476
Views
43
CrossRef citations to date
0
Altmetric
Review

Have there been improvements in Alzheimer’s disease drug discovery over the past 5 years?

Pages 523-538 | Received 12 Jan 2018, Accepted 22 Mar 2018, Published online: 01 Apr 2018

References

  • GBD. 2015 Neurological Disorders Collaborator Group. Global, regional, and national burden of neurological disorders during 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet Neurol. 2017;16(11): 877–897.
  • Chan KY, Wang W, Wu JJ, et al. Global Health Epidemiology Reference Group (GHERG). Epidemiology of Alzheimer’s disease and other forms of dementia in China, 1990–2010: a systematic review and analysis. Lancet. 2013;381(9882):2016–2023.
  • Fiest KM, Roberts JI, Maxwell CJ, et al. The prevalence and incidence of dementia due to Alzheimer’s disease: a systematic review and meta-analysis. Can J Neurol Sci. 2016;43(Suppl 1):S51–82.
  • Cacabelos R, Teijido O, Carril JC. Can cloud-based tools accelerate Alzheimer’s disease drug discovery? Expert Opin Drug Discov. 2016;11(3):215–223.
  • Cacabelos R, Cacabelos P, Torrellas C, et al. Pharmacogenomics of Alzheimer’s disease: novel therapeutic strategies for drug development. Methods Mol Biol. 2014;1175:323–556.
  • Britt DMI, Day GS. Over-prescribed medications, under-appreciated risks: a review of the cognitive effects of anticholinergic medications in older adults. Mo Med. 2016;111(3):207–214.
  • Pasqualetti G, Togniti S, Calsolaro V, et al. Potential drug-drug interactions in Alzheimer patients with behavioral symptoms. Clin Interv Aging. 2015;10:1457–1466.
  • Cummings J, Lee G, Mortsdorf T, et al. Alzheimer’s disease drug development pipeline: 2017. Alzheimers Dement (NY). 2017;3(3):367–384.
  • Hung SY, Fu WM. Drug candidates in clinical trials for Alzheimer’s disease. J Biomed Sci. 2017;24(1):47.
  • Cacabelos R, Torrellas C, Carrera I, et al. Novel therapeutic strategies for dementia. CNS Neurol Disord Drug Targets. 2016;15(2):141–241.
  • Liu H, Wang L, Lv M, et al. AlzPlatform: an Alzheimer’s disease domain-specific chemogenomics knowledgebase for polypharmacology and target identification research. J Chem Inf Model. 2015;54:1050–1060.
  • Kumar A, Nisha CM, Silakari C, et al. Current and novel therapeutic molecules and targets in Alzheimer’s disease. J Formosan Med Assoc. 2016;115:3–10.
  • McHardy SF, Wang HL, McCowen SV, et al. Recent advances in acetylcholinesterase inhibitors and reactivators: an update on the patent literature (2012–2015). Expert Opin Ther. 2017;27(4):455–476.
  • Wattmo C, Londos E, Minthon L. Response to cholinesterase inhibitors affects lifespan in Alzheimer’s disease. BMC Neurology. 2014;14:173.
  • Meguro K, Kasai M, Akanuma K, et al. Donepezil and life expectancy in Alzheimer’s disease: a retrospective analysis in the Tajiri project. BMC Neurology. 2014;14:83.
  • Cacabelos R, Torrellas C, Fernández-Novoa L, et al. Neuroimmune crosstalk in CNS disorders: the histamine connection. Curr Pharm Des. 2016;22(7):819–848.
  • Guzior N, Wieckowska A, Panek D, et al. Recent development of multifunctional agents as potential drug candidates for the treatment of Alzheimer’s disease. Curr Med Chem. 2015;22(3):373–404.
  • Lambracht-Washington D, Rosenberg RN. Anti-amyloid-beta to tau-based immunization: developments in immunotherapy for Alzheimer’s disease. ImmunoTargets Ther. 2013;2:105–114.
  • Karran E, Hardy J. A critique of the drug discovery and phase 3 clinical programs targeting the amyloid hypothesis for Alzheimer disease. Annals Neurol. 2014;76(2):185–205.
  • Wisniewski T, Goñi F. Immunotherapeutic approaches for Alzheimer’s disease. Neuron. 2015;85(6):1162–1176.
