1. 2022 Alzheimer’s disease facts and figures. Alzheimers Dement 2022; 18: 700-789.
2. Tejada-Vera B. Mortality from Alzheimer’s disease in the United States: Data for 2000 and 2010. NCHS Data Brief 2013; 116: 1-8.
3. Ellouze I, Sheffler J, Nagpal R, Arjmandi B. Dietary patterns and Alzheimer’s disease: An updated review linking nutrition to neuroscience. Nutrients 2023; 15:3204.
4. Bagyinszky E, Youn YC, An SS, Kim S. The genetics of Alzheimer’s disease. Clin Interv Aging 2014; 9: 535-551.
5. Jalbert JJ, Daiello LA, Lapane KL. Dementia of the Alzheimer type. Epidemiol Rev 2008; 30: 15-34.
6. Hersi M, Irvine B, Gupta P, Gomes J, Birkett N, Krewski D. Risk factors associated with the onset and progression of Alzheimer’s disease: A systematic review of the evidence. Neurotoxicology 2017; 61: 143-187.
7. Tezel G, Timur SS, Bozkurt İ, Türkoğlu Ö F, Eroğlu İ, Nemutlu E, et al. A snapshot on the current status of Alzheimer’s disease, treatment perspectives, in-vitro and in-vivo research studies and future opportunities. Chem Pharm Bull (Tokyo) 2019; 67: 1030-1041.
8. Cox MA, Bassi C, Saunders ME, Nechanitzky R, Morgado-Palacin I, Zheng C, et al. Beyond neurotransmission: acetylcholine in immunity and inflammation. J Intern Med 2020; 287: 120-133.
9. Wilcock GK, Esiri MM, Bowen DM, Smith CC. Alzheimer’s disease. Correlation of cortical choline acetyltransferase activity with the severity of dementia and histological abnormalities. J Neurol Sci 1982; 57: 407-417.
10. Muir JL. Acetylcholine, aging, and Alzheimer’s disease. Pharmacol Biochem Behav 1997; 56: 687-696.
11. Bartus RT. On neurodegenerative diseases, models, and treatment strategies: lessons learned and lessons forgotten a generation following the cholinergic hypothesis. Exp Neurol 2000; 163: 495-529.
12. Muir JL, Dunnett SB, Robbins TW, Everitt BJ. Attentional functions of the forebrain cholinergic systems: Effects of intraventricular hemicholinium, physostigmine, basal forebrain lesions and intracortical grafts on a multiple-choice serial reaction time task. Exp Brain Res 1992; 89: 611-622.
13. Doody RS, Thomas RG, Farlow M, Iwatsubo T, Vellas B, Joffe S, et al. Phase 3 trials of solanezumab for mild-to-moderate Alzheimer’s disease. N Engl J Med 2014; 370: 311-321.
14. Birks JS, Chong LY, Grimley Evans J. Rivastigmine for Alzheimer’s disease. Cochrane Database Syst Rev 2015; 9: Cd001191.
15. Dajas-Bailador FA, Heimala K, Wonnacott S. The allosteric potentiation of nicotinic acetylcholine receptors by galantamine is transduced into cellular responses in neurons: Ca2+ signals and neurotransmitter release. Mol Pharmacol 2003; 64: 1217-1226.
16. Akk G, Steinbach JH. Galantamine activates muscle-type nicotinic acetylcholine receptors without binding to the acetylcholine-binding site. J Neurosci 2005; 25: 1992-2001.
17. Li Z, Zhang Z, Yu B. Correction to unlocking the therapeutic potential of natural products for Aalzheimer’s disease. J Med Chem 2025; 68: 9018-9024.
18. Panza F, Lozupone M, Logroscino G, Imbimbo BP. A critical appraisal of amyloid-β-targeting therapies for Alzheimer disease. Nat Rev Neurol 2019; 15: 73-88.
