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image of Therapeutic Advances in Alzheimer’s Disease: Integrating Natural, Semi-Synthetic, and Synthetic Drug Strategies

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder associated with age, marked by progressive memory loss linked to the decline of cholinergic neurons, accumulation of amyloid plaques, and the presence of Neurofibrillary Tangles (NFTs). Neuropil threads in the brain contribute to amyloidosis and dementia. Despite extensive research, AD’s etiology remains unclear, and currently, no promising therapy exists. This review examines the role of natural, semi-synthetic, and synthetic drugs in AD treatment. Natural drugs demonstrate safety and efficacy with minimal adverse effects, while most agents, whether natural or synthetic, target multiple steps or directly counteract amyloidogenesis, tau protein pathology, oxidative stress, NMDA receptor activity, inflammation, acetylcholine (AChE) function, or α, β, γ secretase activity. In pursuit of improved treatment outcomes, we explore the effectiveness and challenges of various therapeutic interventions. Our hypothesis underscores the importance of an integrated approach combining these drug types for tailored symptom relief, suggesting combined therapies may offer greater therapeutic benefits compared to single-drug approaches. The drugs discussed show potential in regulating AD, thereby presenting viable options for its management. However, to obtain more favorable results, additional studies are needed by combining these drugs.

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2025-05-29
2025-11-06

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References

  1. Singh Y.P. Rai H. Singh G. Singh G.K. Mishra S. Kumar S. Srikrishna S. Modi G. A review on ferulic acid and analogs based scaffolds for the management of Alzheimer’s disease. Eur. J. Med. Chem. 2021 215 113278 10.1016/j.ejmech.2021.113278 33662757
    [Google Scholar]
  2. Singh Y.P. Tej G.N.V.C. Pandey A. Priya K. Pandey P. Shankar G. Nayak P.K. Rai G. Chittiboyina A.G. Doerksen R.J. Vishwakarma S. Modi G. Design, synthesis and biological evaluation of novel naturally-inspired multifunctional molecules for the management of Alzheimer’s disease. Eur. J. Med. Chem. 2020 198 112257 10.1016/j.ejmech.2020.112257 32375073
    [Google Scholar]
  3. Singh Y.P. Pandey A. Vishwakarma S. Modi G. A review on iron chelators as potential therapeutic agents for the treatment of Alzheimer’s and Parkinson’s diseases. Mol. Divers. 2019 23 2 509 526 10.1007/s11030‑018‑9878‑4 30293116
    [Google Scholar]
  4. DeTure M.A. Dickson D.W. The neuropathological diagnosis of Alzheimer’s disease. Mol. Neurodegener. 2019 14 1 32 10.1186/s13024‑019‑0333‑5 31375134
    [Google Scholar]
  5. Singh S.K. Srivastav S. Yadav A.K. Srikrishna S. Perry G. Overview of Alzheimer’s disease and some therapeutic approaches targeting A β by using several synthetic and herbal compounds. Oxid. Med. Cell. Longev. 2016 2016 1 7361613 10.1155/2016/7361613 27034741
    [Google Scholar]
  6. Chauhan B.S. Kumar R. Kumar P. Kumar P. Sinha S. Mishra S.K. Kumar P. Tiwari K.N. Critchley A.T. Prithiviraj B. Srikrishna S. Neuroprotective potential of flavonoid rich Ascophyllum nodosum (FRAN) fraction from the brown seaweed on an Aβ42 induced Alzheimer’s model of Drosophila. Phytomedicine 2022 95 153872 10.1016/j.phymed.2021.153872 34906893
    [Google Scholar]
  7. Pluta R. A look at the etiology of Alzheimer’s disease based on the brain ischemia model. Curr. Alzheimer Res. 2024 21 3 166 182 10.2174/0115672050320921240627050736 38963100
    [Google Scholar]
  8. Singh Y.P. Shankar G. Jahan S. Singh G. Kumar N. Barik A. Upadhyay P. Singh L. Kamble K. Singh G.K. Tiwari S. Garg P. Gupta S. Modi G. Further SAR studies on natural template based neuroprotective molecules for the treatment of Alzheimer’s disease. Bioorg. Med. Chem. 2021 46 116385 10.1016/j.bmc.2021.116385 34481338
    [Google Scholar]
  9. Rajmohan R. Reddy P.H. Amyloid-beta and phosphorylated tau accumulations cause abnormalities at synapses of alzheimer’s disease neurons. J. Alzheimers Dis. 2017 57 4 975 999 10.3233/JAD‑160612 27567878
    [Google Scholar]
  10. Puri D.V. Nalbalwar S.L. Ingle P.P. EEG-based systematic explainable Alzheimer’s disease and mild cognitive impairment identification using novel rational dyadic biorthogonal wavelet filter banks. Circuits Syst. Signal Process. 2024 43 3 1792 1822 10.1007/s00034‑023‑02540‑x
    [Google Scholar]
  11. Puri D.V. Kachare P.H. Sangle S.B. Kirner R. Jabbari A. Al-Shourbaji I. Abdalraheem M. Alameen A. Leadnet: detection of alzheimer’s disease using spatiotemporal eeg analysis and low-complexity cnn. IEEE Access 2024 12 113888 113897 10.1109/ACCESS.2024.3435768
    [Google Scholar]
  12. Puri D.V. Kachare P.H. Nalbalwar S.L. Metaheuristic optimized time–frequency features for enhancing Alzheimer’s disease identification. Biomed. Signal Process. Control 2024 94 106244 10.1016/j.bspc.2024.106244
