Recent Updates in the Alzheimer’s Disease Etiopathology and Possible Treatment Approaches: A Narrative Review of Current Clinical Trials

Elahe       Zarini-Gakiye; Javad       Amini; Nima       Sanadgol; Gholamhassan       Vaezi; Kazem       Parivar
doi:10.2174/1874467213666200422090135
Abstract

Background: Alzheimer’s disease (AD) is the most frequent subtype of incurable neurodegenerative dementias and its etiopathology is still not clearly elucidated.
Objective: Outline the ongoing clinical trials (CTs) in the field of AD, in order to find novel master regulators.
Methods: We strictly reviewed all scientific reports from Clinicaltrials.gov and PubMed databases from January 2010 to January 2019. The search terms were “Alzheimer's disease” or “dementia” and “medicine” or “drug” or “treatment” and “clinical trials” and “interventions”. Manuscripts that met the objective of this study were included for further evaluations.
Results: Drug candidates have been categorized into two main groups including antibodies, peptides or hormones (such as Ponezumab, Interferon β-1a, Solanezumab, Filgrastim, Levemir, Apidra, and Estrogen), and naturally-derived ingredients or small molecules (such as Paracetamol, Ginkgo, Escitalopram, Simvastatin, Cilostazo, and Ritalin-SR). The majority of natural candidates acted as anti-inflammatory or/and anti-oxidant and antibodies exert their actions via increasing amyloid-beta (Aβ) clearance or decreasing Tau aggregation. Among small molecules, most of them that are present in the last phases act as specific antagonists (Suvorexant, Idalopirdine, Intepirdine, Trazodone, Carvedilol, and Risperidone) or agonists (Dextromethorphan, Resveratrol, Brexpiprazole) and frequently ameliorate cognitive dysfunctions.
Conclusion: The presences of a small number of candidates in the last phase suggest that a large number of candidates have had an undesirable side effect or were unable to pass essential eligibility for future phases. Among successful treatment approaches, clearance of Aβ, recovery of cognitive deficits, and control of acute neuroinflammation are widely chosen. It is predicted that some FDA-approved drugs, such as Paracetamol, Risperidone, Escitalopram, Simvastatin, Cilostazoand, and Ritalin-SR, could also be used in off-label ways for AD. This review improves our ability to recognize novel treatments for AD and suggests approaches for the clinical trial design for this devastating disease in the near future.
Keywords: Alzheimer's disease, clinical trials, dementia, drug interventions, hypothesis, methodology.
Graphical Abstract

[1] 
Henry, W.; Querfurth, H.W.; LaFerla, F.M. Mechanisms of disease Alzheimer’s disease. N. Engl. J. Med.,  2010, 362, 329-344.
[http://dx.doi.org/10.1056/NEJMra0909142] 
[2] 
Garre-Olmo, J. Epidemiology of Alzheimer’s disease and other dementias. Rev. Neurol.,  2018, 66(11), 377-386.
[3] 
Hebert, L.E.; Weuve, J.; Scherr, P.A.; Evans, D.A. Alzheimer disease in the United States (2010-2050) estimated using the 2010 census. Neurology,  2013, 80(19), 1778-1783.
[http://dx.doi.org/10.1212/WNL.0b013e31828726f5] [PMID: 23390181] 
[4] 
Gouras, G.K.; Tampellini, D.; Takahashi, R.H.; Capetillo-Zarate, E. Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease. Acta Neuropathol.,  2010, 119(5), 523-541.
[http://dx.doi.org/10.1007/s00401-010-0679-9] [PMID: 20354705] 
[5] 
Fish, P.V.; Steadman, D.; Bayle, E.D.; Whiting, P. New approaches for the treatment of Alzheimer’s disease. Bioorg. Med. Chem. Lett.,  2019, 29(2), 125-133.
[http://dx.doi.org/10.1016/j.bmcl.2018.11.034] [PMID: 30501965] 
[6] 
Moher, D.; Liberati, A.; Tetzlaff, J.; Altman, D.G. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.,  Ann. Intern. Med., ,  2009, 151(4), 264-269, W64.
[http://dx.doi.org/10.7326/0003-4819-151-4-200908180-00135] [PMID: 19622511] 
[7] 
Agosta, F.; Pievani, M.; Sala, S.; Geroldi, C.; Galluzzi, S.; Frisoni, G.B.; Filippi, M. White matter damage in Alzheimer disease and its relationship to gray matter atrophy. Radiology,  2011, 258(3), 853-863.
[http://dx.doi.org/10.1148/radiol.10101284] [PMID: 21177393] 
[8] 
Eimer, W.A.; Vassar, R. Neuron loss in the 5XFAD mouse model of Alzheimer’s disease correlates with intraneuronal Aβ42 accumulation and Caspase-3 activation. Mol. Neurodegener.,  2013, 8, 2.
[http://dx.doi.org/10.1186/1750-1326-8-2] [PMID: 23316765] 
[9] 
Charidimou, A.; Boulouis, G.; Gurol, M.E.; Ayata, C.; Bacskai, B.J.; Frosch, M.P.; Viswanathan, A.; Greenberg, S.M. Emerging concepts in sporadic cerebral amyloid angiopathy. Brain,  2017, 140(7), 1829-1850.
[http://dx.doi.org/10.1093/brain/awx047] [PMID: 28334869] 
[10] 
Galasko, D.; Montine, T.J. Biomarkers of oxidative damage and inflammation in Alzheimer’s disease. Biomarkers Med.,  2010, 4(1), 27-36.
[http://dx.doi.org/10.2217/bmm.09.89] [PMID: 20383271] 
[11] 
Valko, M.; Jomova, K.; Rhodes, C.J.; Kuča, K.; Musílek, K. Redox- and non-redox-metal-induced formation of free radicals and their role in human disease. Arch. Toxicol.,  2016, 90(1), 1-37.
[http://dx.doi.org/10.1007/s00204-015-1579-5] [PMID: 26343967] 
[12] 
Jang, H.; Arce, F.T.; Ramachandran, S.; Capone, R.; Azimova, R.; Kagan, B.L.; Nussinov, R.; Lal, R. Truncated β-amyloid peptide channels provide an alternative mechanism for Alzheimer’s Disease and Down syndrome. Proc. Natl. Acad. Sci. USA,  2010, 107(14), 6538-6543.
[http://dx.doi.org/10.1073/pnas.0914251107] [PMID: 20308552] 
[13] 
Choi, S.I.; Lee, B.; Woo, J.H.; Jeong, J.B.; Jun, I.; Kim, E.K. APP processing and metabolism in corneal fibroblasts and epithelium as a potential biomarker for Alzheimer’s disease. Exp. Eye Res.,  2019, 182, 167-174.
[http://dx.doi.org/10.1016/j.exer.2019.03.012] [PMID: 30930125] 
[14] 
Sheline, Y.I.; Raichle, M.E.; Snyder, A.Z.; Morris, J.C.; Head, D.; Wang, S.; Mintun, M.A. Amyloid plaques disrupt resting state default mode network connectivity in cognitively normal elderly. Biol. Psychiatry,  2010, 67(6), 584-587.
[http://dx.doi.org/10.1016/j.biopsych.2009.08.024] [PMID: 19833321] 
[15] 
Pham, J.D.; Chim, N.; Goulding, C.W.; Nowick, J.S. Structures of oligomers of a peptide from β-amyloid. J. Am. Chem. Soc.,  2013, 135(33), 12460-12467.
[http://dx.doi.org/10.1021/ja4068854] [PMID: 23927812] 
[16] 
Lu, J.X.; Qiang, W.; Yau, W.M.; Schwieters, C.D.; Meredith, S.C.; Tycko, R. Molecular structure of β-amyloid fibrils in Alzheimer’s disease brain tissue. Cell,  2013, 154(6), 1257-1268.
[http://dx.doi.org/10.1016/j.cell.2013.08.035] [PMID: 24034249] 
[17] 
Xiao, Y.; Ma, B.; McElheny, D.; Parthasarathy, S.; Long, F.; Hoshi, M.; Nussinov, R.; Ishii, Y. Aβ(1-42) fibril structure illuminates self-recognition and replication of amyloid in Alzheimer’s disease. Nat. Struct. Mol. Biol.,  2015, 22(6), 499-505.
[http://dx.doi.org/10.1038/nsmb.2991] [PMID: 25938662] 
[18] 
Benilova, I.; Karran, E.; De Strooper, B. The toxic Aβ oligomer and Alzheimer’s disease: an emperor in need of clothes. Nat. Neurosci.,  2012, 15(3), 349-357.
[http://dx.doi.org/10.1038/nn.3028] [PMID: 22286176] 
[19] 
Jin, M.; Shepardson, N.; Yang, T. 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.
