Alzheimer’s Disease: Current and Future Treatments. A Review
Alzheimer’s disease (AD) is a currently incurable neurodegenerative disorder whose treatment poses a big challenge. Proposed causes of AD include the cholinergic, amyloid and tau hypotheses. Current therapeutic treatments have been aimed at dealing with the neurotransmitter imbalance. These include cholinesterase inhibitors and N-Methyl-D-aspartate (NMDA) antagonists. However, current therapeutics have been unable to halt AD progression. Much research has gone into the development of disease-modifying drugs to interfere with the course of the disease. Approaches include secretase inhibition and immunotherapy aimed at reducing plaque deposition. However, these have not been successful in curing AD as yet. It is believed that the main reason why therapeutics have failed to work is that treatment begins too late in the course of the disease. The future of AD treatment thus appears to lie with prevention rather than cure. In this article, current therapeutics and, from there, the future of AD treatment are discussed.
2. Yiannopoulou KG, Papageorgiou SG. Current and future treatments for Al¬zheimer’s disease. Ther Adv Neurol Disord. 2013 Jan;6(1):19-33.
3. Förstl H, Kurz A. Clinical features of Alzheimer’s disease. EEur Arch Psy¬chiatry Clin Neurosci. 1999;249(6):288-90.
4. Lukiw WJ. Amyloid beta (Aß) peptide modulators and other current treat¬ment strategies for Alzheimer’s disease (AD). Expert Opin Emerg Drugs. 2012 Mar 23. [Epub ahead of print]
5. Ballard C, Corbett A. Management of neuropsychiatric symptoms in people with dementia. CNS Drugs. 2010 Sep;24(9):729-39.
6. Martâinez A. Emerging drugs and targets for Alzheimer’s disease; Volume 1: Beta-Amyloid, Tau protein and glucose metabolism. Cambridge: The Royal Society of Chemistry; 2010.
7. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JP, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Med. 2009 Jul 21;6(7):e1000100.
8. Almkvist O. Neuropsychological features of early Alzheimer’s disease: pre¬clinical and clinical stages. Acta Neurol Scand Suppl. 1996;165:63-71.
9. Galasko D. An integrated approach to the management of Alzheimer’s disease: assessing cognition, function and behaviour. Eur J Neurol. 1998 Oc¬t;5(S4):S9-17.
10. Haupt M, Kurz A. Predictors of nursing home placement in patients with Alzheimer’s disease. Int J Geriatr Psychiatry. 1993 Sep;8(9):741-6.
11. Burns A. Psychiatric phenomena in dementia of the Alzheimer type. Int Psychogeriatr. 1992;4 Suppl 1:43-54.
12. Beard CM, Kokmen E, Sigler C, Smith GE, Petterson T, O'Brien PC. Cause of death in Alzheimer's disease. Ann Epidemiol. 1996 May;6(3):195-200.
13. Blennow K, de Leon MJ, Zetterberg H. Alzheimer's disease. Lancet. 2006 Jul 29;368(9533):387-403.
14. Holtzman DM, Bales KR, Tenkova T, Fagan AM, Parsadanian M, Sartorius LJ, et al. Apoliproprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci U S A. 2000 Mar 14;97(6):2892-7.
15. Piaceri I, Nacmias B, Sorbi S. Genetics of familial and sporadic Alzheimer's disease. Front Biosci (Elite Ed). 2013 Jan 1;5:167-77.
16. Milinois HJ, Florentin MM, Giannopoulos S. Metabolic syndrome and Alzheimer’s disease: A link to a vascular hypothesis?. CNS Spectr. 2008 Jul;13(7):606-13.
17. Skoog I, Gustafson D. Update on hypertension and Alzheimer’s disease. Neurol Res. 2006 Sep;28(6):605-11.
18. Carlsson CM. Type 2 diabetes mellitus, dyslipidemia, and Alzheimer’s disease. J Alzheimers Dis. 2010;20(3):711-22.
19. Naderali EK, Ratcliffe SH, Dale MC. Obesity and Alzheimer's disease: a link between body weight and cognitive function in old age. Am J Alzheimers Dis Other Demen. 2009 Dec-2010 Jan;24(6):445-9.
20. Fratiglioni L, Paillard-Borg S, Winbald B. An active and socially integra¬ted lifestyle in late life might protect against dementia. Lancet Neurol. 2004 Jun;3(6):343-53.
21. Francis PT, Palmer AM, Snape M, Wilcock GK. The cholinergic hypothesis of Alzheimer’s disease: a review of progress. J Neurol Neurosurg Psychiatry. 1999 Feb;66(2):137-47.
