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

Main Article Content

S.O. Bachurin
E.V. Bovina
A.A. Ustyugov


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.

Article Details

How to Cite
Bachurin, S., Bovina, E., & Ustyugov, A. (2018). Current Trends in the Development of Drugs for the Treatment of Alzheimer’s Disease and their Clinical Trials. Biomedical Chemistry: Research and Methods, 1(3), e00015.


  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