[http://dx.doi.org/10.1073/pnas.1017033108] 
[20] 
Reed, M.N.; Hofmeister, J.J.; Jungbauer, L.; Welzel, A.T.; Yu, C.; Sherman, M.A.; Lesné, S.; LaDu, M.J.; Walsh, D.M.; Ashe, K.H.; Cleary, J.P. Cognitive effects of cell-derived and synthetically derived Aβ oligomers. Neurobiol. Aging,  2011, 32(10), 1784-1794.
[http://dx.doi.org/10.1016/j.neurobiolaging.2009.11.007] [PMID: 20031278] 
[21] 
Mura, E.; Lanni, C.; Preda, S.; Pistoia, F.; Sarà, M.; Racchi, M.; Schettini, G.; Marchi, M.; Govoni, S. β-amyloid: a disease target or a synaptic regulator affecting age-related neurotransmitter changes? Curr. Pharm. Des.,  2010, 16(6), 672-683.
[http://dx.doi.org/10.2174/138161210790883723] [PMID: 20388077] 
[22] 
Tan, C.C.; Yu, J.T.; Wang, H.F.; Tan, M.S.; Meng, X.F.; Wang, C.; Jiang, T.; Zhu, X.C.; Tan, L. Efficacy and safety of donepezil, galantamine, rivastigmine, and memantine for the treatment of Alzheimer’s disease: a systematic review and meta-analysis. J. Alzheimers Dis.,  2014, 41(2), 615-631.
[http://dx.doi.org/10.3233/JAD-132690] [PMID: 24662102] 
[23] 
Schneider, L.S.; Mangialasche, F.; Andreasen, N.; Feldman, H.; Giacobini, E.; Jones, R.; Mantua, V.; Mecocci, P.; Pani, L.; Winblad, B.; Kivipelto, M. Clinical trials and late-stage drug development for Alzheimer’s disease: an appraisal from 1984 to 2014. J. Intern. Med.,  2014, 275(3), 251-283.
[http://dx.doi.org/10.1111/joim.12191] [PMID: 24605808] 
[24] 
Shen, H.; Kihara, T.; Hongo, H.; Wu, X.; Kem, W.R.; Shimohama, S.; Akaike, A.; Niidome, T.; Sugimoto, H. Neuroprotection by donepezil against glutamate excitotoxicity involves stimulation of α7 nicotinic receptors and internalization of NMDA receptors. Br. J. Pharmacol.,  2010, 161(1), 127-139.
[http://dx.doi.org/10.1111/j.1476-5381.2010.00894.x] [PMID: 20718745] 
[25] 
Boeddrich, A.; Babila, J.T.; Wiglenda, T. The anti-amyloid compound DO1 decreases plaque pathology and neuroinflammation-related expression changes in 5xFAD transgenic mice. Cell Chem. Biol., 2018.
[26] 
Mullard, A. Pharma pumps up anti-tau Alzheimer pipeline despite first Phase III failure. Nat. Rev. Drug Discov.,  2016, 15(9), 591-592.
[http://dx.doi.org/10.1038/nrd.2016.176] [PMID: 27573221] 
[27] 
Polidori, M.C.; Nelles, G. Antioxidant clinical trials in mild cognitive impairment and Alzheimer’s disease - challenges and perspectives. Curr. Pharm. Des.,  2014, 20(18), 3083-3092.
[http://dx.doi.org/10.2174/13816128113196660706] [PMID: 24079767] 
[28] 
Tobore, T.O. On the central role of mitochondria dysfunction and oxidative stress in Alzheimer’s disease. Neurol. Sci.,  2019, 40(8), 1527-1540.
[http://dx.doi.org/10.1007/s10072-019-03863-x] [PMID: 30982132] 
[29] 
Shahpasand, K.; Uemura, I.; Saito, T.; Asano, T.; Hata, K.; Shibata, K.; Toyoshima, Y.; Hasegawa, M.; Hisanaga, S. Regulation of mitochondrial transport and inter-microtubule spacing by tau phosphorylation at the sites hyperphosphorylated in Alzheimer’s disease. J. Neurosci.,  2012, 32(7), 2430-2441.
[http://dx.doi.org/10.1523/JNEUROSCI.5927-11.2012] [PMID: 22396417] 
[30] 
Iqbal, K.; Liu, F.; Gong, C.X.; Grundke-Iqbal, I. Tau in Alzheimer disease and related tauopathies. Curr. Alzheimer Res.,  2010, 7(8), 656-664.
[http://dx.doi.org/10.2174/156720510793611592] [PMID: 20678074] 
[31] 
Gulisano, W.; Maugeri, D.; Baltrons, M.A.; Fà, M.; Amato, A.; Palmeri, A.; D’Adamio, L.; Grassi, C.; Devanand, D.P.; Honig, L.S.; Puzzo, D.; Arancio, O. Role of Amyloid-β and Tau Proteins in Alzheimer’s Disease: Confuting the Amyloid Cascade. J. Alzheimers Dis.,  2018, 64(s1), S611-S631.
[http://dx.doi.org/10.3233/JAD-179935] [PMID: 29865055] 
[32] 
Santa-Maria, I; Varghese, M; Ksiezak-Reding, H Paired helical filaments from Alzheimer's disease brain induce intracellular accumulation of tau in aggresomes.,  J. Biol. Chem.,  2012, jbc-M111.
[33] 
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.
[34] 
Verghese, P.B.; Castellano, J.M.; Holtzman, D.M. Apolipoprotein E in Alzheimer’s disease and other neurological disorders. Lancet Neurol.,  2011, 10(3), 241-252.
[http://dx.doi.org/10.1016/S1474-4422(10)70325-2] [PMID: 21349439] 
[35] 
Lane-Donovan, C.; Herz, J. ApoE, ApoE receptors, and the synapse in Alzheimer’s disease. Trends Endocrinol. Metab.,  2017, 28(4), 273-284.
[http://dx.doi.org/10.1016/j.tem.2016.12.001] [PMID: 28057414] 
[36] 
Huynh, T.P.; Davis, A.A.; Ulrich, J.D. Apolipoprotein E and Alzheimer Disease: The influence of apoE on amyloid-β and other amyloidogenic proteins. J. Lipid Res.,  2017, 
R075481.
[37] 
Janota, C.; Lemere, C.A.; Brito, M.A. Dissecting the contribution of vascular alterations and aging to Alzheimer’s disease. Mol. Neurobiol.,  2016, 53(6), 3793-3811.
[http://dx.doi.org/10.1007/s12035-015-9319-7] [PMID: 26143259] 
[38] 
Liu, C.C.; Liu, C.C.; Kanekiyo, T.; Xu, H.; Bu, G. Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat. Rev. Neurol.,  2013, 9(2), 106-118.
[http://dx.doi.org/10.1038/nrneurol.2012.263] [PMID: 23296339] 
[39] 
Zhao, J; Fu, Y; Liu, CC Retinoic acid isomers facilitate apolipoprotein E production and lipidation in astrocytes through the RXR/RAR pathway. J. Biol. Chem.,  2014, jbc-M113.
[40] 
Tai, L.M.; Thomas, R.; Marottoli, F.M.; Koster, K.P.; Kanekiyo, T.; Morris, A.W.; Bu, G. The role of APOE in cerebrovascular dysfunction. Acta Neuropathol.,  2016, 131(5), 709-723.
[http://dx.doi.org/10.1007/s00401-016-1547-z] [PMID: 26884068] 
[41] 
Carmona, S.; Zahs, K.; Wu, E.; Dakin, K.; Bras, J.; Guerreiro, R. The role of TREM2 in Alzheimer’s disease and other neurodegenerative disorders. Lancet Neurol.,  2018, 17(8), 721-730.
[http://dx.doi.org/10.1016/S1474-4422(18)30232-1] [PMID: 30033062] 
[42] 
Grimm, A.; Eckert, A. Brain aging and neurodegeneration: from a mitochondrial point of view. J. Neurochem.,  2017, 143(4), 418-431.
[http://dx.doi.org/10.1111/jnc.14037] [PMID: 28397282] 
[43] 
Elfawy, H.A.; Das, B. Crosstalk between mitochondrial dysfunction, oxidative stress, and age-related neurodegenerative disease: etiologies and therapeutic strategies. Life Sci., 2018.
[44] 
Cai, Z.; Hussain, M.D.; Yan, L.J. Microglia, neuroinflammation, and beta-amyloid protein in Alzheimer’s disease. Int. J. Neurosci.,  2014, 124(5), 307-321.
[http://dx.doi.org/10.3109/00207454.2013.833510] [PMID: 23930978] 
[45] 
Yuste, J.E.; Tarragon, E.; Campuzano, C.M.; Ros-Bernal, F. Implications of glial nitric oxide in neurodegenerative diseases. Front. Cell. Neurosci.,  2015, 9, 322.