22. Rogawski MA, Wenk GL. The neuropharmacological basis for the use of Memantine in the treatment of Alzheimer’s disease. CNS Drug Rev. 2003 Fall;9(3):275-308.
23. Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, Younkin S, et al. Correlative memory deficits, Aß elevation, and Amyloid plaques in transgenic mice. Science. 1996 Oct 4;274(5284):99-102.
24. Lacor PN, Buniel MC, Furlow PW, Clemente AS, Velasco PT, Wood M, et al. Abeta oligomer-induced aberrations in synapse composition, shape, and density provide a molecular basis for loss of connectivity in Alzheimer's disease. J Neurosci. 2007 Jan 24;27(4):796-807.
25. Lambert MP, Barlow AK, Chromy BA, Edwards C, Freed R, Liosatos M, et al. Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central ner¬vous system neurotoxins. Proc Natl Acad Sci U S A. 1998 May 26;95(11):6448- 53.
26. Mudher A, Lovestone S. Alzheimer's disease-do tauists and baptists fina¬lly shake hands?. Trends Neurosci. 2002 Jan;25(1):22-6.
27. Trojanowski JQ, Lee VMY. Rous-Whipple Award Lecture. The Alzheimer's brain: finding out what's broken tells us how to fix it. Am J Pathol. 2005 Nov;167(5):1183-8.
28. Tiraboschi P, Hansen LA, Thal LJ, Corey-Bloom J. The importance of neuritic plaques and tangles to the development and evolution of AD. Neurology. 2004 Jun 8;62(11):1984-9.
29. Birks J. Cholinesterase inhibitors for Alzheimer’s disease. Cochrane Data¬base Syst Rev. 2006 Jan 25;(1):CD005593.
30. Courtney C, Farrell D, Gray R, Hills R, Lynch L, Sellwood E, et al. Long-term donepezil treatment in 565 patients with Alzheimer’s disease (AD2000): ran-domized double-blind trial. Lancet. 2004 Jun 26;363(9427):2105-15.
31. Cummings J, Froelich L, Black SE, Bakchine S, Belleli G, Molinuevo JL, et al. Randomized, double-blind, parallel-group, 48-week study for efficacy and safety of a higher-dose rivastigmine patch (15 vs. 10cm2) in Alzheimer’s disease. Dement Geriatr Cogn Disord. 2012;33(5):341-53.
32. Reisberg B, Doody R, Stoffler A, Schmitt F, Ferris S, Mobiue HJ, et al. Me¬mantine in moderate-to-severe Alzheimer’s disease. N Engl J Med. 2003 Apr 3;348(14):1333-41.
33. Maidment ID, Fox CG, Boustani M, Rodriguez J, Brown RC, Katona CK. Effi¬cacy of Memantine on behavioural and psychological symptoms related to dementia: a systematic meta-analysis. Ann Pharmacother. 2008 Jan;42(1):32- 8.
34. Zec RF, Burkett NR. Non-pharmacological and pharmacological treatment of the cognitive and behavioural symptoms of Alzheimer disease. NeuroRe-habilitation. 2008;23(5):425-38.
35. Vigen CL, Mack WJ, Keefe RS, Sano M, Sultzer DL, Stroup TS, et al. Cognitive effects of atypical antipsychotic medications in patients with Alzheimer’s disease: outcomes from CATIE-AD. Am J Psychiatry. 2011 Aug;168(8):831-9.
36. Van Marum RJ. Current and future therapy in Alzheimer’s disease. Fun¬dam Clin Pharmacol. 2008 Jun;22(3):265-74.
37. Weksler ME. The immunotherapy of Alzheimer’s disease. Immun Ageing. 2004 Nov 12;1(1):2.
38. Ghosh AK, Brindisi M, Tang J. Developing ß-secretase inhibitors for treat¬ment of Alzheimer’s disease. J Neurochem. 2012 Jan;120 Suppl 1:71-83.
39. Cai H, Wang Y, McCarthy D, Wen H, Borchelt DR, Price DL, et al. BACE1 is the major beta-secretase for generation of Abeta peptides by neurons. Nat Neurosci. 2001 Mar;4(3):233-4.
40. May PC, Dean RA, Lowe SL, Martenyi F, Sheehan SM, Boggs LN, et al. Robust central reduction of amyloid-ß in humans with orally available, non-peptidic ß-secretase inhibitor. J Neurosci. 2011 Nov 16;31(46):16507-16.