    [Google Scholar]
  13. Singh Y.P. Kumar N. Priya K. Chauhan B.S. Shankar G. Kumar S. Singh G.K. Srikrishna S. Garg P. Singh G. Rai G. Modi G. Exploration of neuroprotective properties of a naturally inspired multifunctional molecule (F24) against oxidative stress and amyloid β induced neurotoxicity in alzheimer’s disease models. ACS Chem. Neurosci. 2022 13 1 27 42 10.1021/acschemneuro.1c00443 34931800
    [Google Scholar]
  14. Gong C.X. Iqbal K. Hyperphosphorylation of microtubule-associated protein tau: A promising therapeutic target for Alzheimer disease. Curr. Med. Chem. 2008 15 23 2321 2328 18855662
    [Google Scholar]
  15. Chen G. Xu T. Yan Y. Zhou Y. Jiang Y. Melcher K. Xu H.E. Amyloid beta: Structure, biology and structure-based therapeutic development. Acta Pharmacol. Sin. 2017 38 9 1205 1235 10.1038/aps.2017.28 28713158
    [Google Scholar]
  16. Olsson F. Schmidt S. Althoff V. Munter L.M. Jin S. Rosqvist S. Lendahl U. Multhaup G. Lundkvist J. Characterization of intermediate steps in amyloid beta (Aβ) production under near-native conditions. J. Biol. Chem. 2014 289 3 1540 1550 24225948
    [Google Scholar]
  17. Takami M. Nagashima Y. Sano Y. Ishihara S. Morishima-Kawashima M. Funamoto S. Ihara Y. γ-Secretase: Successive tripeptide and tetrapeptide release from the transmembrane domain of β-carboxyl terminal fragment. J. Neurosci. 2009 29 41 13042 13052 19828817
    [Google Scholar]
  18. Cukalevski R. Yang X. Meisl G. Weininger U. Bernfur K. Frohm B. Knowles T.P.J. Linse S. The Aβ40 and Aβ42 peptides self-assemble into separate homomolecular fibrils in binary mixtures but cross-react during primary nucleation. Chem. Sci. (Camb.) 2015 6 7 4215 4233 10.1039/C4SC02517B 29218188
    [Google Scholar]
  19. Jin M. Shepardson N. Yang T. Chen G. Walsh D. Selkoe D.J. Soluble amyloid β-protein dimers isolated from Alzheimer cortex directly induce Tau hyperphosphorylation and neuritic degeneration. Proc. Natl. Acad. Sci. USA 2011 108 14 5819 5824 10.1073/pnas.1017033108 21421841
    [Google Scholar]
  20. Holth J.K. Patel T.K. Holtzman D.M. Sleep in Alzheimer’s disease: Beyond Amyloid. Neurobiol. Sleep Circadian Rhythms 2017 2 4 14 10.1016/j.nbscr.2016.08.002 28217760
    [Google Scholar]
  21. LaFerla F.M. Green K.N. Oddo S. Intracellular amyloid-β in Alzheimer’s disease. Nat. Rev. Neurosci. 2007 8 7 499 509 10.1038/nrn2168 17551515
    [Google Scholar]
  22. Pluta R. Barcikowska M. Misicka A. Lipkowski A.W. Spisacka S. Januszewski S. Ischemic rats as a model in the study of the neurobiological role of human β-amyloid peptide. Time-dependent disappearing diffuse amyloid plaques in braina. Neuroreport 1999 10 17 3615 3619 10.1097/00001756‑199911260‑00028 10619654
    [Google Scholar]
  23. Cummings J. Lee G. Nahed P. Kambar M.E.Z.N. Zhong K. Fonseca J. Taghva K. Alzheimer’s disease drug development pipeline: 2022. Alzheimers Dement. (N. Y.) 2022 8 1 e12295 10.1002/trc2.12295 35516416
    [Google Scholar]
  24. Pandey U.B. Nichols C.D. Human disease models in Drosophila melanogaster and the role of the fly in therapeutic drug discovery. Pharmacol. Rev. 2011 63 2 411 436 10.1124/pr.110.003293 21415126
    [Google Scholar]
  25. Muqit M.M. Feany M.B. Modelling neurodegenerative diseases in Drosophila: A fruitful approach? Nat. Rev. Neurosci. 2002 3 3 237 243 11994755
    [Google Scholar]
  26. Yao L. Kan E.M. Kaur C. Dheen S.T. Hao A. Lu J. Ling E.A. Notch-1 signaling regulates microglia activation via NF-κB pathway after hypoxic exposure in vivo and in vitro. PLoS One 2013 8 11 e78439 24223152
    [Google Scholar]
  27. Pir G.J. Choudhary B. Mandelkow E. Mandelkow E.M. Tau mutant A152T, a risk factor for FTD/PSP, induces neuronal dysfunction and reduced lifespan independently of aggregation in a C. elegans Tauopathy model. Mol. Neurodegener. 2016 11 33 27118310
    [Google Scholar]
  28. Howe K. Clark M.D. Torroja C.F. Torrance J. Berthelot C. Muffato M. Collins J.E. Humphray S. McLaren K. Matthews L. McLaren S. Sealy I. Caccamo M. Churcher C. Scott C. Barrett J.C. Koch R. Rauch G.J. White S. Chow W. Kilian B. Quintais L.T. Guerra-Assunção J.A. Zhou Y. Gu Y. Yen J. Vogel J.H. Eyre T. Redmond S. Banerjee R. Chi J. Fu B. Langley E. Maguire S.F. Laird G.K. Lloyd D. Kenyon E. Donaldson S. Sehra H. Almeida-King J. Loveland J. Trevanion S. Jones M. Quail M. Willey D. Hunt A. Burton J. Sims S. McLay K. Plumb B. Davis J. Clee C. Oliver K. Clark R. Riddle C. Elliot D. Threadgold G. Harden G. Ware D. Begum S. Mortimore B. Kerry G. Heath P. Phillimore B. Tracey A. Corby N. Dunn M. Johnson C. Wood J. Clark S. Pelan S. Griffiths G. Smith M. Glithero R. Howden P. Barker N. Lloyd C. Stevens C. Harley J. Holt K. Panagiotidis G. Lovell J. Beasley H. Henderson C. Gordon D. Auger K. Wright D. Collins J. Raisen C. Dyer L. Leung K. Robertson L. Ambridge K. Leongamornlert