  • Ghosh AK, Osswald HL. BACE1 (β-secretase) inhibitors for the treatment of Alzheimer’s disease. Chem Soc Rev. 2014;43(19):6765–6813.
  • Koelsch G. BACE1 function and inhibition: implications of intervention in the amyloid pathway of Alzheimer’s Disease pathology. Molecules. 2017;22:10. pii: E1723.
  • Tagami S, Yanagida K, Kodama TS, et al. Semagacestat is a pseudo-inhibitor of γ-secretase. Cell Rep. 2017;21(1):259–273.
  • Crump CJ, Johnson DS, Li YM. Development and mechanism of γ-secretase modulators for Alzheimer’s disease. Biochemistry. 2013;52(19):3197–3216.
  • Abushouk AI, Elmaraezy A, Aglan A, et al. Bapineuzumab for mild to moderate Alzheimer’s disease: a meta-analysis of randomized controlled trials. BMC Neurol. 2017;17(1):66.
  • Parsons CG, Rammes G. Preclinical to phase II amyloid beta (Aβ) peptide modulators under investigation for Alzheimer’s disease. Expert Opin Investig Drugs. 2017;26(5):579–592.
  • Gold M. Phase II clinical trials of anti-amyloid β antibodies: when is enough, enough? Alzheimers Dement (N Y). 2017;3(3):402–409.
  • Siemers ER, Sundell KL, Carlson C, et al. Phase 3 solanezumab trials: secondary outcomes in mild Alzheimer’s disease patients. Alzheimers Dement. 2016;12(2):110–120.
  • Sevigny J, Chiao P, Bussière T, et al. The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease. Nature. 2016;537(7618):50–56.
  • Doody RS, Thomas RG, Farlow M, et al. Phase 3 trials of solanezumab for mild-to-moderate Alzheimer’s disease. N Engl J Med. 2014;370(4):311–321.
  • Doody RS, Raman R, Farlow M, et al. A phase 3 trial of semagacestat for treatment of Alzheimer’s disease. N Engl J Med. 2013;369(4):341–350.
  • Kohyama K, Matsumoto Y. Alzheimer’s disease and immunotherapy: what is wrong with clinical trials? ImmunoTargets Ther. 2015;4:27–34.
  • Panza F, Solfrizzi V, Seripa D, et al. Tau-centric targets and drugs in clinical development for the treatment of Alzheimer’s disease. BioMed Res Intern. 2016. ID 3245935. DOI:10.1155/2016/3245935
  • Sigurdsson EM. Tau Immunotherapy. Neurodegener Dis. 2016;16(1–2):34–38.
  • Shahpasand K, Shamloo AS, Nabavi SM, et al. Tau immunotherapy: hopes and hindrances. Hum Vaccin Immunother. 2017. DOI:10.1080/21645515.2017.1393594
  • Novak P, Schmidt R, Kontsekova E, et al. Safety and immunogenicity of the tau vaccine AADvac1 in patients with Alzheimer’s disease: a randomised, double-blind, placebo-controlled, phase 1 trial. Lancet Neurol. 2017;16(2):123–134.
  • Li C, Götz J. Tau-based therapies in neurodegeneration: opportunities and challenges. Nat Rev Drug Discov. 2017. DOI:10.1038/nrd.2017.155
  • Yamazaki Y, Painter MM, Bu G, et al. Apolipoprotein E as a therapeutic target in Alzheimer’s disease: a review of basic research and clinical evidence. CNS Drugs. 2016;30(9):773–789.
  • Pankiewicz JE, Baquero-Buitrago J, Sanchez S, et al. APOE genotype differentially modulates effects of anti-Aβ, passive immunization in APP transgenic mice. Mol Neurodeg. 2017;12:12.
  • Cacabelos R. Pleiotropy and promiscuity in pharmacogenomics for the treatment of Alzheimer’s disease and related risk factors. Future Neurol. 2018. Epub ahead of print. DOI:10.2217/fnl-2017-0038
  • Cacciatore I, Marinelli L, Fornasari E, et al. Novel NSAID-derived drugs for the potential treatment of Alzheimer’s disease. Int J Mol Sci. 2016;17(7):pii: E1035.