19. Gillman KW, Starrett JE, Jr., Parker MF, Xie K, Bronson JJ, Marcin LR, et al. Discovery and evaluation of BMS-708163, a potent, selective and orally bioavailable γ-secretase inhibitor. ACS Med Chem Lett 2010; 1: 120-124.
20. Tong G, Wang JS, Sverdlov O, Huang SP, Slemmon R, Croop R, et al. Multicenter, randomized, double-blind, placebo-controlled, single-ascending dose study of the oral γ-secretase inhibitor BMS-708163 (Avagacestat): tolerability profile, pharmacokinetic parameters, and pharmacodynamic markers. Clin Ther 2012; 34: 654-667.
21. Tong G, Wang JS, Sverdlov O, Huang SP, Slemmon R, Croop R, et al. A contrast in safety, pharmacokinetics and pharmacodynamics across age groups after a single 50 mg oral dose of the γ-secretase inhibitor avagacestat. Br J Clin Pharmacol 2013; 75: 136-145.
22. Coric V, Salloway S, van Dyck CH, Dubois B, Andreasen N, Brody M, et al. Targeting prodromal alzheimer disease with avagacestat: a randomized clinical trial. JAMA Neurol 2015; 72: 1324-1333.
23. Henley DB, May PC, Dean RA, Siemers ER. Development of semagacestat (LY450139), a functional gamma-secretase inhibitor, for the treatment of Alzheimer’s disease. Expert Opin Pharmacother 2009; 10: 1657-1664.
24. Siemers E, Skinner M, Dean RA, Gonzales C, Satterwhite J, Farlow M, et al. Safety, tolerability, and changes in amyloid beta concentrations after administration of a gamma-secretase inhibitor in volunteers. Clin Neuropharmacol 2005; 28: 126-132.
25. Siemers ER, Quinn JF, Kaye J, Farlow MR, Porsteinsson A, Tariot P, et al. Effects of a gamma-secretase inhibitor in a randomized study of patients with Alzheimer disease. Neurology 2006; 66: 602-604.
26. Siemers ER, Dean RA, Friedrich S, Ferguson-Sells L, Gonzales C, Farlow MR, et al. Safety, tolerability, and effects on plasma and cerebrospinal fluid amyloid-beta after inhibition of gamma-secretase. Clin Neuropharmacol 2007; 30: 317-325.
27. 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-secretase inhibitor in Alzheimer disease. Arch Neurol 2008; 65: 1031-1038.
28. Doody RS, Raman R, Farlow M, Iwatsubo T, Vellas B, Joffe S, et al. A phase 3 trial of semagacestat for treatment of Alzheimer’s disease. N Engl J Med 2013; 369: 341-350.
29. Potter R, Patterson BW, Elbert DL, Ovod V, Kasten T, Sigurdson W, et al. Increased in vivo amyloid-β42 production, exchange, and loss in presenilin mutation carriers. Sci Transl Med 2013; 5: 189ra177.
30. Cole DC, Stock JR, Kreft AF, Antane M, Aschmies SH, Atchison KP, et al. (S)-N-(5-Chlorothiophene-2-sulfonyl)-beta,beta-diethylalaninol a Notch-1-sparing gamma-secretase inhibitor. Bioorg Med Chem Lett 2009; 19: 926-929.
31. Wolfe MS. γ-Secretase inhibitors and modulators for Alzheimer’s disease. J Neurochem 2012; 120 Suppl 1: 89-98.
32. Imbimbo BP, Hutter-Paier B, Villetti G, Facchinetti F, Cenacchi V, Volta R, et al. CHF5074, a novel gamma-secretase modulator, attenuates brain beta-amyloid pathology and learning deficit in a mouse model of Alzheimer’s disease. Br J Pharmacol 2009; 156: 982-993.
33. Imbimbo BP, Del Giudice E, Cenacchi V, Volta R, Villetti G, Facchinetti F, et al. In vitro and in vivo profiling of CHF5022 and CHF5074 Two beta-amyloid1-42 lowering agents. Pharmacol Res 2007; 55: 318-328.