D. McGuire S. Gilderthorp R. Griffiths C. Manthravadi D. Nichol S. Barker G. Whitehead S. Kay M. Brown J. Murnane C. Gray E. Humphries M. Sycamore N. Barker D. Saunders D. Wallis J. Babbage A. Hammond S. Mashreghi-Mohammadi M. Barr L. Martin S. Wray P. Ellington A. Matthews N. Ellwood M. Woodmansey R. Clark G. Cooper J. Tromans A. Grafham D. Skuce C. Pandian R. Andrews R. Harrison E. Kimberley A. Garnett J. Fosker N. Hall R. Garner P. Kelly D. Bird C. Palmer S. Gehring I. Berger A. Dooley C.M. Ersan-Ürün Z. Eser C. Geiger H. Geisler M. Karotki L. Kirn A. Konantz J. Konantz M. Oberländer M. Rudolph-Geiger S. Teucke M. Lanz C. Raddatz G. Osoegawa K. Zhu B. Rapp A. Widaa S. Langford C. Yang F. Schuster S.C. Carter N.P. Harrow J. Ning Z. Herrero J. Searle S.M. Enright A. Geisler R. Plasterk R.H. Lee C. Westerfield M. de Jong P.J. Zon L.I. Postlethwait J.H. Nüsslein-Volhard C. Hubbard T.J. Roest Crollius H. Rogers J. Stemple D.L. The zebrafish reference genome sequence and its relationship to the human genome. Nature 2013 496 7446 498 503 23594743
    [Google Scholar]
  29. Joshi G. Chi Y. Huang Z. Wang Y. Aβ-induced Golgi fragmentation in Alzheimer’s disease enhances Aβ production. Proc. Natl. Acad. Sci. USA 2014 111 13 E1230 E1239 24639524
    [Google Scholar]
  30. Cohen R.M. Rezai-Zadeh K. Weitz T.M. Rentsendorj A. Gate D. Spivak I. Bholat Y. Vasilevko V. Glabe C.G. Breunig J.J. Rakic P. Davtyan H. Agadjanyan M.G. Kepe V. Barrio J.R. Bannykh S. Szekely C.A. Pechnick R.N. Town T. A transgenic Alzheimer rat with plaques, tau pathology, behavioral impairment, oligomeric aβ, and frank neuronal loss. J. Neurosci. 2013 33 15 6245 6256 23575824
    [Google Scholar]
  31. Do Carmo S. Cuello A. Modeling Alzheimer’s disease in transgenic rats. Mol. Neurodegener. 2013 8 1 37 10.1186/1750‑1326‑8‑37 24161192
    [Google Scholar]
  32. Alharbi K.S. Afzal M. Alzarea S.I. Khan S.A. Alomar F.A. Kazmi I. Rosinidin protects streptozotocin-induced memory impairment-activated neurotoxicity by suppressing oxidative stress and inflammatory mediators in rats. Medicina (Kaunas) 2022 58 8 993 35893108
    [Google Scholar]
  33. Sarasa M. Pesini P. Natural non-trasgenic animal models for research in Alzheimer’s disease. Curr. Alzheimer Res. 2009 6 2 171 178 19355852
    [Google Scholar]
  34. Ekor M. The growing use of herbal medicines: Issues relating to adverse reactions and challenges in monitoring safety. Front. Pharmacol. 2014 4 177 10.3389/fphar.2013.00177 24454289
    [Google Scholar]
  35. Kumar N. Gahlawat A. Kumar R.N. Singh Y.P. Modi G. Garg P. Drug repurposing for Alzheimer’s disease: in silico and in vitro investigation of FDA-approved drugs as acetylcholinesterase inhibitors. J. Biomol. Struct. Dyn. 2022 40 7 2878 2892 10.1080/07391102.2020.1844054 33170091
    [Google Scholar]
  36. Howes M.J. Perry E. The role of phytochemicals in the treatment and prevention of dementia. Drugs Aging 2011 28 6 439 468 21639405
    [Google Scholar]
  37. Janssen B. Schäfer B. Galantamine. ChemTexts. 2017 3 2 7
    [Google Scholar]
  38. Stachlewitz R.F. Arteel G.E. Raleigh J.A. Connor H.D. Mason R.P. Thurman R.G. Development and characterization of a new model of tacrine-induced hepatotoxicity: Role of the sympathetic nervous system and hypoxia-reoxygenation. J. Pharmacol. Exp. Ther. 1997 282 3 1591 1599 10.1016/S0022‑3565(24)36973‑3 9316876
    [Google Scholar]
  39. Castro-Alvarez J.F. Uribe-Arias S.A. Mejía-Raigosa D. Cardona-Gómez G.P. Cyclin-dependent kinase 5, a node protein in diminished tauopathy: A systems biology approach. Front. Aging Neurosci. 2014 6 232 10.3389/fnagi.2014.00232 25225483
    [Google Scholar]
  40. Lordén G. Wozniak J.M. Doré K. Dozier L.E. Cates-Gatto C. Patrick G.N. Gonzalez D.J. Roberts A.J. Tanzi R.E. Newton A.C. Enhanced activity of Alzheimer disease-associated variant of protein kinase Cα drives cognitive decline in a mouse model. Nat. Commun. 2022 13 1 7200 10.1038/s41467‑022‑34679‑7 36418293
    [Google Scholar]
  41. Dolan P.J. Johnson G.V. The role of tau kinases in Alzheimer’s disease. Curr. Opin. Drug Discov. Devel. 2010 13 5 595 603 20812151
    [Google Scholar]
  42. Boutajangout A. Sigurdsson E.M. Krishnamurthy P.K. Tau as a therapeutic target for Alzheimer’s disease. Curr. Alzheimer Res. 2011 8 6 666 677 10.2174/156720511796717195 21679154
    [Google Scholar]
  43. Schwartz T.L. Massa J.L. Gupta S. Al-Samarrai S. Devitt P. Masand P.S. Divalproex sodium versus valproic acid in hospital treatment of psychotic disorders. Prim. Care Companion J. Clin. Psychiatry 2000 2 2 45 48 15014582
    [Google Scholar]
  44. Le Corre S. Klafki H.W. Plesnila N. Hübinger G. Obermeier A. Sahagún H. Monse B. Seneci P. Lewis J. Eriksen J. Zehr C. Yue M. McGowan E. Dickson D.W. Hutton M. Roder H.M. An inhibitor of tau hyperphosphorylation prevents severe motor impairments in tau transgenic mice. Proc. Natl. Acad. Sci. USA 2006 103 25 9673 9678 10.1073/pnas.0602913103 16769887