41. Hu X, Hicks CW, He W, Wong P, Macklin WB, Trapp B, et al. Bace1 modula¬tes myelination in the central and peripheral nervous system. Nat Neurosci. 2006 Dec;9(12):1520-5.
42. Velanac V, Unterbarnscheidt T, Hinrichs W, Gummert MN, Fischer TM, Rossner MJ, et al. Bace1 processing of NRG1 type III produces a myelin-indu¬cing signal but is not essential for the stimulation of myelination. Glia. 2012 Feb;60(2):203-17.
43. Zhao G, Liu Z, Ilagan MX, Kopan R. Gamma-secretase composed of PS1/ Pen2Aph1a can cleave notch and amyloid precursor protein in the absence of nicastrin. J Neurosci. 2010 Feb 3;30(5):1648-56.
44. Zhang Z, Nadeau P, Song W, Donoviel D, Yuan M, Bernstein A, et al. Prese¬nilins are required for gamma-secretase cleavage of beta-APP and transmem¬brane cleavage of Notch-1. Nat Cell Biol. 2000 Jul;2(7):463-5.
45. De Strooper B, Saftig P, Craessaerts K, Vanderstichele H, Guhde G, Annaert W, et al. Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature. 1998 Jan 22;391(6665):387-90.
46. De Strooper B, Annaert W, Cupers P, Saftig P, Craessaerts K, Mumm JS, et al. A presenilin-1-dependent gamma-secretase-like protease mediates relea¬se of Notch intracellular domain. Nature. 1999 Apr 8;398(6727):518-22.
47. De Strooper B, Iwatsubo T, Wolfe MS. Presenilins and ɣ-secretase: structu¬re, function, and role in Alzheimer disease. Cold Spring Harb Perspect Med. 2012 Jan;2(1):a006304.
48. Netzer WJ, Dou F, Cai D, Veach D, Jean S, Li Y, et al. Gleevec inhibits be¬ta-amyloid production but not Notch cleavage. Proc Natl Acad Sci U S A. 2003 Oct 14;100(21):12444-9.
49. Siemers E, Skinner M, Dean RA, Gonzales C, Satterwhite J, Farlow M, et al. Safety, tolerability, and changes in amyloid beta concentrations after admi¬nistration of gamma-secretase inhibitor in volunteers. Clin Neuropharmacol. 2005 May-Jun;28(3):126-32.
50. Henley DB, May PC, Dean RA, Siemers ER. Development of semagacestat (LY450139), a functional gamma-secretase inhibitor, for the treatment of Al¬zheimer’s disease. Expert Opin Pharmacother. 2009 Jul;10(10):1657-64.
51. Fleisher AS, Raman R, Siemers ER, Becerra L, Clark CM, Dean RA, et al. Phase 2 safety trial targeting amyloid beta production with a gamma-secreta¬se inhibitor in Alzheimer disease. Arch Neurol. 2008 Aug;65(8):1031-8.
52. Marder K. Tarenflurbil in patients with mild Alzheimer’s disease. Curr Neurol Neurosci Rep. 2010 Sep;10(5):336-7.
53. Tong G, Wang JS, Sverdlov O, Huang SP, Slemmon R, Croop R, et al. Multi¬center, randomized, double-blind, placebo-controlled, single-ascending dose study of the oral ɣ-secretase inhibitor BMS-708163 (Avagacestat): tolerability profile, pharmacokinetic parameters, and pharmacodynamic markers. Clin Ther. 2012 Mar;34(3):654-67.
54. Coric v, vanDyck CH, Salloway S, Andreasen N, Brody M, Richter RW, et al. Safety and tolerability of the ɣ-secretase inhibitor avagescat in a phase 2 study of mild to moderate Alzheimer disease. Arch Neurol. 2012 Nov;69(11):1430-40.
55. Holmes C, Boche D, Wilkinson D, Yadegarfar G, Hopkins V, Bayer A, et al. Long-term effects of Abeta42 immunisation in Alzheimer's disease: fo¬llow-up of a randomised, placebo-controlled phase I trial. Lancet. 2008 Jul 19;372(9634):216-23.
56. Lippa CF, Nee LE, Mori H, St George-Hyslop P. Abeta-42 deposition precedes other changes in PS-1 Alzheimer's disease. Lancet. 1998 Oct 3;352(9134):1117- 8.
57. St George-Hyslop PH, Morris JC. Will anti-amyloid therapies work for Al¬zheimer’s disease?. Lancet. 2008 Jul 19;372(9634):180-2.
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