[http://dx.doi.org/10.3389/fncel.2015.00322] [PMID: 26347610] 
[46] 
Tramutola, A.; Lanzillotta, C.; Perluigi, M.; Butterfield, D.A. Oxidative stress, protein modification and Alzheimer disease. Brain Res. Bull.,  2017, 133, 88-96.
[http://dx.doi.org/10.1016/j.brainresbull.2016.06.005] [PMID: 27316747] 
[47] 
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.
[http://dx.doi.org/10.1016/j.redox.2017.10.014] [PMID: 29080524] 
[48] 
Bhat, A.H.; Dar, K.B.; Anees, S.; Zargar, M.A.; Masood, A.; Sofi, M.A.; Ganie, S.A. Oxidative stress, mitochondrial dysfunction and neurodegenerative diseases; a mechanistic insight. Biomed. Pharmacother.,  2015, 74, 101-110.
[http://dx.doi.org/10.1016/j.biopha.2015.07.025] [PMID: 26349970] 
[49] 
Santos, R.X.; Correia, S.C.; Zhu, X.; Smith, M.A.; Moreira, P.I.; Castellani, R.J.; Nunomura, A.; Perry, G. Mitochondrial DNA oxidative damage and repair in aging and Alzheimer’s disease. Antioxid. Redox Signal.,  2013, 18(18), 2444-2457.
[http://dx.doi.org/10.1089/ars.2012.5039] [PMID: 23216311] 
[50] 
Eckert, S.H.; Gaca, J.; Kolesova, N.; Friedland, K.; Eckert, G.P.; Muller, W.E. Mitochondrial pharmacology of dimebon (latrepirdine) calls for a new look at its possible therapeutic potential in Alzheimer’s disease. Aging Dis.,  2018, 9(4), 729-744.
[http://dx.doi.org/10.14336/AD.2017.1014] [PMID: 30090660] 
[51] 
Ozben, T.; Ozben, S. Neuro-inflammation and anti-inflammatory treatment options for Alzheimer’s disease. Clin. Biochem.,  2019, 72, 87-89.
[http://dx.doi.org/10.1016/j.clinbiochem.2019.04.001] [PMID: 30954437] 
[52] 
Bhaskar, K.; Maphis, N.; Xu, G.; Varvel, N.H.; Kokiko-Cochran, O.N.; Weick, J.P.; Staugaitis, S.M.; Cardona, A.; Ransohoff, R.M.; Herrup, K.; Lamb, B.T. Microglial derived tumor necrosis factor-α drives Alzheimer’s disease-related neuronal cell cycle events. Neurobiol. Dis.,  2014, 62, 273-285.
[http://dx.doi.org/10.1016/j.nbd.2013.10.007] [PMID: 24141019] 
[53] 
Doens, D.; Fernández, P.L. Microglia receptors and their implications in the response to amyloid β for Alzheimer’s disease pathogenesis. J. Neuroinflammation,  2014, 11(1), 48.
[http://dx.doi.org/10.1186/1742-2094-11-48] [PMID: 24625061] 
[54] 
Henstridge, C.M.; Hyman, B.T.; Spires-Jones, T.L. Beyond the neuron-cellular interactions early in Alzheimer disease pathogenesis. Nat. Rev. Neurosci.,  2019, 20(2), 94-108.
[http://dx.doi.org/10.1038/s41583-018-0113-1] [PMID: 30643230] 
[55] 
Siddiqui, SS; Springer, SA; Verhagen, A The Alzheimer's Disease-protective CD33 splice variant mediates adaptive loss of function via diversion to an intracellular pool. J Biol Chem.,  2017, jbc-M117.
[56] 
Patil, P.O.; Bari, S.B.; Firke, S.D.; Deshmukh, P.K.; Donda, S.T.; Patil, D.A. A comprehensive review on synthesis and designing aspects of coumarin derivatives as monoamine oxidase inhibitors for depression and Alzheimer’s disease. Bioorg. Med. Chem.,  2013, 21(9), 2434-2450.
[http://dx.doi.org/10.1016/j.bmc.2013.02.017] [PMID: 23517722] 
[57] 
Gandhi, S.; Abramov, A.Y. Mechanism of oxidative stress in neurodegeneration. Oxid. Med. Cell. Longev, 2012.
[http://dx.doi.org/10.1155/2012/428010] 
[58] 
Cai, Z. Monoamine oxidase inhibitors: promising therapeutic agents for Alzheimer’s disease. Mol. Med. Rep.,  2014, 9(5), 1533-1541.
[http://dx.doi.org/10.3892/mmr.2014.2040] [PMID: 24626484] 
[59] 
Youdim, M.B.H. Monoamine oxidase inhibitors, and iron chelators in depressive illness and neurodegenerative diseases. J. Neural Transm. (Vienna),  2018, 125(11), 1719-1733.
[http://dx.doi.org/10.1007/s00702-018-1942-9] [PMID: 30341696] 
[60] 
Korábečný, J.; Nepovimová, E.; Cikánková, T. Newly developed drugs for Alzheimer’s disease in relation to energy metabolism, cholinergic and monoaminergic neurotransmission. Neuroscience, 2017.
[61] 
Ando, K.; Laborde, Q.; Lazar, A.; Godefroy, D.; Youssef, I.; Amar, M.; Pooler, A.; Potier, M.C.; Delatour, B.; Duyckaerts, C. Inside Alzheimer brain with CLARITY: senile plaques, neurofibrillary tangles and axons in 3-D. Acta Neuropathol.,  2014, 128(3), 457-459.
[http://dx.doi.org/10.1007/s00401-014-1322-y] [PMID: 25069432] 
[62] 
Godyń, J.; Jończyk, J.; Panek, D.; Malawska, B. Therapeutic strategies for Alzheimer’s disease in clinical trials. Pharmacol. Rep.,  2016, 68(1), 127-138.
[http://dx.doi.org/10.1016/j.pharep.2015.07.006] [PMID: 26721364] 
[63] 
Liu-Seifert, H.; Siemers, E.; Holdridge, K.C.; Andersen, S.W.; Lipkovich, I.; Carlson, C.; Sethuraman, G.; Hoog, S.; Hayduk, R.; Doody, R.; Aisen, P. Delayed-start analysis: Mild Alzheimer’s disease patients in solanezumab trials, 3.5 years. Alzheimers Dement. (N. Y.),  2015, 1(2), 111-121.
[http://dx.doi.org/10.1016/j.trci.2015.06.006] [PMID: 29854931] 
[64] 
Kobayashi, H.; Ohnishi, T.; Nakagawa, R.; Yoshizawa, K. The comparative efficacy and safety of cholinesterase inhibitors in patients with mild-to-moderate Alzheimer’s disease: a Bayesian network meta-analysis. Int. J. Geriatr. Psychiatry,  2016, 31(8), 892-904.
[http://dx.doi.org/10.1002/gps.4405] [PMID: 26680338] 
[65] 
Peauger, L.; Azzouz, R.; Gembus, V.; Ţînţaş, M.L.; Sopková-de Oliveira Santos, J.; Bohn, P.; Papamicaël, C.; Levacher, V. 
                        Donepezil-based central acetylcholinesterase inhibitors by means of a “bio-oxidizable” prodrug strategy: design, synthesis, and 
                        
                           in vitro
                        
                        biological evaluation.
                     J. Med. Chem.,  2017, 60(13), 5909-5926.
[http://dx.doi.org/10.1021/acs.jmedchem.7b00702] [PMID: 28613859] 
[66] 
Ben Halima, S.; Mishra, S.; Raja, K.M.P.; Willem, M.; Baici, A.; Simons, K.; Brüstle, O.; Koch, P.; Haass, C.; Caflisch, A.; Rajendran, L. Specific inhibition of β-secretase processing of the Alzheimer disease amyloid precursor protein. Cell Rep.,  2016, 14(9), 2127-2141.
[http://dx.doi.org/10.1016/j.celrep.2016.01.076] [PMID: 26923602] 
[67] 
Yan, R.; Vassar, R. Targeting the β secretase BACE1 for Alzheimer’s disease therapy. Lancet Neurol.,  2014, 13(3), 319-329.
[http://dx.doi.org/10.1016/S1474-4422(13)70276-X] [PMID: 24556009] 
[68] 
Yuan, J.; Venkatraman, S.; Zheng, Y.; McKeever, B.M.; Dillard, L.W.; Singh, S.B. Structure-based design of β-site APP cleaving enzyme 1 (BACE1) inhibitors for the treatment of Alzheimer’s disease. J. Med. Chem.,  2013, 56(11), 4156-4180.