    [Google Scholar]
  45. Nunan J. Small D.H. Regulation of APP cleavage by α‐, β‐ and γ‐secretases. FEBS Lett. 2000 483 1 6 10 10.1016/S0014‑5793(00)02076‑7 11033346
    [Google Scholar]
  46. Guo T. Zhang D. Zeng Y. Huang T.Y. Xu H. Zhao Y. Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease. Mol. Neurodegener. 2020 15 1 40 10.1186/s13024‑020‑00391‑7 32677986
    [Google Scholar]
  47. Beher D. Graham S.L. Protease inhibitors as potential disease-modifying therapeutics for Alzheimer’s disease. Expert Opin. Investig. Drugs 2005 14 11 1385 1409 16255678
    [Google Scholar]
  48. Menting K.W. Claassen J.A.H.R. β-secretase inhibitor: A promising novel therapeutic drug in Alzheimer’s disease. Front. Aging Neurosci. 2014 6 165 10.3389/fnagi.2014.00165 25100992
    [Google Scholar]
  49. Vassar R. BACE1 inhibitor drugs in clinical trials for Alzheimer’s disease. Alzheimers Res. Ther. 2014 6 9 89 10.1186/s13195‑014‑0089‑7 25621019
    [Google Scholar]
  50. Dekeryte R. Franklin Z. Hull C. Croce L. Kamli-Salino S. Helk O. Hoffmann P.A. Yang Z. Riedel G. Delibegovic M. Platt B. The BACE1 inhibitor LY2886721 improves diabetic phenotypes of BACE1 knock-in mice. Biochim. Biophys. Acta Mol. Basis Dis. 2021 1867 7 166149 33892080
    [Google Scholar]
  51. Blume T. Filser S. Jaworska A. Blain J.F. Koenig G. Moschke K. Lichtenthaler S.F. Herms J. BACE1 inhibitor MK-8931 alters formation but not stability of dendritic spines. Front. Aging Neurosci. 2018 10 229 30093858
    [Google Scholar]
  52. Mullard A. The drug-maker’s guide to the galaxy. Nature 2017 549 7673 445 447 28959982
    [Google Scholar]
  53. Siemers E. Skinner M. Dean R.A. Gonzales C. Satterwhite J. Farlow M. Ness D. May P.C. Safety, tolerability, and changes in amyloid beta concentrations after administration of a gamma-secretase inhibitor in volunteers. Clin. Neuropharmacol. 2005 28 3 126 132 15965311
    [Google Scholar]
  54. Kaur M. Prakash A. Kalia A.N. Neuroprotective potential of antioxidant potent fractions from Convolvulus pluricaulis Chois. in 3-nitropropionic acid challenged rats. Nutr. Neurosci. 2016 19 2 70 78 25896328
    [Google Scholar]
  55. Barakos J. Purcell D. Suhy J. Chalkias S. Burkett P. Grassi C.M. Castrillo-Viguera C. Rubino I. Vijverberg E. Detection and management of amyloid-related imaging abnormalities in patients with Alzheimer’s disease treated with anti-amyloid beta therapy. J. Prev. Alzheimers Dis. 2022 9 2 211 220 10.14283/jpad.2022.21 35542992
    [Google Scholar]
  56. Tong A. Flemming K. McInnes E. Oliver S. Craig J. Enhancing transparency in reporting the synthesis of qualitative research: ENTREQ. BMC Med. Res. Methodol. 2012 12 1 181 10.1186/1471‑2288‑12‑181 23185978
    [Google Scholar]
  57. Qing H. Li N-M. Liu K-F. Qiu Y-J. Zhang H-H. Nakanishi H. Mutations of beta-amyloid precursor protein alter the consequence of Alzheimer’s disease pathogenesis. Neural Regen. Res. 2019 14 4 658 665 10.4103/1673‑5374.247469 30632506
    [Google Scholar]
  58. Vellas B. Sol O. Snyder P.J. Ousset P.J. Haddad R. Maurin M. Lemarié J.C. Désiré L. Pando M.P. EHT0202/002 study group EHT0202 in Alzheimer’s disease: A 3-month, randomized, placebo-controlled, double-blind study. Curr. Alzheimer Res. 2011 8 2 203 212 10.2174/156720511795256053 21222604
    [Google Scholar]
  59. Zhao Y. Zhao B. Oxidative stress and the pathogenesis of Alzheimer’s disease. Oxid. Med. Cell. Longev. 2013 2013 1 10 10.1155/2013/316523 23983897
    [Google Scholar]
  60. Cheignon C. Tomas M. Bonnefont-Rousselot D. Faller P. Hureau C. Collin F. Oxidative stress and the amyloid beta peptide in Alzheimer’s disease. Redox Biol. 2018 14 450 464 10.1016/j.redox.2017.10.014 29080524
    [Google Scholar]
  61. Choi S.J. Jeong C.H. Choi S.G. Chun J.Y. Kim Y.J. Lee J. Shin D.H. Heo H.J. Zeatin prevents amyloid beta-induced neurotoxicity and scopolamine-induced cognitive deficits. J. Med. Food 2009 12 2 271 277 10.1089/jmf.2007.0678 19459726
    [Google Scholar]
  62. Yadang F.S.A. Nguezeye Y. Kom C.W. Betote P.H.D. Mamat A. Tchokouaha L.R.Y. Taiwé G.S. Agbor G.A. Bum E.N. Scopolamine-induced memory impairment in mice: Neuroprotective effects of Carissa edulis (Forssk.) Valh (Apocynaceae) aqueous extract. Int. J. Alzheimers Dis. 2020 2020 1 10 10.1155/2020/6372059 32934845
    [Google Scholar]
  63. Guzman-Martinez L. Maccioni R.B. Andrade V. Navarrete L.P. Pastor M.G. Ramos-Escobar N. Neuroinflammation as a common feature of neurodegenerative disorders. Front. Pharmacol. 2019 10 1008 10.3389/fphar.2019.01008 31572186
    [Google Scholar]
  64. Tabet N. Feldmand H. Ibuprofen for Alzheimer’s disease. Cochrane Database Syst. Rev. 2003 2 2 CD004031 12804498
    [Google Scholar]
  65. Aisen P.S. Davis K.L. Berg J.D. Schafer K. Campbell K. Thomas R.G. Weiner M.F. Farlow M.R. Sano M. Grundman M. Thal L.J. A randomized controlled trial of prednisone in Alzheimer’s disease. Neurology 2000 54 3 588 593 10.1212/WNL.54.3.588 10680787
