbour, B., Walczak, J. S., Palmer, P., Lyons, T., Page, D., Hanna, D., Meara, J. R., Spanswick, D., Guo, J. P., McGeer, E. G., McGeer, P. L., Hobson, P. (2016). Lack of support for bexarotene as a treatment for Alzheimer's disease. Neuropharmacology, 100, 124-130. DOI

  177. Cramer, P. E., Cirrito, J. R., Wesson, D. W., Lee, C. Y., Karlo, J. C., Zinn, A. E., Casali, B. T., Restivo, J. L., Goebel, W. D., James, M. J., Brunden, K. R., Wilson, D. A., Landreth, G. E. (2012). ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models. Science, 335(6075), 1503-1506. DOI

  178. Fukasawa, H., Nakagomi, M., Yamagata, N., Katsuki, H., Kawahara, K., Kitaoka, K., Miki, T., Shudo, K. (2012). Tamibarotene: a candidate retinoid drug for Alzheimer's disease. Biological & Pharmaceutical Bulletin, 35(8), 1206-1212. DOI

  179. Ormerod, A. D., Thind, C. K., Rice, S. A., Reid, I. C., Williams, J. H., McCaffery, P. J. (2012). Influence of isotretinoin on hippocampal-based learning in human subjects. Psychopharmacology (Berlin), 221(4), 667-674. DOI

  180. Lerner, A. J., Gustaw-Rothenberg, K., Smyth, S., Casadesus, G. (2012). Retinoids for treatment of Alzheimer's disease. Biofactors, 38(2), 84-89. DOI

  181. Kelley, B. J. Glasser, S. (2014). Cognitive effects of statin medications. CNS Drugs, 28(5), 411-419. DOI

  182. Kurata, T., Miyazaki, K., Kozuki, M., Morimoto, N., Ohta, Y., Ikeda, Y., Abe, K. (2011). Progressive neurovascular disturbances in the cerebral cortex of Alzheimer's disease-model mice: protection by atorvastatin and pitavastatin. Neuroscience, 197, 358-368. DOI

  183. Zhang, Y. Y., Fan, Y. C., Wang, M., Wang, D., Li, X. H. (2013). Atorvastatin attenuates the production of IL-1beta, IL-6, and TNF-alpha in the hippocampus of an amyloid beta1-42-induced rat model of Alzheimer's disease. Clinical Interventions in Aging, 8, 103-110. DOI

  184. Barone, E., Mancuso, C., Di Domenico, F., Sultana, R., Murphy, M. P., Head, E., Butterfield, D. A. (2012). Biliverdin reductase-A: a novel drug target for atorvastatin in a dog pre-clinical model of Alzheimer disease. Journal of Neurochemistry, 120(1), 135-146. DOI

  185. Tong, X. K., Lecrux, C., Rosa-Neto, P., Hamel, E. (2012). Age-dependent rescue by simvastatin of Alzheimer's disease cerebrovascular and memory deficits. Journal of Neuroscience, 32(14), 4705-4715. DOI

  186. Sano, M., Bell, K. L., Galasko, D., Galvin, J. E., Thomas, R. G., van Dyck, C. H., Aisen, P. S. (2011). A randomized, double-blind, placebo-controlled trial of simvastatin to treat Alzheimer disease. Neurology, 77(6), 556-563. DOI

  187. Liang, T., Li, R., Cheng, O. (2015). Statins for Treating Alzheimer's Disease: Truly Ineffective? European Neurology, 73(5-6), 360-366. DOI

  188. Godyn, J., Jonczyk, J., Panek, D., Malawska, B. (2016). Therapeutic strategies for Alzheimer's disease in clinical trials. Pharmacological Reports, 68(1), 127-138. DOI

  189. Beth Israel Deaconess Medical Center. Memory Aid by Intranasal Insulin in Diabetes (MemAID) (MemAID). Retrieved October 19, 2017, from:

  190. Claxton, A., Baker, L. D., Hanson, A., Trittschuh, E. H., Cholerton, B., Morgan, A., Callaghan, M., Arbuckle, M., Behl, C., Craft, S. (2015). 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, 44(3), 897-906. DOI

  191. Egefjord, L., Gejl, M., Moller, A., Braendgaard, H., Gottrup, H., Antropova, O., Moller, N., Poulsen, H. E., Gjedde, A., Brock, B., Rungby, J. (2012). Effects of liraglutide on neurodegeneration, blood flow and cognition in Alzheimer s disease - protocol for a controlled, randomized double-blinded trial. Danish Medical Journal, 59(10), A4519. PMID: 23158895

  192. Bomba, M., Ciavardelli, D., Silvestri, E., Canzoniero, L. M., Lattanzio, R., Chiappini, P., Piantelli, M., Di Ilio, C., Consoli, A., Sensi, S. L. (2012). Exenatide promotes cognitive enhancement and positive brain metabolic changes in PS1-KI mice but has no effects in 3xTg-AD animals. Cell Death & Disease, 4, e612. DOI