[http://dx.doi.org/10.1021/jm301659n] [PMID: 23509904] 
[69] 
Hung, S.Y.; Fu, W.M. Drug candidates in clinical trials for Alzheimer’s disease. J. Biomed. Sci.,  2017, 24(1), 47.
[http://dx.doi.org/10.1186/s12929-017-0355-7] [PMID: 28720101] 
[70] 
Lladó, J.; Esteban, S.; García-Sevilla, J.A. 
                        The α 2-adrenoceptor antagonist idazoxan is an agonist at 5-HT1A autoreceptors modulating serotonin synthesis in the rat brain 
                        
                           in vivo.
                         Neurosci. Lett.,  1996, 218(2), 111-114.
[http://dx.doi.org/10.1016/S0304-3940(96)13132-3] [PMID: 8945740] 
[71] 
Shen, J.; Yang, X.C.; Yu, M.C.; Xiao, L.; Zhang, X.J.; Sun, H.J.; Chen, H.; Pan, G.X.; Yan, Y.R.; Wang, S.C.; Li, W.; Zhou, L.; Xie, Q.; Yu, L.Q.; Wang, Y.H.; Shao, L.M. Discovery, synthesis, biological evaluation and structure-based optimization of novel piperidine derivatives as acetylcholine-binding protein ligands. Acta Pharmacol. Sin.,  2017, 38(1), 146-155.
[http://dx.doi.org/10.1038/aps.2016.124] [PMID: 27917874] 
[72] 
Froestl, W.; Muhs, A.; Pfeifer, A. Cognitive enhancers (Nootropics). Part 1: drugs interacting with receptors. Update 2014. J. Alzheimers Dis.,  2014, 41(4), 961-1019.
[http://dx.doi.org/10.3233/JAD-140228] [PMID: 24898652] 
[73] 
Bachurin, S.O.; Bovina, E.V.; Ustyugov, A.A. Drugs in clinical trials for Alzheimer’s disease: the major trends. Med. Res. Rev.,  2017, 37(5), 1186-1225.
[http://dx.doi.org/10.1002/med.21434] [PMID: 28084618] 
[74] 
Liu, P.P.; Xie, Y.; Meng, X.Y.; Kang, J.S. History and progress of hypotheses and clinical trials for Alzheimer’s disease. Signal Transduct. Target. Ther.,  2019, 4, 29.
[http://dx.doi.org/10.1038/s41392-019-0063-8] [PMID: 31637009] 
[75] 
Delnomdedieu, M.; Duvvuri, S.; Li, D.J.; Atassi, N.; Lu, M.; Brashear, H.R.; Liu, E.; Ness, S.; Kupiec, J.W. First-In-Human safety and long-term exposure data for AAB-003 (PF-05236812) and biomarkers after intravenous infusions of escalating doses in patients with mild to moderate Alzheimer’s disease. Alzheimers Res. Ther.,  2016, 8(1), 12.
[http://dx.doi.org/10.1186/s13195-016-0177-y] [PMID: 26925577] 
[76] 
Sevigny, J.; Chiao, P.; Williams, L. Aducanumab (BIIB037), an anti-amyloid beta monoclonal antibody, in patients with prodromal or mild Alzheimer’s disease: Interim results of a randomized, double-blind, placebo-controlled, phase 1b study. Alzheimers Dement.,  2015, 11(7), 277.
[http://dx.doi.org/10.1016/j.jalz.2015.07.367] 
[77] 
Lacosta, A.M.; Pascual-Lucas, M.; Pesini, P.; Casabona, D.; Pérez-Grijalba, V.; Marcos-Campos, I.; Sarasa, L.; Canudas, J.; Badi, H.; Monleón, I.; San-José, I.; Munuera, J.; Rodríguez-Gómez, O.; Abdelnour, C.; Lafuente, A.; Buendía, M.; Boada, M.; Tárraga, L.; Ruiz, A.; Sarasa, M. Safety, tolerability and immunogenicity of an active anti-Aβ40 vaccine (ABvac40) in patients with Alzheimer’s disease: a randomised, double-blind, placebo-controlled, phase I trial. Alzheimers Res. Ther.,  2018, 10(1), 12.
[http://dx.doi.org/10.1186/s13195-018-0340-8] [PMID: 29378651] 
[78] 
Leyhe, T.; Andreasen, N.; Simeoni, M.; Reich, A.; von Arnim, C.A.; Tong, X.; Yeo, A.; Khan, S.; Loercher, A.; Chalker, M.; Hottenstein, C.; Zetterberg, H.; Hilpert, J.; Mistry, P. Modulation of β-amyloid by a single dose of GSK933776 in patients with mild Alzheimer’s disease: a phase I study. Alzheimers Res. Ther.,  2014, 6(2), 19.
[http://dx.doi.org/10.1186/alzrt249] [PMID: 24716469] 
[79] 
Novak, P.; Schmidt, R.; Kontsekova, E.; Zilka, N.; Kovacech, B.; Skrabana, R.; Vince-Kazmerova, Z.; Katina, S.; Fialova, L.; Prcina, M.; Parrak, V.; Dal-Bianco, P.; Brunner, M.; Staffen, W.; Rainer, M.; Ondrus, M.; Ropele, S.; Smisek, M.; Sivak, R.; Winblad, B.; Novak, M. Safety and immunogenicity of the tau vaccine AADvac1 in patients with Alzheimer’s disease: a randomised, double-blind, placebo-controlled, phase 1 trial. Lancet Neurol.,  2017, 16(2), 123-134.
[http://dx.doi.org/10.1016/S1474-4422(16)30331-3] [PMID: 27955995] 
[80] 
Pomara, N.; Bruno, D.; Sidtis, J.J.; Lutz, M.W.; Greenblatt, D.J.; Saunders, A.M.; Roses, A.D. Translocase of outer mitochondrial membrane 40 homolog (TOMM40) poly-T length modulates lorazepam-related cognitive toxicity in healthy APOE ε4-negative elderly. J. Clin. Psychopharmacol.,  2011, 31(4), 544-546.
[http://dx.doi.org/10.1097/JCP.0b013e318222810e] [PMID: 21720235] 
[81] 
Egan, M.F.; Kost, J.; Voss, T.; Mukai, Y.; Aisen, P.S.; Cummings, J.L.; Tariot, P.N.; Vellas, B.; van Dyck, C.H.; Boada, M.; Zhang, Y.; Li, W.; Furtek, C.; Mahoney, E.; Harper Mozley, L.; Mo, Y.; Sur, C.; Michelson, D. Randomized Trial of Verubecestat for Prodromal Alzheimer’s Disease. N. Engl. J. Med.,  2019, 380(15), 1408-1420.
[http://dx.doi.org/10.1056/NEJMoa1812840] [PMID: 30970186] 
[82] 
O’Neill, B.T.; Beck, E.M.; Butler, C.R.; Nolan, C.E.; Gonzales, C.; Zhang, L.; Doran, S.D.; Lapham, K.; Buzon, L.M.; Dutra, J.K.; Barreiro, G.; Hou, X.; Martinez-Alsina, L.A.; Rogers, B.N.; Villalobos, A.; Murray, J.C.; Ogilvie, K.; LaChapelle, E.A.; Chang, C.; Lanyon, L.F.; Steppan, C.M.; Robshaw, A.; Hales, K.; Boucher, G.G.; Pandher, K.; Houle, C.; Ambroise, C.W.; Karanian, D.; Riddell, D.; Bales, K.R.; Brodney, M.A. Design and Synthesis of Clinical Candidate PF-06751979: A Potent, Brain Penetrant, β-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Inhibitor Lacking Hypopigmentation. J. Med. Chem.,  2018, 61(10), 4476-4504.
[http://dx.doi.org/10.1021/acs.jmedchem.8b00246] [PMID: 29613789] 
[83] 
Willis, B.; Martenyi, F.; Dean, R. Central BACE1 inhibition by LY2886721 produces opposing effects on APP processing as reflected by cerebrospinal fluid sAPPalpha and sAPPbeta. Alzheimers Dement.,  2012, 8(4), 582.
[http://dx.doi.org/10.1016/j.jalz.2012.05.1584] 
[84] 
May, P.; Boggs, L.; Brier, R. Preclinical characterization of LY2886721: A BACE1 inhibitor in clinical development for early Alzheimer’s disease. Alzheimers Dement.,  2012, 8(4), 95.
[http://dx.doi.org/10.1016/j.jalz.2012.05.235] 
[85] 
Blennow, K.; Nikolcheva, T.; Lasser, R.A. Gantenerumab treatment reduces biomarkers of neuronal and synaptic degeneration in Alzheimer’s disease. Alzheimers Dement.,  2016, 12(7), 198.
[http://dx.doi.org/10.1016/j.jalz.2016.06.346] 
[86] 
Galimberti, D.; Scarpini, E. Idalopirdine as a treatment for Alzheimer’s disease. Expert Opin. Investig. Drugs,  2015, 24(7), 981-987.