    [Google Scholar]
  66. Imbimbo B.P. Solfrizzi V. Panza F. Are NSAIDs useful to treat Alzheimer’s disease or mild cognitive impairment? Front. Aging Neurosci. 2010 2 1517 10.3389/fnagi.2010.00019 20725517
    [Google Scholar]
  67. Weggen S. Eriksen J.L. Sagi S.A. Pietrzik C.U. Ozols V. Fauq A. Golde T.E. Koo E.H. Evidence that nonsteroidal anti-inflammatory drugs decrease amyloid β 42 production by direct modulation of γ-secretase activity. J. Biol. Chem. 2003 278 34 31831 31837 10.1074/jbc.M303592200 12805356
    [Google Scholar]
  68. Jantzen P.T. Connor K.E. DiCarlo G. Wenk G.L. Wallace J.L. Rojiani A.M. Coppola D. Morgan D. Gordon M.N. Microglial activation and beta -amyloid deposit reduction caused by a nitric oxide-releasing nonsteroidal anti-inflammatory drug in amyloid precursor protein plus presenilin-1 transgenic mice. J. Neurosci. 2002 22 6 2246 2254 10.1523/JNEUROSCI.22‑06‑02246.2002 11896164
    [Google Scholar]
  69. Chen Y. Lyga J. Brain-skin connection: Stress, inflammation and skin aging. Inflamm. Allergy Drug Targets 2014 13 3 177 190 10.2174/1871528113666140522104422 24853682
    [Google Scholar]
  70. Hartmann S. Möbius H.J. Tolerability of memantine in combination with cholinesterase inhibitors in dementia therapy. Int. Clin. Psychopharmacol. 2003 18 2 81 85 10.1097/00004850‑200303000‑00003 12598818
    [Google Scholar]
  71. Klatte E.T. Scharre D.W. Nagaraja H.N. Davis R.A. Beversdorf D.Q. Combination therapy of donepezil and vitamin E in Alzheimer disease. Alzheimer Dis. Assoc. Disord. 2003 17 2 113 116 10.1097/00002093‑200304000‑00010 12794389
    [Google Scholar]
  72. Kabir M.T. Uddin M.S. Mamun A.A. Jeandet P. Aleya L. Mansouri R.A. Ashraf G.M. Mathew B. Bin-Jumah M.N. Abdel-Daim M.M. Combination drug therapy for the management of Alzheimer’s disease. Int. J. Mol. Sci. 2020 21 9 3272 10.3390/ijms21093272 32380758
    [Google Scholar]
  73. Knorz A.L. Quante A. Alzheimer’s disease: Efficacy of mono-and combination therapy. A systematic review. J. Geriatr. Psychiatry Neurol. 2022 35 4 475 486 10.1177/08919887211044746 34476990
    [Google Scholar]
  74. Petersen R.C. Thomas R.G. Grundman M. Bennett D. Doody R. Ferris S. Galasko D. Jin S. Kaye J. Levey A. Pfeiffer E. Sano M. van Dyck C.H. Thal L.J. Alzheimer’s Disease Cooperative Study Group Vitamin E and donepezil for the treatment of mild cognitive impairment. N. Engl. J. Med. 2005 352 23 2379 2388 15829527
    [Google Scholar]
  75. Devi R. Kumari S. Elancheran R. Phytochemical screening, antioxidant, antityrosinase, and antigenotoxic potential of Amaranthus viridis extract. Indian J. Pharmacol. 2018 50 3 130 138 10.4103/ijp.IJP_77_18 30166750
    [Google Scholar]
  76. Hardy J. Selkoe D.J. The amyloid hypothesis of Alzheimer’s disease: Progress and problems on the road to therapeutics. Science 2002 297 5580 353 356 10.1126/science.1072994 12130773
    [Google Scholar]
  77. Salloway S. Chalkias S. Barkhof F. Burkett P. Barakos J. Purcell D. Suhy J. Forrestal F. Tian Y. Umans K. Wang G. Singhal P. Budd Haeberlein S. Smirnakis K. Amyloid-related imaging abnormalities in 2 phase 3 studies evaluating aducanumab in patients with early Alzheimer disease. JAMA Neurol. 2022 79 1 13 21 10.1001/jamaneurol.2021.4161 34807243
    [Google Scholar]
  78. Gauthier S. Aisen P.S. Cummings J. Detke M.J. Longo F.M. Raman R. Sabbagh M. Schneider L. Tanzi R. Tariot P. Weiner M. Touchon J. Vellas B. EU/US CTAD Task Force Non-amyloid approaches to disease modification for Alzheimer’s disease: An EU/US CTAD task force report. J. Prev. Alzheimers Dis. 2020 7 3 152 157 10.14283/jpad.2020.18 32420298
    [Google Scholar]
  79. Doody R.S. Raman R. Farlow M. Iwatsubo T. Vellas B. Joffe S. Kieburtz K. He F. Sun X. Thomas R.G. Aisen P.S. Siemers E. Sethuraman G. Mohs R. Alzheimer’s Disease Cooperative Study Steering Committee Semagacestat Study Group A phase 3 trial of semagacestat for treatment of Alzheimer’s disease. N. Engl. J. Med. 2013 369 4 341 350 10.1056/NEJMoa1210951 23883379
    [Google Scholar]
  80. Pandey M.K. DeGrado T.R. Glycogen synthase Kinase-3 (GSK-3)-Targeted therapy and imaging. Theranostics 2016 6 4 571 593 10.7150/thno.14334 26941849
    [Google Scholar]
  81. Birks J.S. Chong L.Y. Grimley Evans J. Rivastigmine for Alzheimer’s disease. Cochrane Database Syst. Rev. 2015 9 9 CD001191 26393402
    [Google Scholar]
  82. Grill J.D. Karlawish J. Addressing the challenges to successful recruitment and retention in Alzheimer’s disease clinical trials. Alzheimers Res. Ther. 2010 2 6 34 10.1186/alzrt58 21172069
    [Google Scholar]
  83. Cai Z. Wang C. Yang W. Role of berberine in Alzheimer’s disease. Neuropsychiatr. Dis. Treat. 2016 12 2509 2520 27757035
    [Google Scholar]
  84. Eldufani J. Blaise G. The role of acetylcholinesterase inhibitors such as neostigmine and rivastigmine on chronic pain and cognitive function in aging: A review of recent clinical applications. Alzheimers Dement. (N. Y.) 2019 5 175 183 31194017