  193. Shah, R. C., Matthews, D. C., Andrews, R. D., Capuano, A. W., Fleischman, D. A., VanderLugt, J. T., Colca, J. R. (2014). An evaluation of MSDC-0160, a prototype mTOT modulating insulin sensitizer, in patients with mild Alzheimer's disease. Current Alzheimer Research, 11(6), 564-573. DOI

  194. Sato, T., Hanyu, H., Hirao, K., Kanetaka, H., Sakurai, H., Iwamoto, T. (2011). Efficacy of PPAR-gamma agonist pioglitazone in mild Alzheimer disease. Neurobiology of Aging, 32(9), 1626-1633. DOI

  195. Lupin. A Randomized, Double-blind, Placebo-controlled, Parallel Group, Comparative, Multicenter, Phase 2 Clinical Study to Evaluate Efficacy and Safety of Two Doses of LND101001 Monotherapy in Patients with Mild to Moderate Alzheimer's Disease (EudraCT 2013-001851-11). Retrieved June 19, 2015, from:

  196. Yaari, R. Hake, A. (2015). Alzheimer's disease clinical trials: past failures and future opportunities. Clinical Investigation, 5(3), 297-309. DOI

  197. Merck&Co. Efficacy and Safety of MK-7622 as Adjunct Therapy in Participants With Alzheimer's Disease (MK-7622-012) (NCT01852110). Retrieved March 12, 2018, from: https:

  198. Garakani, A., Murrough, J. W., Iosifescu, D. V. (2014). Advances in Psychopharmacology for Anxiety Disorders. FOCUS, 12(2), 152-162. DOI

  199. Lavrovsky, Y., Ivachtchenko, A. V., Morozova, M., Salimov, R. M., Kasey, V. (2010). Preclinical and early clinical studies of AVN-101, a novel balanced molecule for the treatment of Alzheimer's disease. Alzheimer's & Dementia: The Journal of the Alzheimer's Association, 6(4), S583. DOI

  200. RegeneraPharma. A Randomized SAD and MAD Study Evaluating the Safety and Tolerability of RPh201 in Healthy Subjects and in Adults With Alzheimer's Disease (NCT01513967). Retrieved December 06, 2016, from:

  201. Gutzmann, H. Hadler, D. (1998). Sustained efficacy and safety of idebenone in the treatment of Alzheimer's disease: update on a 2-year double-blind multicentre study. Journal of Neural Transmission. Supplementa, 54, 301-310. DOI

  202. Bukatina, E. E., Grigor'eva, I. V., Sokol'chik, E. I. (1993). The effectiveness of amiridin in senile dementia of the Alzheimer's type. Neuroscience and Behavioral Physiology, 23(1), 83-89. DOI

  203. Qian, Z. M. Ke, Y. (2014). Huperzine A: Is it an Effective Disease-Modifying Drug for Alzheimer's Disease? Frontiers in Aging Neuroscience, 6, 216. DOI

  204. Salomone, S., Caraci, F., Leggio, G. M., Fedotova, J., Drago, F. (2012). New pharmacological strategies for treatment of Alzheimer's disease: focus on disease modifying drugs. British Journal of Clinical Pharmacology, 73(4), 504-517. DOI

  205. Corbett, A., Pickett, J., Burns, A., Corcoran, J., Dunnett, S. B., Edison, P., Hagan, J. J., Holmes, C., Jones, E., Katona, C., Kearns, I., Kehoe, P., Mudher, A., Passmore, A., Shepherd, N., Walsh, F., Ballard, C. (2012). Drug repositioning for Alzheimer's disease. Nature Reviews Drug Discovery, 11(11), 833-846. DOI

  206. Ustyugov, A., Shevtsova, E., Bachurin, S. (2015). Novel Sites of Neuroprotective Action of Dimebon (Latrepirdine). Molecular Neurobiology, 52(2), 970-978. DOI

  207. Schneider, L. S., Mangialasche, F., Andreasen, N., Feldman, H., Giacobini, E., Jones, R., Mantua, V., Mecocci, P., Pani, L., Winblad, B., Kivipelto, M. (2014). Clinical trials and late-stage drug development for Alzheimer's disease: an appraisal from 1984 to 2014. Journal of Internal Medicine, 275(3), 251-283. DOI

  208. Iqbal, K. Grundke-Iqbal, I. (2007). Developing pharmacological therapies for Alzheimer disease. Cellular and Molecular Life Sciences, 64(17), 2234-2244. DOI

  209. Pal, R., Larsen, J. P., Moller, S. G. (2015). The Potential of Proteomics in Understanding Neurodegeneration. International Review of Neurobiology, 121, 25-58. DOI

  210. Whalen, J. Experimental Alzheimer's Drug Fails in Clinical Trial. The Wall Street Journal. Retrieved July 27, 2016, from:

  211. American Academy of Neurology. Women's Better Verbal Memory Skills May Mask Early Signs of Alzheimer's. Retrieved October 05, 2016, from:

  212. Begley, S. (2016). Alzheimer's researchers see the over years of missteps after latest drug failure. Retrieved July 28, 2016, from:

  213. Mangialasche, F., Solomon, A., Winblad, B., Mecocci, P., Kivipelto, M. (2010). Alzheimer's disease: clinical trials and drug development. The Lancet Neurology, 9(7), 702-716. DOI