34. Imbimbo BP, Del Giudice E, Colavito D, D’Arrigo A, Carbonare MD, Villetti G, et al. 1-(3′,4′-Dichloro-2-fluoro[1,1′-biphenyl]-4-yl)-cyclopropanecarboxylic Acid (CHF5074), a novel γ-secretase modulator, reduces brain β-amyloid pathology in a transgenic mouse model of Alzheimer’s disease without causing peripheral toxicity. J Pharmacol Exp Ther 2007; 323: 822-830.
35. Imbimbo BP, Giardino L, Sivilia S, Giuliani A, Gusciglio M, Pietrini V, et al. CHF5074, a novel gamma-secretase modulator, restores hippocampal neurogenesis potential and reverses contextual memory deficit in a transgenic mouse model of Alzheimer’s disease. J Alzheimers Dis 2010; 20: 159-173.
36. Balducci C, Mehdawy B, Mare L, Giuliani A, Lorenzini L, Sivilia S, et al. The γ-secretase modulator CHF5074 restores memory and hippocampal synaptic plasticity in plaque-free Tg2576 mice. J Alzheimers Dis 2011; 24: 799-816.
37. Lichtenstein MP, Carriba P, Baltrons MA, Wojciak-Stothard B, Peterson JR, García A, et al. Secretase-independent and RhoGTPase/PAK/ERK-dependent regulation of cytoskeleton dynamics in astrocytes by NSAIDs and derivatives. J Alzheimers Dis 2010; 22: 1135-1155.
38. Kounnas MZ, Danks AM, Cheng S, Tyree C, Ackerman E, Zhang X, et al. Modulation of gamma-secretase reduces beta-amyloid deposition in a transgenic mouse model of Alzheimer’s disease. Neuron 2010; 67: 769-780.
39. Kounnas MZ, Lane-Donovan C, Nowakowski DW, Herz J, Comer WT. NGP 555, a γ-secretase modulator, lowers the amyloid biomarker, Aβ(42,) in cerebrospinal fluid while preventing alzheimer’s disease cognitive decline in rodents. Alzheimers Dement (N Y) 2017; 3: 65-73.
40. Liu Q, Waltz S, Woodruff G, Ouyang J, Israel MA, Herrera C, et al. Effect of potent γ-secretase modulator in human neurons derived from multiple presenilin 1-induced pluripotent stem cell mutant carriers. JAMA Neurol 2014; 71: 1481-1489.
41. Martone RL, Zhou H, Atchison K, Comery T, Xu JZ, Huang X, et al. Begacestat (GSI-953): A novel, selective thiophene sulfonamide inhibitor of amyloid precursor protein gamma-secretase for the treatment of Alzheimer’s disease. J Pharmacol Exp Ther 2009; 331: 598-608.
42. Mayer SC, Kreft AF, Harrison B, Abou-Gharbia M, Antane M, Aschmies S, et al. Discovery of begacestat, a Notch-1-sparing gamma-secretase inhibitor for the treatment of Alzheimer’s disease. J Med Chem 2008; 51: 7348-7351.
43. Hampel H, Vassar R, De Strooper B, Hardy J, Willem M, Singh N, et al. The β-Secretase BACE1 in Alzheimer’s disease. Biological Psychiatry 2021; 89: 745-756.
44. May PC, Dean RA, Lowe SL, Martenyi F, Sheehan SM, Boggs LN, et al. Robust central reduction of amyloid-β in humans with an orally available, non-peptidic β-secretase inhibitor. J Neurosci 2011; 31: 16507-16516.
45. Hey JA, Kocis P, Hort J, Abushakra S, Power A, Vyhnálek M, et al. Discovery and identification of an endogenous metabolite of tramiprosate and its prodrug ALZ-801 that inhibits beta amyloid oligomer formation in the human brain. CNS Drugs 2018; 32: 849-861.
46. Gervais F, Paquette J, Morissette C, Krzywkowski P, Yu M, Azzi M, et al. Targeting soluble Abeta peptide with Tramiprosate for the treatment of brain amyloidosis. Neurobiol Aging 2007; 28: 537-547.
