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Current Topics in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1568-0266
ISSN (Online): 1873-4294

Review Article

Navigating the Alzheimer's Treatment Landscape: Unraveling Amyloid-beta Complexities and Pioneering Precision Medicine Approaches

Author(s): Mohsina Patwekar*, Faheem Patwekar, Shahzad Khan, Rohit Sharma* and Dileep Kumar

Volume 24, Issue 19, 2024

Published on: 19 April, 2024

Page: [1665 - 1682] Pages: 18

DOI: 10.2174/0115680266295495240415114919

Price: $65

Abstract

A variety of cutting-edge methods and good knowledge of the illness's complex causes are causing a sea change in the field of Alzheimer's Disease (A.D.) research and treatment. Precision medicine is at the vanguard of this change, where individualized treatment plans based on genetic and biomarker profiles give a ray of hope for customized therapeutics. Combination therapies are becoming increasingly popular as a way to address the multifaceted pathology of Alzheimer's by simultaneously attacking Aβ plaques, tau tangles, neuroinflammation, and other factors. The article covers several therapeutic design efforts, including BACE inhibitors, gamma- secretase modulators, monoclonal antibodies (e.g., Aducanumab and Lecanemab), and anti- Aβ vaccinations. While these techniques appear promising, clinical development faces safety concerns and uneven efficacy. To address the complicated Aβ pathology in Alzheimer's disease, a multimodal approach is necessary. The statement emphasizes the continued importance of clinical trials in addressing safety and efficacy concerns. Looking ahead, it suggests that future treatments may take into account genetic and biomarker traits in order to provide more personalized care. Therapies targeting Aβ, tau tangles, neuroinflammation, and novel drug delivery modalities are planned. Nanoparticles and gene therapies are only two examples of novel drug delivery methods that have the potential to deliver treatments more effectively, with fewer side effects, and with better therapeutic results. In addition, medicines that target tau proteins in addition to Aβ are in the works. Early intervention, based on precise biomarkers, is a linchpin of Alzheimer's care, emphasizing the critical need for detecting the disease at its earliest stages. Lifestyle interventions, encompassing diet, exercise, cognitive training, and social engagement, are emerging as key components in the fight against cognitive decline. Data analytics and art are gaining prominence as strategies to mitigate the brain's inflammatory responses. To pool knowledge and resources in the fight against Alzheimer's, international cooperation between scientists, doctors, and pharmaceutical companies is still essential. In essence, a complex, individualized, and collaborative strategy will characterize Alzheimer's research and therapy in the future. Despite obstacles, these encouraging possibilities show the ongoing commitment of the scientific and medical communities to combat A.D. head-on, providing a glimmer of hope to the countless people and families touched by this savage sickness.

Graphical Abstract

[1]
A, A.; M, P.; Hamdi, M.; Bourouis, S.; Rastislav, K.; Mohmed, F. Evaluation of neuro images for the diagnosis of Alzheimer’s disease using deep learning neural network. Front. Public Health, 2022, 10, 834032.
[http://dx.doi.org/10.3389/fpubh.2022.834032] [PMID: 35198526]
[2]
Finder, V.H. Alzheimer’s disease: A general introduction and pathomechanism. J. Alzheimers Dis., 2010, 22(S3), S5-S19.
[http://dx.doi.org/10.3233/JAD-2010-100975] [PMID: 20858960]
[3]
Jack, C.R., Jr; Albert, M.S.; Knopman, D.S.; McKhann, G.M.; Sperling, R.A.; Carrillo, M.C.; Thies, B.; Phelps, C.H. Introduction to the recommendations from the national institute on aging-alzheimer’s association workgroups on diagnostic guidelines for alzheimer’s disease. Alzheimers Dement., 2011, 7(3), 257-262.
[http://dx.doi.org/10.1016/j.jalz.2011.03.004] [PMID: 21514247]
[4]
Legleiter, J.; Czilli, D.L.; Gitter, B.; DeMattos, R.B.; Holtzman, D.M.; Kowalewski, T. Effect of different anti-Abeta antibodies on Abeta fibrillogenesis as assessed by atomic force microscopy. J. Mol. Biol., 2004, 335(4), 997-1006.
[http://dx.doi.org/10.1016/j.jmb.2003.11.019] [PMID: 14698294]
[5]
John, V.; Beck, J.P.; Bienkowski, M.J.; Sinha, S.; Heinrikson, R.L. Human β-secretase (BACE) and BACE inhibitors. J. Med. Chem., 2003, 46(22), 4625-4630.
[http://dx.doi.org/10.1021/jm030247h] [PMID: 14561080]
[6]
Pange, S.S.; Patwekar, M.; Patwekar, F.; Alghamdi, S.; Babalghith, A.O.; Abdulaziz, O.; Jawaid, T.; Kamal, M.; Tabassum, S.; Mallick, J. A potential notion on alzheimer’s disease: Nanotechnology as an alternative solution. J. Nanomater., 2022, 2022, 1-8.
[http://dx.doi.org/10.1155/2022/6910811]
[7]
Bittar, A.; Bhatt, N.; Kayed, R. Advances and considerations in AD tau-targeted immunotherapy. Neurobiol. Dis., 2020, 134, 104707.