    [Google Scholar]
  85. Olin J. Schneider L. Galantamine for Alzheimer’s disease. Cochrane Database Syst. Rev. 2002 3 CD001747 12137632
    [Google Scholar]
  86. Jung H.A. Min B.S. Yokozawa T. Lee J.H. Kim Y.S. Choi J.S. Anti-Alzheimer and antioxidant activities of Coptidis Rhizoma alkaloids. Biol. Pharm. Bull. 2009 32 8 1433 1438 19652386
    [Google Scholar]
  87. Winblad B. Giacobini E. Frölich L. Friedhoff L.T. Bruinsma G. Becker R.E. Greig N.H. Phenserine efficacy in Alzheimer’s disease. J. Alzheimers Dis. 2011 22 4 1201 1208 10.3233/JAD‑2010‑101311 20930279
    [Google Scholar]
  88. Coelho F. Birks J. Physostigmine for Alzheimer’s disease. Cochrane Database Syst. Rev. 2001 2001 2 CD001499 11405996
    [Google Scholar]
  89. Antuono P.G. Mentane Study Group Effectiveness and safety of velnacrine for the treatment of Alzheimer’s disease. A double-blind, placebo-controlled study. Arch. Intern. Med. 1995 155 16 1766 1772 7654110
    [Google Scholar]
  90. Qian Z.M. Ke Y. Huperzine A. Huperzine A: Is it an effective disease-modifying drug for alzheimer’s disease? Front. Aging Neurosci. 2014 6 216 25191267
    [Google Scholar]
  91. Qizilbash N. Birks J. López-Arrieta J. Lewington S. Szeto S. Tacrine for Alzheimer’s disease. Cochrane Database Syst. Rev. 2000 1999 2 CD000202 10796507
    [Google Scholar]
  92. Cummings J.L. Cyrus P.A. Bieber F. Mas J. Orazem J. Gulanski B. Metrifonate Study Group Metrifonate treatment of the cognitive deficits of Alzheimer’s disease. Neurology 1998 50 5 1214 1221 9595966
    [Google Scholar]
  93. Weinreb O. Amit T. Bar-Am O. Youdim M.B. A novel anti-Alzheimer’s disease drug, ladostigil neuroprotective, multimodal brain-selective monoamine oxidase and cholinesterase inhibitor. Int. Rev. Neurobiol. 2011 100 191 215 21971009
    [Google Scholar]
  94. Knowles J. Donepezil in Alzheimer’s disease: An evidence-based review of its impact on clinical and economic outcomes. Core Evid. 2006 1 3 195 219 22500154
    [Google Scholar]
  95. Chauhan B.S. Rai A. Sonkar A.K. Tripathi K. Upadhyay S. Mishra L. Srikrishna S. Neuroprotective activity of a novel synthetic rhodamine-based hydrazone against Cu2+-induced Alzheimer’s Disease in Drosophila. ACS Chem. Neurosci. 2022 13 10 1566 1579 35476931
    [Google Scholar]
  96. Singh S.K. Sinha P. Mishra L. Srikrishna S. Neuroprotective role of a novel copper chelator against Aβ 42 induced neurotoxicity. Int. J. Alzheimers Dis. 2013 2013 567128 24159420
    [Google Scholar]
  97. Zhou F. Chen S. Xiong J. Li Y. Qu L. Luteolin reduces zinc-induced tau phosphorylation at Ser262/356 in an ROS-dependent manner in SH-SY5Y cells. Biol. Trace Elem. Res. 2012 149 2 273 279 22528780
    [Google Scholar]
  98. Palomo V. Perez D.I. Perez C. Morales-Garcia J.A. Soteras I. Alonso-Gil S. Encinas A. Castro A. Campillo N.E. Perez-Castillo A. Gil C. Martinez A. 5-imino-1,2,4-thiadiazoles: First small molecules as substrate competitive inhibitors of glycogen synthase kinase 3. J. Med. Chem. 2012 55 4 1645 1661 22257026
    [Google Scholar]
  99. Gunosewoyo H. Midzak A. Gaisina I.N. Sabath E.V. Fedolak A. Hanania T. Brunner D. Papadopoulos V. Kozikowski A.P. Characterization of maleimide-based glycogen synthase kinase-3 (GSK-3) inhibitors as stimulators of steroidogenesis. J. Med. Chem. 2013 56 12 5115 5129 23725591
    [Google Scholar]
  100. Leost M. Schultz C. Link A. Wu Y.Z. Biernat J. Mandelkow E.M. Bibb J.A. Snyder G.L. Greengard P. Zaharevitz D.W. Gussio R. Senderowicz A.M. Sausville E.A. Kunick C. Meijer L. Paullones are potent inhibitors of glycogen synthase kinase-3beta and cyclin-dependent kinase 5/p25. Eur. J. Biochem. 2000 267 19 5983 5994 10998059
    [Google Scholar]
  101. Zhang S.G. Wang X.S. Zhang Y.D. Di Q. Shi J.P. Qian M. Xu L.G. Lin X.J. Lu J. Indirubin-3′-monoxime suppresses amyloid-beta-induced apoptosis by inhibiting tau hyperphosphorylation. Neural Regen. Res. 2016 11 6 988 993 27482230
    [Google Scholar]
  102. Croft C.L. Kurbatskaya K. Hanger D.P. Noble W. Inhibition of glycogen synthase kinase-3 by BTA-EG4 reduces tau abnormalities in an organotypic brain slice culture model of Alzheimer’s disease. Sci. Rep. 2017 7 1 7434 28785087
    [Google Scholar]
  103. Jhang K.A. Park J.S. Kim H.S. Chong Y.H. Resveratrol ameliorates Tau hyperphosphorylation at Ser396 site and oxidative damage in rat hippocampal Slices Exposed to Vanadate: Implication of ERK1/2 and GSK-3β signaling cascades. J. Agric. Food Chem. 2017 65 44 9626 9634 29022339
    [Google Scholar]
  104. Javidnia M. Hebron M.L. Xin Y. Kinney N.G. Moussa C.E.H. Pazopanib reduces phosphorylated Tau levels and alters astrocytes in a mouse model of tauopathy. J. Alzheimers Dis. 2017 60 2 461 481 10.3233/JAD‑170429 28869476
    [Google Scholar]