[http://dx.doi.org/10.1517/13543784.2015.1052402] [PMID: 26022777] 
[87] 
Berger, M.; Nadler, J.W.; Friedman, A.; McDonagh, D.L.; Bennett, E.R.; Cooter, M.; Qi, W.; Laskowitz, D.T.; Ponnusamy, V.; Newman, M.F.; Shaw, L.M.; Warner, D.S.; Mathew, J.P.; James, M.L. The effect of propofol versus isoflurane anesthesia on human cerebrospinal fluid markers of Alzheimer’s disease: results of a randomized trial. J. Alzheimers Dis.,  2016, 52(4), 1299-1310.
[http://dx.doi.org/10.3233/JAD-151190] [PMID: 27079717] 
[88] 
Irwin, R.W.; Wang, J.M.; Chen, S.; Brinton, R.D. Neuroregenerative mechanisms of allopregnanolone in Alzheimer’s disease. Front. Endocrinol. (Lausanne),  2012, 2, 117.
[http://dx.doi.org/10.3389/fendo.2011.00117] [PMID: 22654847] 
[89] 
Singhrao, S.K.; Olsen, I. 
                      Assessing the role of 
                        Porphyromonas gingivalis
                         in periodontitis to determine a causative relationship with Alzheimer’s disease.
                     J. Oral Microbiol.,  2019, 11(1), 
1563405.
[http://dx.doi.org/10.1080/20002297.2018.1563405] [PMID: 30728914] 
[90] 
Raven, F.; Ward, J.F.; Zoltowska, K.M.; Wan, Y.; Bylykbashi, E.; Miller, S.J.; Shen, X.; Choi, S.H.; Rynearson, K.D.; Berezovska, O.; Wagner, S.L.; Tanzi, R.E.; Zhang, C. Soluble Gamma-secretase Modulators Attenuate Alzheimer’s β-amyloid Pathology and Induce Conformational Changes in Presenilin 1. EBioMedicine,  2017, 24, 93-101.
[http://dx.doi.org/10.1016/j.ebiom.2017.08.028] [PMID: 28919280] 
[91] 
Kounnas, M.Z.; Lane-Donovan, C.; Nowakowski, D.W. NGP 555, a g-secretase modulator, lowers the amyloid biomarker, Ab42, in cerebrospinal fluid while preventing Alzheimer’s disease cognitive decline in rodents. Alzheimers Dement.,  2016, 10.
[92] 
Campos, F.; Sobrino, T.; Ramos-Cabrer, P.; Castillo, J. Oxaloacetate: a novel neuroprotective for acute ischemic stroke. Int. J. Biochem. Cell Biol.,  2012, 44(2), 262-265.
[http://dx.doi.org/10.1016/j.biocel.2011.11.003] [PMID: 22085530] 
[93] 
Wang, S.; Yang, H.; Yu, L.; Jin, J.; Qian, L.; Zhao, H.; Xu, Y.; Zhu, X. Oridonin attenuates Aβ1-42-induced neuroinflammation and inhibits NF-κB pathway. PLoS One,  2014, 9(8), 
e104745.
[http://dx.doi.org/10.1371/journal.pone.0104745] [PMID: 25121593] 
[94] 
Sheerin, M.; Adejare, A. Alzheimer’s Disease Drugs in Clinical Trials. In: Drug Discovery Approaches for the Treatment of Neurodegenerative Disorders; , 2017; pp. 249-265.
[http://dx.doi.org/10.1016/B978-0-12-802810-0.00013-1] 
[95] 
Barten, D.M.; Fanara, P.; Andorfer, C.; Hoque, N.; Wong, P.Y.; Husted, K.H.; Cadelina, G.W.; Decarr, L.B.; Yang, L.; Liu, V.; Fessler, C.; Protassio, J.; Riff, T.; Turner, H.; Janus, C.G.; Sankaranarayanan, S.; Polson, C.; Meredith, J.E.; Gray, G.; Hanna, A.; Olson, R.E.; Kim, S.H.; Vite, G.D.; Lee, F.Y.; Albright, C.F. Hyperdynamic microtubules, cognitive deficits, and pathology are improved in tau transgenic mice with low doses of the microtubule-stabilizing agent BMS-241027. J. Neurosci.,  2012, 32(21), 7137-7145.
[http://dx.doi.org/10.1523/JNEUROSCI.0188-12.2012] [PMID: 22623658] 
[96] 
Brunden, K.R.; Zhang, B.; Carroll, J.; Yao, Y.; Potuzak, J.S.; Hogan, A.M.; Iba, M.; James, M.J.; Xie, S.X.; Ballatore, C.; Smith, A.B., III; Lee, V.M.; Trojanowski, J.Q. Epothilone D improves microtubule density, axonal integrity, and cognition in a transgenic mouse model of tauopathy. J. Neurosci.,  2010, 30(41), 13861-13866.
[http://dx.doi.org/10.1523/JNEUROSCI.3059-10.2010] [PMID: 20943926] 
[97] 
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.
[http://dx.doi.org/10.1016/j.bmc.2015.04.009] [PMID: 25934229] 
[98] 
Dennis, S.H.; Pasqui, F.; Colvin, E.M.; Sanger, H.; Mogg, A.J.; Felder, C.C.; Broad, L.M.; Fitzjohn, S.M.; Isaac, J.T.; Mellor, J.R. Activation of Muscarinic M1 Acetylcholine Receptors Induces Long-Term Potentiation in the Hippocampus. Cereb. Cortex,  2016, 26(1), 414-426.
[http://dx.doi.org/10.1093/cercor/bhv227] [PMID: 26472558] 
[99] 
Gulati, A.; Hornick, M.G.; Briyal, S.; Lavhale, M.S. A novel neuroregenerative approach using ET(B) receptor agonist, IRL-1620, to treat CNS disorders. Physiol. Res.,  2018, 67(Suppl. 1), S95-S113.
[http://dx.doi.org/10.33549/physiolres.933859] [PMID: 29947531] 
[100] 
Philippidis, A. Unlucky 13: Top Clinical Trial Failures of 2018: Biopharmas pursue costly studies despite low success rates. Genet. Eng. Biotechnol. News,  2019, 39(3), 14-16.
[http://dx.doi.org/10.1089/gen.39.03.05] 
[101] 
Golding, J.F.; Wesnes, K.A.; Leaker, B.R. The effects of the selective muscarinic M3 receptor antagonist darifenacin, and of hyoscine (scopolamine), on motion sickness, skin conductance & cognitive function. Br. J. Clin. Pharmacol.,  2018, 84(7), 1535-1543.
[http://dx.doi.org/10.1111/bcp.13579] [PMID: 29522648] 
[102] 
Bajo, R.; Pusil, S.; López, M.E.; Canuet, L.; Pereda, E.; Osipova, D.; Maestú, F.; Pekkonen, E. Scopolamine effects on functional brain connectivity: a pharmacological model of Alzheimer’s disease. Sci. Rep.,  2015, 5, 9748.
[http://dx.doi.org/10.1038/srep09748] [PMID: 26130273] 
[103] 
Chau, S.A.; Liu, C.S.; Ruthirakuhan, M. Pharmacotherapy of dementia; Mental Health and Illness of the Elderly, 2017, pp. 1-26.
[104] 
Santiago, A.; Soares, L.M.; Schepers, M.; Milani, H.; Vanmierlo, T.; Prickaerts, J.; Weffort de Oliveira, R.M. Roflumilast promotes memory recovery and attenuates white matter injury in aged rats subjected to chronic cerebral hypoperfusion. Neuropharmacology,  2018, 138, 360-370.
[http://dx.doi.org/10.1016/j.neuropharm.2018.06.019] [PMID: 29933009] 
[105] 
Thappali, S.R.; Varanasi, K.V.; Veeraraghavan, S.; Vakkalanka, S.K.; Mukkanti, K. Simultaneous quantitation of IC87114, roflumilast and its active metabolite roflumilast N-oxide in plasma by LC-MS/MS: application for a pharmacokinetic study. J. Mass Spectrom.,  2012, 47(12), 1612-1619.
[http://dx.doi.org/10.1002/jms.3103] [PMID: 23280750] 
[106] 
Xu, Y; Yang, M; Zhang, HT A selective phosphodiesterase 4D inhibitor BPN14770 reverses beta amyloid-induced memory impairment in humanized PDE4D mice. FASEB J,  2019, 33(1_supplement), 806-4.