47. Hey JA, Yu JY, Versavel M, Abushakra S, Kocis P, Power A, et al. Clinical pharmacokinetics and safety of ALZ-801, a Novel prodrug of tramiprosate in development for the treatment of Alzheimer’s disease. Clin Pharmacokinet 2018; 57: 315-333.
48. Aisen PS, Gauthier S, Ferris SH, Saumier D, Haine D, Garceau D, et al. Tramiprosate in mild-to-moderate Alzheimer’s disease - a randomized, double-blind, placebo-controlled, multi-centre study (the Alphase Study). Arch Med Sci 2011; 7: 102-111.
49. Abushakra S, Porsteinsson A, Vellas B, Cummings J, Gauthier S, Hey JA, et al. Clinical benefits of tramiprosate in Alzheimer’s disease are associated with higher number of APOE4 Alleles: The “APOE4 gene-dose effect”. J Prev Alzheimers Dis 2016; 3: 219-228.
50. Abushakra S, Porsteinsson A, Scheltens P, Sadowsky C, Vellas B, Cummings J, et al. Clinical effects of tramiprosate in APOE4/4 homozygous patients with mild Alzheimer’s disease suggest disease modification potential. J Prev Alzheimers Dis 2017; 4: 149-156.
51. Fuchino K, Mitsuoka Y, Masui M, Kurose N, Yoshida S, Komano K, et al. Rational design of novel 1,3-oxazine based β-secretase (BACE1) inhibitors: incorporation of a double bond to reduce p-gp efflux leading to robust aβ reduction in the brain. J Med Chem 2018; 61: 5122-5137.
52. Oehlrich D, Prokopcova H, Gijsen HJ. The evolution of amidine-based brain penetrant BACE1 inhibitors. Bioorg Med Chem Lett 2014; 24: 2033-2045.
53. Koriyama Y, Hori A, Ito H, Yonezawa S, Baba Y, Tanimoto N, et al. Discovery of atabecestat (JNJ-54861911): A thiazine-based β-amyloid precursor protein cleaving enzyme 1 inhibitor advanced to the phase 2b/3 early clinical trial. J Med Chem 2021; 64: 1873-1888.
54. May PC, Willis BA, Lowe SL, Dean RA, Monk SA, Cocke PJ, et al. The potent BACE1 inhibitor LY2886721 elicits robust central Aβ pharmacodynamic responses in mice, dogs, and humans. J Neurosci 2015; 35: 1199-1210.
55. Kennedy ME, Stamford AW, Chen X, Cox K, Cumming JN, Dockendorf MF, et al. The BACE1 inhibitor verubecestat (MK-8931) reduces CNS β-amyloid in animal models and in Alzheimer’s disease patients. Sci Transl Med 2016; 8: 363ra150.
56. Egan MF, Kost J, Voss T, Mukai Y, Aisen PS, Cummings JL, et al. Randomized trial of verubecestat for prodromal Alzheimer’s disease. N Engl J Med 2019; 380: 1408-1420.
57. Hawkes N. Merck ends trial of potential Alzheimer’s drug verubecestat. Bmj 2017; 356: j845.
58. Govaerts L, Schoenen J, Bouhy D. [Pathogenesis of Alzheimer’s disease: Molecular and cellular mechanisms]. Rev Med Liege 2007; 62: 209-216.
59. LaFerla FM, Green KN, Oddo S. Intracellular amyloid-beta in Alzheimer’s disease. Nat Rev Neurosci 2007; 8: 499-509.
60. Cebers G, Alexander RC, Haeberlein SB, Han D, Goldwater R, Ereshefsky L, et al. AZD3293: Pharmacokinetic and pharmacodynamic effects in healthy subjects and patients with Alzheimer’s disease. J Alzheimers Dis 2017; 55: 1039-1053.