  • D’Onofrio G, Sancarlo D, Ruan Q, et al. Phytochemicals in the treatment of Alzheimer’s disease: a systematic review. Curr Drug Targets. 2017;18(13):1487–1498.
  • Libro R, Giacoppo S, Rajan TS, et al. Natural phytochemicals in the treatment and prevention of Dementia: an overview. Molecules. 2016;21:518.
  • Pasinetti GM, Wang J, Ho L, et al. Roles of resveratrol and other grape-derived polyphenols in Alzheimer’s disease prevention and treatment. Biochimica Biophysica Acta. 2015;1852:1202–1208.
  • Xu J, Lacoske MH, Theodorakis EA. Neurotrophic natural products: chemistry and biology. Angew Chem Int Ed Engl. 2014;53(4):956–987.
  • Turner RS, Thomas RG, Craft S, et al. A randomized, double-blind, placebo-controlled trial of resveratrol for Alzheimer disease. Neurology. 2015;85:1383–1391.
  • Shen JS, Zhou Q, Li P, et al. Update on phytochemistry and pharmacology of naturally occurring resveratrol oligomers. Molecules. 2017;22:2050.
  • Lei X, Yu J, Niu Q, et al. The FDA-approved natural product dihydroergocristine reduces the production of the Alzheimer’s disease amyloid-β peptides. Scientific Reports. 2015;5:16541.
  • Singh SK, Srivastav S, Yadav AK, et al. Overview of Alzheimer’s disease and some therapeutic approaches targeting Aβ by using several synthetic and herbal compounds. Oxid Med Cell Longevity. 2016; ID 7361613. DOI:10.1155/2016/7361613
  • Canevelli M, Adali N, Kelaiditi E, et al. Effects of gingko biloba supplementation in Alzheimer’s disease patients receiving cholinesterase inhibitors: data from the ICTUS study. Phytomedicine. 2014;21:888–892.
  • May BH, Feng M, Hyde AJ, et al. Comparisons between traditional medicines and pharmacotherapies for Alzheimer disease: a systematic review and meta-analysis of cognitive outcomes. Int J Geriatr Psychiatry. 2018;33(3):449-458
  • Teng E, Taylor K, Bilousova T, et al. Dietary DHA supplementation in an APP/PS1 transgenic rat model of AD reduces behavioral and Aβ pathology and modulates Aβ oligomerization. Neurobiol Dis. 2015;82:552–560.
  • Asua D, Bougamra G, Calleja M, et al. Peptides acting as cognitive enhancers. Neuroscience. 2017;pii: S0306-4522(17)30721–2. DOI:10.1016/j.neuroscience.2017.10.002
  • Wu Y, Luo X, Liu X, et al. Intraperitoneal administration of a novel TAT-BDNF peptide ameliorates cognitive impairments via modulating multiple pathways in two Alzheimer’s rodent models. Scientific Reports. 2015;5:15032.
  • Tuszynski MH, Yang JH, Barba D, et al. Nerve growth factor gene therapy activates neuronal responses in Alzheimer’s disease. JAMA Neurol. 2015;72(10):1139–1147.
  • Bathina S, Das UN. Brain-derived neurotrophic factor and its clinical implications. Arch Med Sci. 2015;11(6):1164–1178.
  • Henderson VW. Alzheimer’s disease: review of hormone therapy trials and implications for treatment and prevention after menopause. J Steroid Biochem Mol Biol. 2014;142:99–106.
  • Gleason CE, Dowling NM, Wharton W, et al. Effects of hormone therapy on cognition and mood in recently postmenopausal women: findings from the randomized, controlled KEEPS-cognitive and affective study. Plos Med. 2015;12(6):e1001833.
  • Stephenson D, Perry D, Carrillo MC, et al. Building a roadmap for developing combination therapies for Alzheimer’s disease. Expert Rev Neurother. 2015;15(3):327–333.
  • Matsunaga S, Kishi T, Iwata N. Combination therapy with cholinesterase inhibitors and memantine for Alzheimer’s disease: a systematic review and meta-analysis. Int J Neuropsychopharmacol. 2015;1–11.doi: 10.1093/ijpnp/pyn115
  • Cacabelos R, Torrellas C. Epigenetic drug discovery for Alzheimer’s disease. Expert Opin Drug Discov. 2014;9(9):1059–1086.