  105. Liang Z. Li Q.X. Discovery of Selective, substrate-competitive, and passive membrane permeable glycogen synthase Kinase-3β inhibitors: Synthesis, biological evaluation, and molecular modeling of new C -Glycosylflavones. ACS Chem. Neurosci. 2018 9 5 1166 1183 10.1021/acschemneuro.8b00010 29381861
    [Google Scholar]
  106. Giroux V. Lento A.A. Islam M. Pitarresi J.R. Kharbanda A. Hamilton K.E. Whelan K.A. Long A. Rhoades B. Tang Q. Nakagawa H. Lengner C.J. Bass A.J. Wileyto E.P. Klein-Szanto A.J. Wang T.C. Rustgi A.K. Long-lived keratin 15+ esophageal progenitor cells contribute to homeostasis and regeneration. J. Clin. Invest. 2017 127 6 2378 2391 10.1172/JCI88941 28481227
    [Google Scholar]
  107. Zhou D. Liu H. Li C. Wang F. Shi Y. Liu L. Zhao X. Liu A. Zhang J. Wang C. Chen Z. Atorvastatin ameliorates cognitive impairment, Aβ1-42 production and Tau hyperphosphorylation in APP/PS1 transgenic mice. Metab. Brain Dis. 2016 31 3 693 703 10.1007/s11011‑016‑9803‑4 26883430
    [Google Scholar]
  108. Annamalai B. Won J.S. Choi S. Singh I. Singh A.K. Role of S-nitrosoglutathione mediated mechanisms in tau hyper-phosphorylation. Biochem. Biophys. Res. Commun. 2015 458 1 214 219 10.1016/j.bbrc.2015.01.093 25640839
    [Google Scholar]
  109. Liu Y. Su Y. Wang J. Sun S. Wang T. Qiao X. Run X. Li H. Liang Z. Rapamycin decreases tau phosphorylation at Ser214 through regulation of cAMP-dependent kinase. Neurochem. Int. 2013 62 4 458 467 10.1016/j.neuint.2013.01.014 23357480
    [Google Scholar]
  110. Ballatore C. Brunden K.R. Huryn D.M. Trojanowski J.Q. Lee V.M.Y. Smith A.B. III Microtubule stabilizing agents as potential treatment for Alzheimer’s disease and related neurodegenerative tauopathies. J. Med. Chem. 2012 55 21 8979 8996 10.1021/jm301079z 23020671
    [Google Scholar]
  111. Hamann M. Alonso D. Martín-Aparicio E. Fuertes A. Pérez-Puerto M.J. Castro A. Morales S. Navarro M.L. del Monte-Millán M. Medina M. Pennaka H. Balaiah A. Peng J. Cook J. Wahyuono S. Martínez A. Glycogen synthase kinase-3 (GSK-3) inhibitory activity and structure-activity relationship (SAR) studies of the manzamine alkaloids. Potential for Alzheimer’s disease. J. Nat. Prod. 2007 70 9 1397 1405 10.1021/np060092r 17708655
    [Google Scholar]
  112. Brunden K.R. Yao Y. Potuzak J.S. Ferrer N.I. Ballatore C. James M.J. Hogan A.M.L. Trojanowski J.Q. Smith A.B. III Lee V.M.Y. The characterization of microtubule-stabilizing drugs as possible therapeutic agents for Alzheimer’s disease and related tauopathies. Pharmacol. Res. 2011 63 4 341 351 10.1016/j.phrs.2010.12.002 21163349
    [Google Scholar]
  113. Frost D. Meechoovet B. Wang T. Gately S. Giorgetti M. Shcherbakova I. Dunckley T. β-carboline compounds, including harmine, inhibit DYRK1A and tau phosphorylation at multiple Alzheimer’s disease-related sites. PLoS One 2011 6 5 e19264 10.1371/journal.pone.0019264 21573099
    [Google Scholar]
  114. Peterson D.W. George R.C. Scaramozzino F. LaPointe N.E. Anderson R.A. Graves D.J. Lew J. Cinnamon extract inhibits tau aggregation associated with Alzheimer’s disease in vitro. J. Alzheimers Dis. 2009 17 3 585 597 10.3233/JAD‑2009‑1083 19433898
    [Google Scholar]
  115. Iuvone T. De Filippis D. Esposito G. D’Amico A. Izzo A.A. The spice sage and its active ingredient rosmarinic acid protect PC12 cells from amyloid-beta peptide-induced neurotoxicity. J. Pharmacol. Exp. Ther. 2006 317 3 1143 1149 10.1124/jpet.105.099317 16495207
    [Google Scholar]
  116. Caccamo A. Oddo S. Tran L.X. LaFerla F.M. Lithium reduces tau phosphorylation but not A beta or working memory deficits in a transgenic model with both plaques and tangles. Am. J. Pathol. 2007 170 5 1669 1675 10.2353/ajpath.2007.061178 17456772
    [Google Scholar]
  117. Xia H. Wu L. Chu M. Feng H. Lu C. Wang Q. He M. Ge X. Effects of breviscapine on amyloid beta 1-42 induced Alzheimer’s disease mice: A HPLC-QTOF-MS based plasma metabonomics study. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 2017 1057 92 100 10.1016/j.jchromb.2017.05.003 28511119
    [Google Scholar]
  118. Garcez M.L. Mina F. Bellettini-Santos T. Carneiro F.G. Luz A.P. Schiavo G.L. Andrighetti M.S. Scheid M.G. Bolfe R.P. Budni J. Minocycline reduces inflammatory parameters in the brain structures and serum and reverses memory impairment caused by the administration of amyloid β (1-42) in mice. Prog. Neuropsychopharmacol. Biol. Psychiatry 2017 77 23 31 10.1016/j.pnpbp.2017.03.010 28336494
    [Google Scholar]
  119. Gong L. Li S.L. Li H. Zhang L. Ginsenoside Rg1 protects primary cultured rat hippocampal neurons from cell apoptosis induced by β-amyloid protein. Pharm. Biol. 2011 49 5 501 507 10.3109/13880209.2010.521514 21438847
    [Google Scholar]
  120. Sabogal-Guáqueta A.M. Muñoz-Manco J.I. Ramírez-Pineda J.R. Lamprea-Rodriguez M. Osorio E. Cardona-Gómez G.P. The flavonoid quercetin ameliorates Alzheimer’s disease pathology and protects cognitive and emotional function in aged triple transgenic Alzheimer’s disease model mice. Neuropharmacology 2015 93 134 145 10.1016/j.neuropharm.2015.01.027 25666032