61. Wessels AM, Tariot PN, Zimmer JA, Selzler KJ, Bragg SM, Andersen SW, et al. Efficacy and safety of lanabecestat for treatment of early and mild alzheimer disease: The AMARANTH and DAYBREAK-ALZ randomized clinical trials. JAMA Neurol 2020; 77: 199-209.
62. Janson J, Eketjäll S, Tunblad K, Jeppsson F, Von Berg S, Niva C, et al. Population PKPD modeling of BACE1 inhibitor-induced reduction in Aβ levels in vivo and correlation to in vitro potency in primary cortical neurons from mouse and guinea pig. Pharm Res 2014; 31: 670-683.
63. Janelidze S, Stomrud E, Brix B, Hansson O. Towards a unified protocol for handling of CSF before β-amyloid measurements. Alzheimers Res Ther 2019; 11: 63.
64. Lynch SY, Kaplow J, Zhao J, Dhadda S, Luthman J, Albala B. Elenbecestat, E2609, a BACE inhibitor: Results from a phase 2 study in subjects with mild cognitive impairment and mild-to-moderate dementia due to Alzheimer’s disease. Alzheimers Dement 2018; 14: 1623.
65. Miranda A, Montiel E, Ulrich H, Paz C. Selective secretase targeting for Alzheimer’s disease therapy. J Alzheimers Dis 2021; 81: 1-17.
66. Jeppsson F, Eketjäll S, Janson J, Karlström S, Gustavsson S, Olsson LL, et al. Discovery of AZD3839, a potent and selective BACE1 inhibitor clinical candidate for the treatment of Alzheimer disease. J Biol Chem 2012; 287: 41245-41257.
67. Geschwindner S, Olsson LL, Albert JS, Deinum J, Edwards PD, de Beer T, et al. Discovery of a novel warhead against beta-secretase through fragment-based lead generation. J Med Chem 2007; 50: 5903-5911.
68. Swahn BM, Holenz J, Kihlström J, Kolmodin K, Lindström J, Plobeck N, et al. Aminoimidazoles as BACE-1 inhibitors: The challenge to achieve in vivo brain efficacy. Bioorg Med Chem Lett 2012; 22: 1854-1859.
69. Swahn BM, Kolmodin K, Karlström S, von Berg S, Söderman P, Holenz J, et al. Design and synthesis of β-site amyloid precursor protein cleaving enzyme (BACE1) inhibitors with in vivo brain reduction of β-amyloid peptides. J Med Chem 2012; 55: 9346-9361.
70. Quartino A, Huledal G, Sparve E, Lüttgen M, Bueters T, Karlsson P, et al. Population pharmacokinetic and pharmacodynamic analysis of plasma Aβ40 and Aβ42 following single oral doses of the BACE1 inhibitor AZD3839 to healthy volunteers. Clin Pharmacol Drug Dev 2014; 3: 396-405.
71. Abdul Manap AS, Almadodi R, Sultana S, Sebastian MG, Kavani KS, Lyenouq VE, et al. Alzheimer’s disease: A review on the current trends of the effective diagnosis and therapeutics. Front Aging Neurosci 2024; 16: 1429211.
72. Cummings J, Osse AML, Cammann D, Powell J, Chen J. Anti-amyloid monoclonal antibodies for the treatment of Alzheimer’s disease. BioDrugs 2024; 38: 5-22.
73. Marsool MDM, Prajjwal P, Reddy YB, Marsool ADM, Lam JR, Nandwana V. Newer modalities in the management of Alzheimer’s dementia along with the role of aducanumab and lecanemab in the treatment of its refractory cases. Dis Mon 2023; 69: 101547.
74. Zhang Y, Chen H, Li R, Sterling K, Song W. Amyloid β-based therapy for Alzheimer’s disease: Challenges, successes and future. Signal Transduct Target Ther 2023; 8: 248.
75. Rinauro DJ, Chiti F, Vendruscolo M, Limbocker R. Misfolded protein oligomers: Mechanisms of formation, cytotoxic effects, and pharmacological approaches against protein misfolding diseases. Mol Neurodegener 2024; 19: 20.
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