[http://dx.doi.org/10.1016/j.nbd.2019.104707] [PMID: 31841678]
[8]
Novak, P.; Kontsekova, E.; Zilka, N.; Novak, M. Ten years of tau-targeted immunotherapy: The path walked and the roads ahead. Front. Neurosci., 2018, 12, 798.
[http://dx.doi.org/10.3389/fnins.2018.00798] [PMID: 30450030]
[9]
Noble, W.; Sanchez, J.M.; Nievas, P.B.G.; Hanger, D.P. Considerations for future tau-targeted therapeutics: Can they deliver? Expert Opin. Drug Discov., 2020, 15(3), 265-267.
[http://dx.doi.org/10.1080/17460441.2020.1685977] [PMID: 31661994]
[10]
Götz, J.; Ittner, A.; Ittner, L.M. Tau-targeted treatment strategies in Alzheimer’s disease. Br. J. Pharmacol., 2012, 165(5), 1246-1259.
[http://dx.doi.org/10.1111/j.1476-5381.2011.01713.x] [PMID: 22044248]
[11]
Gu, X.; Chen, H.; Gao, X. Nanotherapeutic strategies for the treatment of Alzheimer’s disease. Ther. Deliv., 2015, 6(2), 177-195.
[http://dx.doi.org/10.4155/tde.14.97] [PMID: 25690086]
[12]
Spencer, J.P.E.; Vafeiadou, K.; Williams, R.J.; Vauzour, D. Neuroinflammation: Modulation by flavonoids and mechanisms of action. Mol. Aspects Med., 2012, 33(1), 83-97.
[http://dx.doi.org/10.1016/j.mam.2011.10.016] [PMID: 22107709]
[13]
Noviandy, T.R.; Maulana, A.; Idroes, G.M.; Maulydia, N.B.; Patwekar, M.; Suhendra, R.; Idroes, R. Integrating genetic algorithm and lightgbm for qsar modeling of acetylcholinesterase inhibitors in alzheimer’s disease drug discovery. Malacca Pharmaceutics, 2023, 1(2), 48-54.
[http://dx.doi.org/10.60084/mp.v1i2.60]
[14]
Garden, G.A. Epigenetics and the modulation of neuroinflammation. Neurotherapeutics, 2013, 10(4), 782-788.
[http://dx.doi.org/10.1007/s13311-013-0207-4] [PMID: 23963788]
[15]
Innamorato, N.G.; Lastres-Becker, I.; Cuadrado, A. Role of microglial redox balance in modulation of neuroinflammation. Curr. Opin. Neurol., 2009, 22(3), 308-314.
[http://dx.doi.org/10.1097/WCO.0b013e32832a3225] [PMID: 19359988]
[16]
Wang, Y.; Ge, P.; Yang, L.; Wu, C.; Zha, H.; Luo, T.; Zhu, Y. Protection of ischemic post conditioning against transient focal ischemia-induced brain damage is associated with inhibition of neuroinflammation via modulation of TLR2 and TLR4 pathways. J. Neuroinflammation, 2014, 11(1), 15.
[http://dx.doi.org/10.1186/1742-2094-11-15] [PMID: 24460643]
[17]
Campo, G.M.; Avenoso, A.; Nastasi, G.; Micali, A.; Prestipino, V.; Vaccaro, M.; D’Ascola, A.; Calatroni, A.; Campo, S. Hyaluronan reduces inflammation in experimental arthritis by modulating TLR-2 and TLR-4 cartilage expression. Biochim. Biophys. Acta Mol. Basis Dis., 2011, 1812(9), 1170-1181.
[http://dx.doi.org/10.1016/j.bbadis.2011.06.006] [PMID: 21723389]
[18]
Patwekar, M.; Patwekar, F.; Sanaullah, S.; Shaikh, D.; Almas, U.; Sharma, R. Harnessing artificial intelligence for enhanced Parkinson’s disease management: Pathways, treatment, and prospects. Trends. Immunother., 2023, 7(2), 2395.
[http://dx.doi.org/10.24294/ti.v7.i2.2395]
[19]
Kusumi, I.; Boku, S.; Takahashi, Y. Psychopharmacology of atypical antipsychotic drugs: From the receptor binding profile to neuroprotection and neurogenesis. Psychiatry Clin. Neurosci., 2015, 69(5), 243-258.
[http://dx.doi.org/10.1111/pcn.12242] [PMID: 25296946]
[20]
Shao, B.; Cheng, Y.; Jin, K. Estrogen, neuroprotection and neurogenesis after ischemic stroke. Curr. Drug Targets, 2012, 13(2), 188-198.
[http://dx.doi.org/10.2174/138945012799201702] [PMID: 22204318]
[21]
Selvi̇, S.; Polat, R.; Çakilcioğlu, U.; Celep, F.; Di̇rmenci̇, T.; Ertuğ, Z.F. An ethnobotanical review on medicinal plants of the Lamiaceae family in Turkey. Turk. J. Bot., 2022, 46(4), 283-332.
[http://dx.doi.org/10.55730/1300-008X.2712]
[22]
David Åberg, N.; Lind, J.; Isgaard, J.; Georg Kuhn, H. Peripheral growth hormone induces cell proliferation in the intact adult rat brain. Growth Horm. IGF Res., 2010, 20(3), 264-269.