    [Google Scholar]
  121. Aso E. Ferrer I. Cannabinoids for treatment of Alzheimer’s disease: Moving toward the clinic. Front. Pharmacol. 2014 5 37 24634659
    [Google Scholar]
  122. Garrido-Mesa N. Zarzuelo A. Gálvez J. What is behind the non-antibiotic properties of minocycline? Pharmacol. Res. 2013 67 1 18 30 23085382
    [Google Scholar]
  123. Caltagirone C. Ferrannini L. Marchionni N. Nappi G. Scapagnini G. Trabucchi M. The potential protective effect of tramiprosate (homotaurine) against Alzheimer’s disease: A review. Aging Clin. Exp. Res. 2012 24 6 580 587 22961121
    [Google Scholar]
  124. Garcia-Alloza M. Borrelli L.A. Rozkalne A. Hyman B.T. Bacskai B.J. Curcumin labels amyloid pathology in vivo, disrupts existing plaques, and partially restores distorted neurites in an Alzheimer mouse model. J. Neurochem. 2007 102 4 1095 1104 17472706
    [Google Scholar]
  125. Zhang C. Tanzi R.E. Natural modulators of amyloid-beta precursor protein processing. Curr. Alzheimer Res. 2012 ••• Epub ahead of print 22998566
    [Google Scholar]
  126. Peng Y. Sun J. Hon S. Nylander A.N. Xia W. Feng Y. Wang X. Lemere C.A. L-3-n-butylphthalide improves cognitive impairment and reduces amyloid-beta in a transgenic model of Alzheimer’s disease. J. Neurosci. 2010 30 24 8180 8189 10.1523/JNEUROSCI.0340‑10.2010 20554868
    [Google Scholar]
  127. Kukar T. Prescott S. Eriksen J.L. Holloway V. Murphy M.P. Koo E.H. Golde T.E. Nicolle M.M. Chronic administration of R-flurbiprofen attenuates learning impairments in transgenic amyloid precursor protein mice. BMC Neurosci. 2007 8 1 54 10.1186/1471‑2202‑8‑54 17650315
    [Google Scholar]
  128. Telerman A. Ofir R. Kashman Y. Elmann A. 3,5,4′-trihydroxy-6,7,3′-trimethoxyflavone protects against beta amyloid-induced neurotoxicity through antioxidative activity and interference with cell signaling. BMC Complement. Altern. Med. 2017 17 1 332 10.1186/s12906‑017‑1840‑y 28645294
    [Google Scholar]
  129. Kim J. Cho C.H. Hahn H.G. Choi S.Y. Cho S.W. Neuroprotective effects of N-adamantyl-4-methylthiazol-2-amine against amyloid β-induced oxidative stress in mouse hippocampus. Brain Res. Bull. 2017 128 22 28 27816554
    [Google Scholar]
  130. Grimm M.O. Mett J. Hartmann T. The impact of Vitamin E and other fat-soluble vitamins on alzheimer´s disease. Int. J. Mol. Sci. 2016 17 11 1785 27792188
    [Google Scholar]
  131. Reinisalo M. Kårlund A. Koskela A. Kaarniranta K. Karjalainen R.O. Polyphenol Stilbenes: Molecular mechanisms of defence against oxidative stress and aging-related diseases. Oxid. Med. Cell. Longev. 2015 2015 340520 26180583
    [Google Scholar]
  132. Lobo V. Patil A. Phatak A. Chandra N. Free radicals, antioxidants and functional foods: Impact on human health. Pharmacogn. Rev. 2010 4 8 118 126 22228951
    [Google Scholar]
  133. Shi C. Liu J. Wu F. Yew D.T. Ginkgo biloba extract in Alzheimer’s disease: From action mechanisms to medical practice. Int. J. Mol. Sci. 2010 11 1 107 123 20162004
    [Google Scholar]
  134. Pham-Huy L.A. He H. Pham-Huy C. Free radicals, antioxidants in disease and health. Int. J. Biomed. Sci. 2008 4 2 89 96 23675073
    [Google Scholar]
  135. Carman A.J. Dacks P.A. Lane R.F. Shineman D.W. Fillit H.M. Current evidence for the use of coffee and caffeine to prevent age-related cognitive decline and Alzheimer’s disease. J. Nutr. Health Aging 2014 18 4 383 392 24676319
    [Google Scholar]
  136. Xie S. Chen J. Li X. Su T. Wang Y. Wang Z. Huang L. Li X. Synthesis and evaluation of selegiline derivatives as monoamine oxidase inhibitor, antioxidant and metal chelator against Alzheimer’s disease. Bioorg. Med. Chem. 2015 23 13 3722 3729 25934229
    [Google Scholar]
  137. Singh S.K. Gaur R. Kumar A. Fatima R. Mishra L. Srikrishna S. The flavonoid derivative 2-(4′ Benzyloxyphenyl)-3-hydroxy-chromen-4-one protects against Aβ42-induced neurodegeneration in transgenic Drosophila: Insights from in silico and in vivo studies. Neurotox. Res. 2014 26 4 331 350 24706035
    [Google Scholar]
  138. Chauhan B.S. Singh Y.P. Phytochemistry and pharmacological advances of Ascophyllum nodosum in the management of human diseases: A comprehensive review. Phytomed. Plus 2024 5 1 100718
    [Google Scholar]
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Therapeutic Advances in Alzheimer’s Disease: Integrating Natural, Semi-Synthetic, and Synthetic Drug Strategies
Bentham Science Publishers ; https://doi.org/10.2174/0115672050366727250513061730
/content/journals/car/10.2174/0115672050366727250513061730
/content/journals/car/10.2174/0115672050366727250513061730
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  • Article Type:     Review Article
Keywords: semi-synthetic ; synergistic approach ; Alzheimer’s disease ; neurofibrillary tangles ; and synthetic drugs ; natural drugs

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