[107] 
Zhang, C.; Xu, Y.; Chowdhary, A.; Fox, D., III; Gurney, M.E.; Zhang, H.T.; Auerbach, B.D.; Salvi, R.J.; Yang, M.; Li, G.; O’Donnell, J.M. Memory enhancing effects of BPN14770, an allosteric inhibitor of phosphodiesterase-4D, in wild-type and humanized mice. Neuropsychopharmacology,  2018, 43(11), 2299-2309.
[http://dx.doi.org/10.1038/s41386-018-0178-6] [PMID: 30131563] 
[108] 
Alexander, R.; Budd, S.; Russell, M. AZD3293 A novel BACE1 inhibitor: Safety, tolerability, and effects on plasma and CSF aβ peptides following single-and multiple-dose administration. Neurobiol. Aging,  2014, (35), S2.
[http://dx.doi.org/10.1016/j.neurobiolaging.2014.01.033] 
[109] 
Zhou, B; Rothlein, R; Shen, J.  TTP4000, a soluble fusion protein inhibitor of Receptor for Advanced Glycation End Products (RAGE) is an effective therapy in animal models of Alzheimer’s disease, 2013, pp. 803-1.
[110] 
O’Neill, B.V.; Dodds, C.M.; Miller, S.R.; Gupta, A.; Lawrence, P.; Bullman, J.; Chen, C.; Dewit, O.; Kumar, S.; Dustagheer, M.; Price, J.; Shabbir, S.; Nathan, P.J. The effects of GSK2981710, a medium-chain triglyceride, on cognitive function in healthy older participants: A randomised, placebo-controlled study. Hum. Psychopharmacol.,  2019, 34(3), 
e2694.
[http://dx.doi.org/10.1002/hup.2694] [PMID: 31124194] 
[111] 
LaClair, K.D.; Manaye, K.F.; Lee, D.L.; Allard, J.S.; Savonenko, A.V.; Troncoso, J.C.; Wong, P.C. Treatment with bexarotene, a compound that increases apolipoprotein-E, provides no cognitive benefit in mutant APP/PS1 mice. Mol. Neurodegener.,  2013, 8(1), 18.
[http://dx.doi.org/10.1186/1750-1326-8-18] [PMID: 23764200] 
[112] 
Manini, M.L.; Camilleri, M.; Goldberg, M.; Sweetser, S.; McKinzie, S.; Burton, D.; Wong, S.; Kitt, M.M.; Li, Y.P.; Zinsmeister, A.R. 2010, Effects of Velusetrag (TD-5108) on gastrointestinal transit and bowel function in health and pharmacokinetics in health and constipation. Neurogastroenterol. Motil.,  , 2010, , 22(1), 42-49-e7-e8.
[PMID: 19691492] 
[113] 
Goldberg, M.; Li, Y.P.; Johanson, J.F.; Mangel, A.W.; Kitt, M.; Beattie, D.T.; Kersey, K.; Daniels, O. Clinical trial: the efficacy and tolerability of velusetrag, a selective 5-HT4 agonist with high intrinsic activity, in chronic idiopathic constipation - a 4-week, randomized, double-blind, placebo-controlled, dose-response study. Aliment. Pharmacol. Ther.,  2010, 32(9), 1102-1112.
[http://dx.doi.org/10.1111/j.1365-2036.2010.04456.x] [PMID: 21039672] 
[114] 
Baddeley, T.C.; McCaffrey, J.; Storey, J.M.; Cheung, J.K.; Melis, V.; Horsley, D.; Harrington, C.R.; Wischik, C.M. Complex disposition of methylthioninium redox forms determines efficacy in tau aggregation inhibitor therapy for Alzheimer’s disease. J. Pharmacol. Exp. Ther.,  2015, 352(1), 110-118.
[http://dx.doi.org/10.1124/jpet.114.219352] [PMID: 25320049] 
[115] 
Parsons, C.G.; Rammes, G. Preclinical to phase II amyloid beta (Aβ) peptide modulators under investigation for Alzheimer’s disease. Expert Opin. Investig. Drugs,  2017, 26(5), 579-592.
[http://dx.doi.org/10.1080/13543784.2017.1313832] [PMID: 28362514] 
[116] 
Panarsky, R.; Luques, L.; Weinstock, M. Anti-inflammatory effects of ladostigil and its metabolites in aged rat brain and in microglial cells. J. Neuroimmune Pharmacol.,  2012, 792, 488-498.
[117] 
Youdim, M.B. Multi target neuroprotective and neurorestorative anti-Parkinson and anti-Alzheimer drugs ladostigil and m30 derived from rasagiline. Exp. Neurobiol.,  2013, 22(1), 1-10.
[http://dx.doi.org/10.5607/en.2013.22.1.1] [PMID: 23585716] 
[118] 
Rinne, J.O.; Wesnes, K.; Hänninen, J. Safety and efficacy of ORM-12741 on cognitive and behavioral symptoms in patients with Alzheimer’s disease: A randomized, double-blind, proof-of-concept study. J. Neurol. Sci.,  2013, 333e322.
[http://dx.doi.org/10.1016/j.jns.2013.07.1199] 
[119] 
Deardorff, W.J.; Shobassy, A.; Grossberg, G.T. Safety and clinical effects of EVP-6124 in subjects with Alzheimer’s disease currently or previously receiving an acetylcholinesterase inhibitor medication. Expert Rev. Neurother.,  2015, 15(1), 7-17.
[http://dx.doi.org/10.1586/14737175.2015.995639] [PMID: 25495510] 
[120] 
Florian, H.; Meier, A.; Gauthier, S.; Lipschitz, S.; Lin, Y.; Tang, Q.; Othman, A.A.; Robieson, W.Z.; Gault, L.M. Efficacy and safety of ABT-126 in subjects with mild-to-moderate Alzheimer’s disease on stable doses of acetylcholinesterase inhibitors: a randomized, double-blind, placebo-controlled study. J. Alzheimers Dis.,  2016, 51(4), 1237-1247.
[http://dx.doi.org/10.3233/JAD-150978] [PMID: 26967214] 
[121] 
Koenig, A.M.; Mechanic-Hamilton, D.; Xie, S.X.; Combs, M.F.; Cappola, A.R.; Xie, L.; Detre, J.A.; Wolk, D.A.; Arnold, S.E. Effects of the insulin sensitizer metformin in Alzheimer’s disease: Pilot data from a randomized placebo-controlled crossover study. Alzheimer Dis. Assoc. Disord.,  2017, 31(2), 107-113.
[http://dx.doi.org/10.1097/WAD.0000000000000202] [PMID: 28538088] 
[122] 
Luchsinger, J.A.; Perez, T.; Chang, H.; Mehta, P.; Steffener, J.; Pradabhan, G.; Ichise, M.; Manly, J.; Devanand, D.P.; Bagiella, E. Metformin in amnestic mild cognitive impairment: results of a pilot randomized placebo controlled clinical trial. J. Alzheimers Dis.,  2016, 51(2), 501-514.
[http://dx.doi.org/10.3233/JAD-150493] [PMID: 26890736] 
[123] 
Farlow, M.R.; Andreasen, N.; Riviere, M.E.; Vostiar, I.; Vitaliti, A.; Sovago, J.; Caputo, A.; Winblad, B.; Graf, A. Long-term treatment with active Aβ immunotherapy with CAD106 in mild Alzheimer’s disease. Alzheimers Res. Ther.,  2015, 7(1), 23.
[http://dx.doi.org/10.1186/s13195-015-0108-3] [PMID: 25918556] 
[124] 
Leurent, C.; Goodman, J.A.; Zhang, Y.; He, P.; Polimeni, J.R.; Gurol, M.E.; Lindsay, M.; Frattura, L.; Sohur, U.S.; Viswanathan, A.; Bednar, M.M.; Smith, E.E.; Greenberg, S.M. Immunotherapy with ponezumab for probable cerebral amyloid angiopathy. Ann. Clin. Transl. Neurol.,  2019, 6(4), 795-806.
[http://dx.doi.org/10.1002/acn3.761] [PMID: 31020004] 
[125] 
Hull, M.; Sadowsky, C.; Arai, H.; Le Prince Leterme, G.; Holstein, A.; Booth, K.; Peng, Y.; Yoshiyama, T.; Suzuki, H.; Ketter, N.; Liu, E.; Ryan, J.M. Long-Term Extensions of Randomized Vaccination Trials of ACC-001 and QS-21 in Mild to Moderate Alzheimer’s Disease. Curr. Alzheimer Res.,  2017, 14(7), 696-708.
[http://dx.doi.org/10.2174/1567205014666170117101537] [PMID: 28124589] 
[126] 
Champagne, D.; Pearson, D.; Dea, D.; Rochford, J.; Poirier, J. The cholesterol-lowering drug probucol increases apolipoprotein E production in the hippocampus of aged rats: implications for Alzheimer’s disease. Neuroscience,  2003, 121(1), 99-110.