  • Cacabelos R. Epigenomic networking in drug development: from pathogenic mechanisms to pharmacogenomics. Drug Dev Res. 2014;75(6):348–365.
  • Cacabelos R, Torrellas C. Epigenetics of aging and Alzheimer’s disease: implications for pharmacogenomics and drug response. Int J Mol Sci. 2015;16:30483–30543.
  • Manczak M, Reddy PH. RNA silencing of genes involved in Alzheimer’s disease enhances mitochondrial function and synaptic activity. Biochimica Biophysica Acta. 2013;1832:2368–2378.
  • Choong CJ, Baba K, Mochizuki H. Gene therapy for neurological disorders. Expert Opin Biol Ther. 2016;16(2):143–159.
  • Haston KM, Finkbeiner S. Clinical trials in a dish: the potential of pluripotent stem cells to develop therapies for neurodegenerative diseases. Annu Rev Pharmacol Toxicol. 2016;56:489–510.
  • Arber C, Lovejoy C, Wray S. Stem cell models of Alzheimer’s disease: progress and challenges. Alzheimer Res Ther. 2017;9:42.
  • Lai S, Zhang M, Xu D, et al. Direct reprogramming of induced neural progenitors: a new promising strategy for AD treatment. Transl Neurodeg. 2015;4:7.
  • Navarro-Yepes J, Zavala-Flores L, Anandhan A, et al. Antioxidant gene therapy against neuronal cell death. Pharmacol Ther. 2014;142(2):206–230.
  • Törmälehto S, Martikainen J, Bell JS, et al. Use of psychotropic medications in relation to neuropsychiatric symptoms, cognition and functional performance in Alzheimer’s disease over a three-year period: kuopio ALSOVA study. Int Psychogeriatr. 2017;29(10):1723–1733.
  • Nielsen RE, Lolk A, Rodrigo-Domingo M, et al. Antipsychotic treatment effects on cardiovascular, cancer, infection, and intentional self-harm as cause of death in patients with Alzheimer’s dementia. Eur Psychiatry. 2017;42:14–23.
  • Martinez C, Jones RW, Rietbrock S. Trends in the prevalence of antipsychotic drug use among patients with Alzheimer’s disease and other dementias including those treated with antidementia drugs in the community in the UK: a cohort study. BMJ Open. 2013;3(1):pii: e002080.
  • Koller D, Hua T, Bynum JP. Treatment patterns with antidementia drugs in the United States: medicare cohort study. J Am Geriatr Soc. 2016;64(8):1540–1548. [ Epub 2016 Jun 24].
  • Tsolaki M, Papaliagkas V, Frisoni G, et al. MCI patients in europe: medication and comorbidities. The DESCRIPA study. Curr Alzheimer Res. 2016;13(12):1407–1413.
  • Kadohara K, Sato I, Doi Y, et al. Prescription patterns of medications for Alzheimer’s disease in Japan from 2010 to 2015: a descriptive pharmacy claims database study. Neurol Ther. 2017;6(1):25–37.
  • Cacabelos R, Torrellas C, Teijido O, et al. Pharmacogenetic considerations in the treatment of Alzheimer’s disease. Pharmacogenomics. 2016;17(9):1041–1074.
  • Cacabelos R, Carril JC, Cacabelos P, et al. Pharmacogenomics of Alzheimer’s disease: genetic determinants of phenotypic variation and therapeutic outcome. J Genomic Med Pharmacogenomics. 2016;1(2):151–209.
  • Schneider LS, Mangialasche F, Andreasen N, et al. Clinical trials and late-stage drug development for Alzheimer’s disease: an appraisal from 1984 to 2014. J Intern Med. 2014;275(3):251–283.
  • Brodney MA, Beck EM, Butler CR, et al. Utilizing structures of CYP2D6 and BACE1 complexes to reduce risk of drug-drug interactions with a novel series of centrally efficacious BACE1 inhibitors. J Med Chem. 2015;58(7):3223–3252.
  • Cacabelos R, Meyyazhagan A, Carril JC, et al. Pharmacogenetics of vascular risk factors in Alzheimer’s disease. J Pers Med. 2018;8:3.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.