[http://dx.doi.org/10.1016/j.ghir.2009.12.003] [PMID: 20106687]
[23]
Patwekar, M; Patwekar, F; Shaikh, D; Fatema, SR; Aher, SJ; Sharma, R Receptor-based approaches and therapeutic targets in Alzheimer’s disease along with role of AI in drug designing: Unraveling pathologies and advancing treatment strategies. Appl. Chem. Eng., 2023, 6(3), 1-29.
[24]
de la Monte, S.M. Contributions of brain insulin resistance and deficiency in amyloid-related neurodegeneration in Alzheimer’s disease. Drugs, 2012, 72(1), 49-66.
[http://dx.doi.org/10.2165/11597760-000000000-00000] [PMID: 22191795]
[25]
Çakılcıoğlu, U.; Türkoğlu, I. Plants used for hemorrhoid treatment in Elaziğ central district. Acta Hortic., 2009, (826), 89-96.
[http://dx.doi.org/10.17660/ActaHortic.2009.826.11]
[26]
Titmuss, A.T.; Srinivasan, S. Metabolic syndrome in children and adolescents: Old concepts in a young population. J. Paediatr. Child Health, 2016, 52(10), 928-934.
[http://dx.doi.org/10.1111/jpc.13190] [PMID: 27301065]
[27]
Ezkurdia, A.; Ramírez, M.J.; Solas, M. Metabolic syndrome as a risk factor for Alzheimer’s disease: A focus on insulin resistance. Int. J. Mol. Sci., 2023, 24(5), 4354.
[http://dx.doi.org/10.3390/ijms24054354] [PMID: 36901787]
[28]
Sharma, V.K.; Singh, T.G. Insulin resistance and bioenergetic manifestations: Targets and approaches in Alzheimer’s disease. Life Sci., 2020, 262, 118401.
[http://dx.doi.org/10.1016/j.lfs.2020.118401] [PMID: 32926928]
[29]
Willette, A.A.; Bendlin, B.B.; Starks, E.J.; Birdsill, A.C.; Johnson, S.C.; Christian, B.T.; Okonkwo, O.C.; La Rue, A.; Hermann, B.P.; Koscik, R.L.; Jonaitis, E.M.; Sager, M.A.; Asthana, S. Association of insulin resistance with cerebral glucose uptake in late middle–aged adults at risk for Alzheimer disease. JAMA Neurol., 2015, 72(9), 1013-1020.
[http://dx.doi.org/10.1001/jamaneurol.2015.0613] [PMID: 26214150]
[30]
Kalaria, R.N.; Cohen, D.L.; Premkumar, D.R.D.; Nag, S.; LaManna, J.C.; Lust, W.D. Vascular endothelial growth factor in Alzheimer’s disease and experimental cerebral ischemia. Brain Res. Mol. Brain Res., 1998, 62(1), 101-105.
[http://dx.doi.org/10.1016/S0169-328X(98)00190-9] [PMID: 9795165]
[31]
Mateo, I.; Llorca, J.; Infante, J.; Rodríguez, R.E.; Quintana, S.C.; Juan, S.P.; Berciano, J.; Combarros, O. Case-control study of vascular endothelial growth factor (VEGF) genetic variability in Alzheimer’s disease. Neurosci. Lett., 2006, 401(1-2), 171-173.
[http://dx.doi.org/10.1016/j.neulet.2006.03.020] [PMID: 16569480]
[32]
Martins, I.J.; Hone, E.; Foster, J.K.; Sünram-Lea, S.I.; Gnjec, A.; Fuller, S.J.; Nolan, D.; Gandy, S.E.; Martins, R.N. Apolipoprotein E, cholesterol metabolism, diabetes, and the convergence of risk factors for Alzheimer’s disease and cardiovascular disease. Mol. Psychiatry, 2006, 11(8), 721-736.
[http://dx.doi.org/10.1038/sj.mp.4001854] [PMID: 16786033]
[33]
Seripa, D.; Panza, F.; Franceschi, M.; D’Onofrio, G.; Solfrizzi, V.; Dallapiccola, B.; Pilotto, A. Non-apolipoprotein E and apolipoprotein E genetics of sporadic Alzheimer’s disease. Ageing Res. Rev., 2009, 8(3), 214-236.
[http://dx.doi.org/10.1016/j.arr.2008.12.003] [PMID: 19496238]
[34]
Williams, T.; Borchelt, D.R.; Chakrabarty, P. Therapeutic approaches targeting Apolipoprotein E function in Alzheimer’s disease. Mol. Neurodegener., 2020, 15(1), 8.
[http://dx.doi.org/10.1186/s13024-020-0358-9] [PMID: 32005122]
[35]
Lanoiselée, H.M.; Nicolas, G.; Wallon, D.; Lecrux, R.A.; Lacour, M.; Rousseau, S.; Richard, A.C.; Pasquier, F.; Sillaire, R.A.; Martinaud, O.; Muraine, Q.M.; de la Sayette, V.; Bretonniere, B.C.; Bouyx, E.F.; Chauviré, V.; Sarazin, M.; le Ber, I.; Epelbaum, S.; Jonveaux, T.; Rouaud, O.; Ceccaldi, M.; Félician, O.; Godefroy, O.; Formaglio, M.; Croisile, B.; Auriacombe, S.; Chamard, L.; Vincent, J.L.; Sauvée, M.; Marelli-Tosi, C.; Gabelle, A.; Ozsancak, C.; Pariente, J.; Paquet, C.; Hannequin, D.; Campion, D. APP, PSEN1, and PSEN2 mutations in early-onset Alzheimer disease: A genetic screening study of familial and sporadic cases. PLoS Med., 2017, 14(3), e1002270.