[http://dx.doi.org/10.1016/S0306-4522(03)00361-0] [PMID: 12946703] 
[127] 
Poirier, J.; Miron, J.; Picard, C.; Gormley, P.; Théroux, L.; Breitner, J.; Dea, D. Apolipoprotein E and lipid homeostasis in the etiology and treatment of sporadic Alzheimer’s disease. Neurobiol. Aging,  2014, 35(Suppl. 2), S3-S10.
[http://dx.doi.org/10.1016/j.neurobiolaging.2014.03.037] [PMID: 24973118] 
[128] 
Willis, B.A.; Lowe, S.L.; Daugherty, L.L. Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of LY3202626, A Novel BACE1 inhibitor, in healthy subjects and patients with Alzheimer’s Disease. Alzheimers Dement.,  2016, 12(7)
[http://dx.doi.org/10.1016/j.jalz.2016.06.791] 
[129] 
Lopez Lopez, C.; Caputo, A.; Liu, F.; Riviere, M.E.; Rouzade-Dominguez, M.L.; Thomas, R.G.; Langbaum, J.B.; Lenz, R.; Reiman, E.M.; Graf, A.; Tariot, P.N. The Alzheimer’s Prevention Initiative Generation Program: Evaluating CNP520 Efficacy in the Prevention of Alzheimer’s Disease. J. Prev. Alzheimers Dis.,  2017, 4(4), 242-246.
[130] 
Ufer, M.; Rouzade-Dominguez, M.L.; Huledal, G. Results from a First-in-Human Study with the Bace Inhibitor Cnp520. Alzheimers Dement.,  2016, 12(7)
[http://dx.doi.org/10.1016/j.jalz.2016.06.351] 
[131] 
Timmers, M.; Streffer, J.R.; Russu, A.; Tominaga, Y.; Shimizu, H.; Shiraishi, A.; Tatikola, K.; Smekens, P.; Börjesson-Hanson, A.; Andreasen, N.; Matias-Guiu, J.; Baquero, M.; Boada, M.; Tesseur, I.; Tritsmans, L.; Van Nueten, L.; Engelborghs, S. Pharmacodynamics of atabecestat (JNJ-54861911), an oral BACE1 inhibitor in patients with early Alzheimer’s disease: randomized, double-blind, placebo-controlled study. Alzheimers Res. Ther.,  2018, 10(1), 85.
[http://dx.doi.org/10.1186/s13195-018-0415-6] [PMID: 30134967] 
[132] 
Timmers, M.; Van Broeck, B.; Ramael, S.; Slemmon, J.; De Waepenaert, K.; Russu, A.; Bogert, J.; Stieltjes, H.; Shaw, L.M.; Engelborghs, S.; Moechars, D.; Mercken, M.; Liu, E.; Sinha, V.; Kemp, J.; Van Nueten, L.; Tritsmans, L.; Streffer, J.R. Profiling the dynamics of CSF and plasma Aβ reduction after treatment with JNJ-54861911, a potent oral BACE inhibitor. Alzheimers Dement. (N. Y.),  2016, 2(3), 202-212.
[http://dx.doi.org/10.1016/j.trci.2016.08.001] [PMID: 29067308] 
[133] 
Amani, M.; Shokouhi, G.; Salari, A.A. Minocycline prevents the development of depression-like behavior and hippocampal inflammation in a rat model of Alzheimer’s disease. Psychopharmacology (Berl.),  2018, 4, 1-2.
[134] 
Shah, R.C.; Matthews, D.C.; Andrews, R.D.; Capuano, A.W.; Fleischman, D.A.; VanderLugt, J.T.; Colca, J.R. An evaluation of MSDC-0160, a prototype mTOT modulating insulin sensitizer, in patients with mild Alzheimer’s disease. Curr. Alzheimer Res.,  2014, 11(6), 564-573.
[http://dx.doi.org/10.2174/1567205011666140616113406] [PMID: 24931567] 
[135] 
Ma, K.; Thomason, L.A.; McLaurin, J. scyllo-Inositol, preclinical, and clinical data for Alzheimer’s disease. Adv. Pharmacol.,  2012, 64, 177-212.
[http://dx.doi.org/10.1016/B978-0-12-394816-8.00006-4] [PMID: 22840748] 
[136] 
Chase, T.N.; Farlow, M.R.; Clarence-Smith, K. Donepezil plus Solifenacin (CPC-201) treatment for Alzheimer’s disease. Neurotherapeutics,  2017, 14(2), 405-416.
[http://dx.doi.org/10.1007/s13311-016-0511-x] [PMID: 28138837] 
[137] 
Duggan, KC; Walters, MJ; Musee, J Molecular basis for cyclooxygenase inhibition by the non-steroidal anti-inflammatory drug, naproxen.,  J. Biol. Chem.,  2010, jbc, M110.
[138] 
Martorana, A.; Di Lorenzo, F.; Esposito, Z.; Lo Giudice, T.; Bernardi, G.; Caltagirone, C.; Koch, G. Dopamine D2-agonist rotigotine effects on cortical excitability and central cholinergic transmission in Alzheimer’s disease patients. Neuropharmacology,  2013, 64, 108-113.
[http://dx.doi.org/10.1016/j.neuropharm.2012.07.015] [PMID: 22863599] 
[139] 
Bennett, J.; Burns, J.; Welch, P.; Bothwell, R. Safety and tolerability of R (+) pramipexole in mild-to-moderate Alzheimer’s disease. J. Alzheimers Dis.,  2016, 49(4), 1179-1187.
[http://dx.doi.org/10.3233/JAD-150788] [PMID: 26682692] 
[140] 
Guo, C.; Sun, L.; Chen, X.; Zhang, D. Oxidative stress, mitochondrial damage and neurodegenerative diseases. Neural Regen. Res.,  2013, 8(21), 2003-2014.
[141] 
Claxton, A.; Baker, L.D.; Hanson, A.; Trittschuh, E.H.; Cholerton, B.; Morgan, A.; Callaghan, M.; Arbuckle, M.; Behl, C.; Craft, S. Long-acting intranasal insulin detemir improves cognition for adults with mild cognitive impairment or early-stage Alzheimer’s disease dementia. J. Alzheimers Dis.,  2015, 44(3), 897-906.
[http://dx.doi.org/10.3233/JAD-141791] [PMID: 25374101] 
[142] 
Lues, I.; Weber, F.; Meyer, A.; Bühring, U.; Hoffmann, T.; Kühn-Wache, K.; Manhart, S.; Heiser, U.; Pokorny, R.; Chiesa, J.; Glund, K. A phase 1 study to evaluate the safety and pharmacokinetics of PQ912, a glutaminyl cyclase inhibitor, in healthy subjects. Alzheimers Dement. (N. Y.),  2015, 1(3), 182-195.
[http://dx.doi.org/10.1016/j.trci.2015.08.002] [PMID: 29854937] 
[143] 
Hoffmann, T.; Meyer, A.; Heiser, U.; Kurat, S.; Böhme, L.; Kleinschmidt, M.; Bühring, K.U.; Hutter-Paier, B.; Farcher, M.; Demuth, H.U.; Lues, I.; Schilling, S. Glutaminyl cyclase inhibitor PQ912 improves cognition in mouse models of Alzheimer’s disease—studies on relation to effective target occupancy. J. Pharmacol. Exp. Ther.,  2017, 362(1), 119-130.
[http://dx.doi.org/10.1124/jpet.117.240614] [PMID: 28446518] 
[144] 
Lovestone, S.; Boada, M.; Dubois, B.; Hüll, M.; Rinne, J.O.; Huppertz, H.J.; Calero, M.; Andrés, M.V.; Gómez-Carrillo, B.; León, T.; del Ser, T. A phase II trial of tideglusib in Alzheimer’s disease. J. Alzheimers Dis.,  2015, 45(1), 75-88.
[http://dx.doi.org/10.3233/JAD-141959] [PMID: 25537011] 
[145] 
del Ser, T.; Steinwachs, K.C.; Gertz, H.J.; Andrés, M.V.; Gómez-Carrillo, B.; Medina, M.; Vericat, J.A.; Redondo, P.; Fleet, D.; León, T. Treatment of Alzheimer’s disease with the GSK-3 inhibitor tideglusib: a pilot study. J. Alzheimers Dis.,  2013, 33(1), 205-215.
[http://dx.doi.org/10.3233/JAD-2012-120805] [PMID: 22936007] 
[146] 
Folch, J.; Petrov, D.; Ettcheto, M.; Abad, S.; Sánchez-López, E.; García, M.L.; 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] [PMID: 26881137] 
[147] 
Berk, C.; Paul, G.; Sabbagh, M. Investigational drugs in Alzheimer’s disease: current progress. Expert Opin. Investig. Drugs,  2014, 23(6), 837-846.