[http://dx.doi.org/10.1371/journal.pmed.1002270] [PMID: 28350801]
[36]
Giau, V.V.; Bagyinszky, E.; Youn, Y.C.; An, S.S.A.; Kim, S. APP, PSEN1, and PSEN2 mutations in Asian patients with early-onset Alzheimer disease. Int. J. Mol. Sci., 2019, 20(19), 4757.
[http://dx.doi.org/10.3390/ijms20194757] [PMID: 31557888]
[37]
Cruchaga, C.; Haller, G.; Chakraverty, S.; Mayo, K.; Vallania, F.L.; Mitra, R.D.; Faber, K.; Williamson, J.; Bird, T.; Arrastia, D.R.; Foroud, T.M.; Boeve, B.F.; Radford, G.N.R.; St Jean, P.; Lawson, M.; Ehm, M.G.; Mayeux, R.; Goate, A.M. Rare variants in APP, PSEN1 and PSEN2 increase risk for AD in late-onset Alzheimer’s disease families. PLoS One, 2012, 7(2), e31039.
[http://dx.doi.org/10.1371/journal.pone.0031039] [PMID: 22312439]
[38]
Hampel, H.; O’Bryant, S.E.; Castrillo, J.I.; Ritchie, C.; Rojkova, K.; Broich, K.; Benda, N.; Nisticò, R.; Frank, R.A.; Dubois, B.; Escott-Price, V.; Lista, S. Precision medicine-the golden gate for detection, treatment and prevention of Alzheimer’s disease. J. Prev. Alzheimers Dis., 2016, 3(4), 1-17.
[http://dx.doi.org/10.14283/jpad.2016.112] [PMID: 28344933]
[39]
Hampel, H.; O’Bryant, S.E.; Durrleman, S.; Younesi, E.; Rojkova, K.; Escott-Price, V.; Corvol, J-C.; Broich, K.; Dubois, B.; Lista, S. A precision medicine initiative for alzheimer’s disease: The road ahead to biomarker-guided integrative disease modeling. Climacteric, 2017, 20(2), 107-118.
[http://dx.doi.org/10.1080/13697137.2017.1287866] [PMID: 28286989]
[40]
Silva-Spínola, A.; Baldeiras, I.; Arrais, J.P.; Santana, I. The road to personalized medicine in Alzheimer’s disease: The use of artificial intelligence. Biomedicines, 2022, 10(2), 315.
[http://dx.doi.org/10.3390/biomedicines10020315] [PMID: 35203524]
[41]
Morley, J.E.; Morris, J.C.; Berg-Weger, M.; Borson, S.; Carpenter, B.D.; del Campo, N.; Dubois, B.; Fargo, K.; Fitten, L.J.; Flaherty, J.H.; Ganguli, M.; Grossberg, G.T.; Malmstrom, T.K.; Petersen, R.D.; Rodriguez, C.; Saykin, A.J.; Scheltens, P.; Tangalos, E.G.; Verghese, J.; Wilcock, G.; Winblad, B.; Woo, J.; Vellas, B. Brain health: the importance of recognizing cognitive impairment: An IAGG consensus conference. J. Am. Med. Dir. Assoc., 2015, 16(9), 731-739.
[http://dx.doi.org/10.1016/j.jamda.2015.06.017] [PMID: 26315321]
[42]
De la Rosa, A.; Gonzalez, O.G.; Chagnaud, A.C.; Millan, F.; Pascual, S.A.; Lucerga, G.C.; Lafarga, B.C.; Dominguez, G.E.; Carretero, A.; Correas, A.G.; Viña, J.; Cabrera, G.M.C. Physical exercise in the prevention and treatment of Alzheimer’s disease. J. Sport Health Sci., 2020, 9(5), 394-404.
[http://dx.doi.org/10.1016/j.jshs.2020.01.004] [PMID: 32780691]
[43]
Redolat, R.; Mesa-Gresa, P. Brain health as a key concept in the development of strategies for delaying age-related cognitive decline and alzheimer’s disease. J. Parkinsons Dis. Alzheimers Dis., 2015, 2(2), 4.
[44]
Sikanyika, N.L.; Parkington, H.C.; Smith, A.I.; Kuruppu, S. Powering amyloid beta degrading enzymes: A possible therapy for Alzheimer’s disease. Neurochem. Res., 2019, 44(6), 1289-1296.
[http://dx.doi.org/10.1007/s11064-019-02756-x] [PMID: 30806879]
[45]
Polanco, J.C.; Li, C.; Bodea, L.G.; Martinez-Marmol, R.; Meunier, F.A.; Götz, J. Amyloid-β and tau complexity — towards improved biomarkers and targeted therapies. Nat. Rev. Neurol., 2018, 14(1), 22-39.
[http://dx.doi.org/10.1038/nrneurol.2017.162] [PMID: 29242522]
[46]
Khan, A.; Corbett, A.; Ballard, C. Emerging treatments for Alzheimer’s disease for non-amyloid and non-tau targets. Expert Rev. Neurother., 2017, 17(7), 683-695.
[http://dx.doi.org/10.1080/14737175.2017.1326818] [PMID: 28490260]
[47]
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. 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.
[PMID: 32420298]
[48]
Quader, S.; Van Guyse, J.F.R. Bioresponsive polymers for nanomedicine—expectations and reality! Polymers, 2022, 14(17), 3659.
[http://dx.doi.org/10.3390/polym14173659] [PMID: 36080733]
[49]
Novakovic, D.; Feligioni, M.; Scaccianoce, S.; Caruso, A.; Piccinin, S.; Schepisi, C.; Errico, F.; Mercuri, N.B.; Nicoletti, F.; Nisticò, R. Profile of gantenerumab and its potential in the treatment of Alzheimer’s disease. Drug Des. Devel. Ther., 2013, 7, 1359-1364.
[PMID: 24255592]
[50]
Kwan, T.H.A.; Arfaie, S.; Therriault, J.; Rosa-Neto, P.; Gauthier, S. Lessons learnt from the second generation of anti-amyloid monoclonal antibodies clinical trials. Dement. Geriatr. Cogn. Disord., 2020, 49(4), 334-348.
[http://dx.doi.org/10.1159/000511506] [PMID: 33321511]
[51]
Vaz, M.; Silva, V.; Monteiro, C.; Silvestre, S. Role of aducanumab in the treatment of Alzheimer’s disease: Challenges and opportunities. Clin. Interv. Aging, 2022, 17, 797-810.
[http://dx.doi.org/10.2147/CIA.S325026] [PMID: 35611326]
[52]
Folch, J; Petrov, D; Ettcheto, M; Abad, S; López, SE; García, ML; Olloquequi, J; Beas-Zarate, C; Auladell, C; Camins, A Current research therapeutic strategies for Alzheimer’s disease treatment. Neural. Plast., 2016, 2016, 8501693.
[http://dx.doi.org/10.1155/2016/8501693]
[53]
Rofo, F.; Buijs, J.; Falk, R.; Honek, K.; Lannfelt, L.; Lilja, A.M.; Metzendorf, N.G.; Gustavsson, T.; Sehlin, D.; Söderberg, L.; Hultqvist, G. Novel multivalent design of a monoclonal antibody improves binding strength to soluble aggregates of amyloid beta. Transl. Neurodegener., 2021, 10(1), 38.
[http://dx.doi.org/10.1186/s40035-021-00258-x] [PMID: 34579778]
[54]
Baidya, F.; Bohra, M.; Datta, A.; Sarmah, D.; Shah, B.; Jagtap, P.; Raut, S.; Sarkar, A.; Singh, U.; Kalia, K.; Borah, A.; Wang, X.; Dave, K.R.; Yavagal, D.R.; Bhattacharya, P. Neuroimmune crosstalk and evolving pharmacotherapies in neurodegenerative diseases. Immunology, 2021, 162(2), 160-178.
[http://dx.doi.org/10.1111/imm.13264] [PMID: 32939758]
[55]
Menéndez-González, M.; Pérez-Piñera, P.; Martínez-Rivera, M.; Muñiz, A.L.; Vega, J.A. Immunotherapy for Alzheimer’s disease: Rational basis in ongoing clinical trials. Curr. Pharm. Des., 2011, 17(5), 508-520.
[http://dx.doi.org/10.2174/138161211795164112] [PMID: 21375481]
[56]
Weiner, H.L.; Frenkel, D. Immunology and immunotherapy of Alzheimer’s disease. Nat. Rev. Immunol., 2006, 6(5), 404-416.
[http://dx.doi.org/10.1038/nri1843] [PMID: 16639431]
[57]
Barbu, E.; Molnàr, É.; Tsibouklis, J.; Górecki, D.C. The potential for nanoparticle-based drug delivery to the brain: overcoming the blood–brain barrier. Expert Opin. Drug Deliv., 2009, 6(6), 553-565.
[http://dx.doi.org/10.1517/17425240902939143] [PMID: 19435406]
[58]
Daily, J.W.; Kang, S.; Park, S. Protection against Alzheimer’s disease by luteolin: Role of brain glucose regulation, anti-inflammatory activity, and the gut microbiota-liver-brain axis. Biofactors, 2021, 47(2), 218-231.
[http://dx.doi.org/10.1002/biof.1703] [PMID: 33347668]
[59]
Largent, E.A.; Peterson, A.; Karlawish, J.; Lynch, H.F. Aspiring to reasonableness in accelerated approval: Anticipating and avoiding the next aducanumab. Drugs Aging, 2022, 39(6), 389-400.
[http://dx.doi.org/10.1007/s40266-022-00949-8] [PMID: 35696021]
[60]
Tampi, R.R.; Forester, B.P.; Agronin, M. Aducanumab: Evidence from clinical trial data and controversies. Drugs Context, 2021, 10, 1-9.
[http://dx.doi.org/10.7573/dic.2021-7-3] [PMID: 34650610]
[61]
Heled, Y.; Rutschman, S.A.; Vertinsky, L. Regulatory reactivity in FDA's approval of the alzheimer's disease drug aducanumab (Aduhelm). Emory Legal Studies Research Paper No. 21-17, 2021.
[62]
Shi, M.; Chu, F.; Zhu, F.; Zhu, J. Impact of anti-amyloid-β monoclonal antibodies on the pathology and clinical profile of Alzheimer’s disease: A focus on aducanumab and lecanemab. Front. Aging Neurosci., 2022, 14, 870517.
[http://dx.doi.org/10.3389/fnagi.2022.870517] [PMID: 35493943]
[63]
Swanson, C.J.; Zhang, Y.; Dhadda, S.; Wang, J.; Kaplow, J.; Lai, R.Y.K.; Lannfelt, L.; Bradley, H.; Rabe, M.; Koyama, A.; Reyderman, L.; Berry, D.A.; Berry, S.; Gordon, R.; Kramer, L.D.; Cummings, J.L. A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer’s disease with lecanemab, an anti-Aβ protofibril antibody. Alzheimers Res. Ther., 2021, 13(1), 80.
[http://dx.doi.org/10.1186/s13195-021-00813-8] [PMID: 33865446]
[64]
Savory, J.; Exley, C.; Forbes, W.F.; Huang, Y.; Joshi, J.G.; Kruck, T.; McLachlan, D.R.; Wakayama, I. Can the controversy of the role of aluminum in alzheimer’s disease be resolved? what are the suggested approaches to this controversy and methodological issues to be considered? J. Toxicol. Environ. Health, 1996, 48(6), 615-636.
[http://dx.doi.org/10.1080/009841096161104] [PMID: 8772802]
[65]
Se Thoe, E.; Fauzi, A.; Tang, Y.Q.; Chamyuang, S.; Chia, A.Y.Y. A review on advances of treatment modalities for Alzheimer’s disease. Life Sci., 2021, 276, 119129.
[http://dx.doi.org/10.1016/j.lfs.2021.119129] [PMID: 33515559]
[66]
Ferretti, M.T.; Allard, S.; Partridge, V.; Ducatenzeiler, A.; Cuello, A.C. Minocycline corrects early, pre-plaque neuroinflammation and inhibits BACE-1 in a transgenic model of Alzheimer’s disease-like amyloid pathology. J. Neuroinflammation, 2012, 9(1), 62.
[http://dx.doi.org/10.1186/1742-2094-9-62] [PMID: 22472085]
[67]
Neumann, U.; Ufer, M.; Jacobson, L.H.; Dominguez, R.M.L.; Huledal, G.; Kolly, C.; Lüönd, R.M.; Machauer, R.; Veenstra, S.J.; Hurth, K.; Rueeger, H.; Blomley, T.M.; Staufenbiel, M.; Shimshek, D.R.; Perrot, L.; Frieauff, W.; Dubost, V.; Schiller, H.; Vogg, B.; Beltz, K.; Avrameas, A.; Kretz, S.; Pezous, N.; Rondeau, J.M.; Beckmann, N.; Hartmann, A.; Vormfelde, S.; David, O.J.; Galli, B.; Ramos, R.; Graf, A.; Lopez Lopez, C. The BACE -1 inhibitor CNP 520 for prevention trials in Alzheimer’s disease. EMBO Mol. Med., 2018, 10(11), e9316.
[http://dx.doi.org/10.15252/emmm.201809316] [PMID: 30224383]
[68]
Patel, S.; Bansoad, A.V.; Singh, R.; Khatik, G.L. BACE1: A key regulator in Alzheimer’s disease progression and current development of its inhibitors. Curr. Neuropharmacol., 2022, 20(6), 1174-1193.
[http://dx.doi.org/10.2174/1570159X19666211201094031] [PMID: 34852746]
[69]
Bazzari, F.H.; Bazzari, A.H. BACE1 Inhibitors for alzheimer’s disease: The past, present and any future? Molecules, 2022, 27(24), 8823.
[http://dx.doi.org/10.3390/molecules27248823] [PMID: 36557955]
[70]
Hsiao, C.C.; Rombouts, F.; Gijsen, H.J.M. New evolutions in the BACE1 inhibitor field from 2014 to 2018. Bioorg. Med. Chem. Lett., 2019, 29(6), 761-777.
[http://dx.doi.org/10.1016/j.bmcl.2018.12.049] [PMID: 30709653]
[71]
Bursavich, M.G.; Harrison, B.A.; Blain, J.F. Gamma secretase modulators: New Alzheimer’s drugs on the horizon? J. Med. Chem., 2016, 59(16), 7389-7409.
[http://dx.doi.org/10.1021/acs.jmedchem.5b01960] [PMID: 27007185]
[72]
Findeis, M.A.; Schroeder, F.; McKee, T.D.; Yager, D.; Fraering, P.C.; Creaser, S.P.; Austin, W.F.; Clardy, J.; Wang, R.; Selkoe, D.; Eckman, C.B. Discovery of a novel pharmacological and structural class of gamma secretase modulators derived from the extract of Actaea racemosa. ACS Chem. Neurosci., 2012, 3(11), 941-951.
[http://dx.doi.org/10.1021/cn3000857] [PMID: 23205187]
[73]
Pissarnitski, D. Advances in gamma-secretase modulation. Curr. Opin. Drug Discov. Devel., 2007, 10(4), 392-402.
[PMID: 17659480]
[74]
Gu, K.; Li, Q.; Lin, H.; Zhu, J.; Mo, J.; He, S.; Lu, X.; Jiang, X.; Sun, H. Gamma secretase inhibitors: A patent review (2013 - 2015). Expert Opin. Ther. Pat., 2017, 27(7), 851-866.
[http://dx.doi.org/10.1080/13543776.2017.1313231] [PMID: 28350212]
[75]
Gertsik, N. The interaction between gamma-secretase and its inhibitors and modulators-structural insights. Doctoral dissertation, Weill Medical College of Cornell University,
[76]
Wolfe, M.S. γ-Secretase as a target for Alzheimer’s disease. Adv. Pharmacol., 2012, 64, 127-153.
[http://dx.doi.org/10.1016/B978-0-12-394816-8.00004-0] [PMID: 22840746]
[77]
Sakamoto, K.; Matsuki, S.; Matsuguma, K.; Yoshihara, T.; Uchida, N.; Azuma, F.; Russell, M.; Hughes, G.; Haeberlein, S.B.; Alexander, R.C.; Eketjäll, S.; Kugler, A.R. BACE1 inhibitor lanabecestat (AZD3293) in a phase 1 study of healthy Japanese subjects: Pharmacokinetics and effects on plasma and cerebrospinal fluid Aβ peptides. J. Clin. Pharmacol., 2017, 57(11), 1460-1471.
[http://dx.doi.org/10.1002/jcph.950] [PMID: 28618005]
[78]
Ye, N.; Monk, S.A.; Daga, P.; Bender, D.M.; Rosen, L.B.; Mullen, J.; Minkwitz, M.C.; Kugler, A.R. Clinical bioavailability of the novel BACE1 inhibitor lanabecestat (AZD3293): Assessment of tablet formulations versus an oral solution and the impact of gastric pH on pharmacokinetics. Clin. Pharmacol. Drug Dev., 2018, 7(3), 233-243.
[http://dx.doi.org/10.1002/cpdd.422] [PMID: 29319935]
[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. A phase 3 trial of semagacestat for treatment of Alzheimer’s disease. N. Engl. J. Med., 2013, 369(4), 341-350.
[http://dx.doi.org/10.1056/NEJMoa1210951] [PMID: 23883379]
[80]
Henley, D.B.; May, P.C.; Dean, R.A.; Siemers, E.R. Development of semagacestat (LY450139), a functional γ-secretase inhibitor, for the treatment of Alzheimer’s disease. Expert Opin. Pharmacother., 2009, 10(10), 1657-1664.
[http://dx.doi.org/10.1517/14656560903044982] [PMID: 19527190]
[81]
Loeffler, DA Antibody-mediated clearance of brain amyloid-β: Mechanisms of action, effects of natural and monoclonal anti-aβ antibodies, and downstream effects. J Alzheimers Dis Rep, 2023, 7(1), 873-899.
[82]
Jung, M.; Lee, S.; Park, S.; Hong, J.; Kim, C.; Cho, I.; Sohn, H.S.; Kim, K.; Park, I.W.; Yoon, S.; Kwon, S.; Shin, J.; Lee, D.; Kang, M.; Go, S.; Moon, S.; Chung, Y.; Kim, Y.; Kim, B.S. A therapeutic nanovaccine that generates anti-amyloid antibodies and amyloid-specific regulatory T cells for alzheimer’s disease. Adv. Mater., 2023, 35(3), 2207719.
[http://dx.doi.org/10.1002/adma.202207719] [PMID: 36329674]
[83]
Cheng, Y.; Chen, C.; Zhang, F. Immunity orchestrates a bridge in gut-brain axis of neurodegenerative diseases. Ageing Res. Rev., 2023, 85, 101857.
[http://dx.doi.org/10.1016/j.arr.2023.101857] [PMID: 36669690]
[84]
Mason, H.D.; McGavern, D.B. How the immune system shapes neurodegenerative diseases. Trends Neurosci., 2022, 45(10), 733-748.
[http://dx.doi.org/10.1016/j.tins.2022.08.001] [PMID: 36075783]
[85]
Rego, S.; Sanchez, G.; Da Mesquita, S. Current views on meningeal lymphatics and immunity in aging and Alzheimer’s disease. Mol. Neurodegener., 2023, 18(1), 55.
[http://dx.doi.org/10.1186/s13024-023-00645-0] [PMID: 37580702]
[86]
Zieneldien, T.; Kim, J.; Sawmiller, D.; Cao, C. The immune system as a therapeutic target for Alzheimer’s disease. Life, 2022, 12(9), 1440.
[http://dx.doi.org/10.3390/life12091440] [PMID: 36143476]
[87]
Tousi, B.; Sabbagh, M.N. Editorial: A time of transition of alzheimer’s disease in the advent of anti-amyloid monoclonal antibodies. Neurol. Ther., 2021, 10(2), 409-413.
[http://dx.doi.org/10.1007/s40120-021-00286-9] [PMID: 34643892]
[88]
Imbimbo, B.P.; Watling, M. What have we learned from past failures of investigational drugs for Alzheimer’s disease? Expert Opin. Investig. Drugs, 2021, 30(12), 1175-1182.
[http://dx.doi.org/10.1080/13543784.2021.2017881] [PMID: 34890262]
[89]
Villa, P.G.; Perry, G. Lessons from anti amyloid-β immunotherapies in Alzheimer’s disease. In: Handbook of clinical neurology; Elsevier, 2023; 193, pp. 267-292.
[90]
Tatiparti, K.; Sau, S.; Rauf, M.A.; Iyer, A.K. Smart treatment strategies for alleviating tauopathy and neuroinflammation to improve clinical outcome in Alzheimer’s disease. Drug Discov. Today, 2020, 25(12), 2110-2129.
[http://dx.doi.org/10.1016/j.drudis.2020.09.025] [PMID: 33011341]
[91]
Harrison, C.H.; Sakai, K.; Johnston, D.A.; Holmes, C.; Boche, D.; Nicoll, J.A. Capillary angiopathy and aquaporin 4 after Aβ immunisation in Alzheimers disease–potential relevance to Amyloid–Related Imaging Abnormalities. medRxiv, 2022.
[92]
Nicoll, J.A.R.; Buckland, G.R.; Harrison, C.H.; Page, A.; Harris, S.; Love, S.; Neal, J.W.; Holmes, C.; Boche, D. Persistent neuropathological effects 14 years following amyloid-β immunization in Alzheimer’s disease. Brain, 2019, 142(7), 2113-2126.
[http://dx.doi.org/10.1093/brain/awz142] [PMID: 31157360]
[93]
Lin, P.; Sun, J.; Cheng, Q.; Yang, Y.; Cordato, D.; Gao, J. The development of pharmacological therapies for Alzheimer’s disease. Neurol. Ther., 2021, 10(2), 609-626.
[http://dx.doi.org/10.1007/s40120-021-00282-z] [PMID: 34532845]
[94]
Kim, J.; Jeon, H.; Yun Kim, H.; Kim, Y. Failure, success, and future direction of alzheimer drugs targeting amyloid-β cascade: Pros and cons of chemical and biological modalities. ChemBioChem, 2023, 24(19), e202300328.
[http://dx.doi.org/10.1002/cbic.202300328] [PMID: 37497809]
[95]
Nimmo, J.T.; Kelly, L.; Verma, A.; Carare, R.O.; Nicoll, J.A.R.; Dodart, J.C. Amyloid-β and α-synuclein immunotherapy: from experimental studies to clinical trials. Front. Neurosci., 2021, 15, 733857.
[http://dx.doi.org/10.3389/fnins.2021.733857] [PMID: 34539340]
[96]
Shukla, R.; Singh, A.; Handa, M.; Flora, S.J.S.; Kesharwani, P. Nanotechnological approaches for targeting amyloid-β aggregation with potential for neurodegenerative disease therapy and diagnosis. Drug Discov. Today, 2021, 26(8), 1972-1979.
[http://dx.doi.org/10.1016/j.drudis.2021.04.011] [PMID: 33892144]
[97]
Yu, H.J.; Dickson, S.P.; Wang, P.N.; Chiu, M.J.; Huang, C.C.; Chang, C.C.; Liu, H.; Hendrix, S.B.; Dodart, J.C.; Verma, A.; Wang, C.Y.; Cummings, J. Safety, tolerability, immunogenicity, and efficacy of UB-311 in participants with mild Alzheimer’s disease: A randomised, double-blind, placebo-controlled, phase 2a study. EBioMedicine, 2023, 94, 104665.
[http://dx.doi.org/10.1016/j.ebiom.2023.104665] [PMID: 37392597]
[98]
Haddad, H.W.; Malone, G.W.; Comardelle, N.J.; Degueure, A.E.; Kaye, A.M.; Kaye, A.D. Aducanumab, a novel anti-amyloid monoclonal antibody, for the treatment of Alzheimer’s disease: A comprehensive review. Health Psychol. Res., 2022, 10(1), 31925.
[http://dx.doi.org/10.52965/001c.31925] [PMID: 35928986]
[99]
Li, T.; Lu, L.; Pember, E.; Li, X.; Zhang, B.; Zhu, Z. New insights into neuroinflammation involved in pathogenic mechanism of Alzheimer’s disease and its potential for therapeutic intervention. Cells, 2022, 11(12), 1925.
[http://dx.doi.org/10.3390/cells11121925] [PMID: 35741054]
[100]
Song, N.; Sun, S.; Chen, K.; Wang, Y.; Wang, H.; Meng, J.; Guo, M.; Zhang, X.D.; Zhang, R. Emerging nanotechnology for Alzheimer’s disease: From detection to treatment. J. Control. Release, 2023, 360, 392-417.
[http://dx.doi.org/10.1016/j.jconrel.2023.07.004] [PMID: 37414222]
[101]
Hrubešová, K.; Fousková, M.; Habartová, L.; Fišar, Z.; Jirák, R.; Raboch, J.; Setnička, V. Search for biomarkers of Alzheimer’s disease: Recent insights, current challenges and future prospects. Clin. Biochem., 2019, 72, 39-51.
[http://dx.doi.org/10.1016/j.clinbiochem.2019.04.002] [PMID: 30953619]
[102]
Chopra, H.; Bibi, S.; Singh, I.; Kamal, M.A.; Islam, F.; Alhumaydhi, F.A.; Emran, T.B.; Cavalu, S. Nanomedicines in the management of Alzheimer’s disease: Current view and future prospects. Front. Aging Neurosci., 2022, 14, 879114.
[http://dx.doi.org/10.3389/fnagi.2022.879114] [PMID: 35875806]

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