[http://dx.doi.org/10.1517/13543784.2014.905542] [PMID: 24702504] 
[148] 
Purón-Sierra, L.; Miranda, M.I. Histaminergic modulation of cholinergic release from the nucleus basalis magnocellularis into insular cortex during taste aversive memory formation. PLoS One,  2014, 9(3), 
e91120.
[http://dx.doi.org/10.1371/journal.pone.0091120] [PMID: 24625748] 
[149] 
Sepehri, H.; Mehrazin, E. Effect of filgrastim (recombinant human granulocyte colony stimulating factor) on spatial memory in aged rats. Natl. J. Physiol. Pharm. Pharmacol.,  2015, 5(5), 421-425.
[http://dx.doi.org/10.5455/njppp.2015.5.1308201568] 
[150] 
Ye, M.; Chung, H.S.; An, Y.H.; Lim, S.J.; Choi, W.; Yu, A.R.; Kim, J.S.; Kang, M.; Cho, S.; Shim, I.; Bae, H. Standardized herbal formula PM012 decreases cognitive impairment and promotes neurogenesis in the 3xTg AD mouse model of Alzheimer’s disease. Mol. Neurobiol.,  2016, 53(8), 5401-5412.
[http://dx.doi.org/10.1007/s12035-015-9458-x] [PMID: 26446019] 
[151] 
Sohn, S.H.; Kim, S.J.; Kim, Y.; Shim, I.; Bae, H. Safety and efficacy assessment of standardized herbal formula PM012. BMC Complement. Altern. Med.,  2012, 12(1), 24.
[http://dx.doi.org/10.1186/1472-6882-12-24] [PMID: 22458507] 
[152] 
Harandi, A.A.; Ashrafi, F.; Tabatabaei, M. Efficacy and tolerability of MLC601 in patients with mild to moderate Alzheimer disease who were unable to tolerate or failed to benefit from treatment with rivastigmine. Br. J. Med. Med. Res.,  2013, 3(2), 341.
[153] 
Erdoğan, M.E.; Aydın, S.; Yanar, K.; Mengi, M.; Kansu, A.D.; Cebe, T.; Belce, A.; Çelikten, M.; Çakatay, U. The effects of lipoic acid on redox status in brain regions and systemic circulation in streptozotocin-induced sporadic Alzheimer’s disease model. Metab. Brain Dis.,  2017, 32(4), 1017-1031.
[http://dx.doi.org/10.1007/s11011-017-9983-6] [PMID: 28299625] 
[154] 
Zhang, Y.H.; Wang, D.W.; Xu, S.F.; Zhang, S.; Fan, Y.G.; Yang, Y.Y.; Guo, S.Q.; Wang, S.; Guo, T.; Wang, Z.Y.; Guo, C. α-Lipoic acid improves abnormal behavior by mitigation of oxidative stress, inflammation, ferroptosis, and tauopathy in P301S Tau transgenic mice. Redox Biol.,  2018, 14, 535-548.
[http://dx.doi.org/10.1016/j.redox.2017.11.001] [PMID: 29126071] 
[155] 
Lee, J.H.; Jahrling, J.B.; Denner, L. Targeting Insulin for Alzheimer’s Disease: Mechanisms, Status and Potential Directions. J. Alzheimers Dis.,  2018, 1-27.
[156] 
Grimaldi, L.M.; Zappalà, G.; Iemolo, F.; Castellano, A.E.; Ruggieri, S.; Bruno, G.; Paolillo, A. A pilot study on the use of interferon beta-1a in early Alzheimer’s disease subjects. J. Neuroinflammation,  2014, 11(1), 30.
[http://dx.doi.org/10.1186/1742-2094-11-30] [PMID: 24524367] 
[157] 
Thapa, A.; Carroll, N.J. Dietary modulation of oxidative stress in Alzheimer’s disease. Int. J. Mol. Sci.,  2017, 18(7), 1583.
[http://dx.doi.org/10.3390/ijms18071583] [PMID: 28753984] 
[158] 
Ricci, B.; Sturm, S.; Seneca, N. Brain MAO-B inhibition in healthy elderly and people with Alzheimer’s disease after oral administration of RO4602522. Alzheimers Dement.,  2013, 9(4), 667.
[http://dx.doi.org/10.1016/j.jalz.2013.05.1374] 
[159] 
Borroni, E.; Wyler, R.; Messer, J. Preclinical characterization of RO4602522, a novel, selective and orally active monoamine oxidase type B inhibitor for the treatment of Alzheimer’s disease. Alzheimers Dement.,  2013, 9(4), 818.
[http://dx.doi.org/10.1016/j.jalz.2013.05.1757] 
[160] 
Verma, S.; Kumar, A.; Tripathi, T.; Kumar, A. Muscarinic and nicotinic acetylcholine receptor agonists: current scenario in Alzheimer’s disease therapy. J. Pharm. Pharmacol.,  2018, 70(8), 985-993.
[http://dx.doi.org/10.1111/jphp.12919] [PMID: 29663387] 
[161] 
Hong-Qi, Y.; Zhi-Kun, S.; Sheng-Di, C. Current advances in the treatment of Alzheimer’s disease: focused on considerations targeting Aβ and tau. Transl. Neurodegener.,  2012, 1(1), 21.
[http://dx.doi.org/10.1186/2047-9158-1-21] [PMID: 23210837] 
[162] 
Frölich, L.; Ashwood, T.; Nilsson, J.; Eckerwall, G. Effects of AZD3480 on cognition in patients with mild-to-moderate Alzheimer’s disease: a phase IIb dose-finding study. J. Alzheimers Dis.,  2011, 24(2), 363-374.
[http://dx.doi.org/10.3233/JAD-2011-101554] [PMID: 21258153] 
[163] 
Weintraub, D.; Mavandadi, S.; Mamikonyan, E.; Siderowf, A.D.; Duda, J.E.; Hurtig, H.I.; Colcher, A.; Horn, S.S.; Nazem, S.; Ten Have, T.R.; Stern, M.B. Atomoxetine for depression and other neuropsychiatric symptoms in Parkinson disease. Neurology,  2010, 75(5), 448-455.
[http://dx.doi.org/10.1212/WNL.0b013e3181ebdd79] [PMID: 20679638] 
[164] 
Tong, M.; Deochand, C.; Didsbury, J.; de la Monte, S.M. T3D-959: A multi-faceted disease remedial drug candidate for the treatment of Alzheimer’s disease. J. Alzheimers Dis.,  2016, 51(1), 123-138.
[http://dx.doi.org/10.3233/JAD-151013] [PMID: 26836193] 
[165] 
de la Monte, S.M.; Tong, M.; Schiano, I.; Didsbury, J. Improved brain insulin/IGF signaling and reduced neuroinflammation with T3D-959 in an experimental model of sporadic Alzheimer’s disease. J. Alzheimers Dis.,  2017, 55(2), 849-864.
[http://dx.doi.org/10.3233/JAD-160656] [PMID: 27802237] 
[166] 
Alam, J.; Blackburn, K.; Patrick, D. 3. Alam J, Blackburn K, Patrick D. Neflamapimod: clinical phase 2b-ready oral small molecule inhibitor of p38alpha to reverse synaptic dysfunction in early Alzheimer’s disease. J. Prev. Alzheimers Dis.,  2017, 4(4), 273-278.
[167] 
Rosenbrock, H.; Marti, A.; Koros, E. Improving synaptic plasticity and cognitive function in rodents by the novel phosphodiesterase 9A inhibitor bi 409306. Alzheimers Dement.,  2015, 11(7), 612.
[http://dx.doi.org/10.1016/j.jalz.2015.06.852] 
[168] 
Wunderlich, G.; Thamer, C.; Roehrle, M. Study design and characteristics of two-phase ii proof-of-concept clinical trials of the pde9 inhibitor bi 409306 in early Alzheimer’s disease. Alzheimers Dement.,  2016, 12(7), 820-821.
[http://dx.doi.org/10.1016/j.jalz.2016.06.1666] 
[169] 
Schrott, L.M.; Jackson, K.; Yi, P.; Dietz, F.; Johnson, G.S.; Basting, T.F.; Purdum, G.; Tyler, T.; Rios, J.D.; Castor, T.P.; Alexander, J.S. Acute oral Bryostatin-1 administration improves learning deficits in the APP/PS1 transgenic mouse model of Alzheimer’s disease. Curr. Alzheimer Res.,  2015, 12(1), 22-31.
[http://dx.doi.org/10.2174/1567205012666141218141904] [PMID: 25523423] 
[170] 
Holthoewer, D.; Endres, K.; Schuck, F.; Hiemke, C.; Schmitt, U.; Fahrenholz, F. Acitretin, an enhancer of alpha-secretase expression, crosses the blood-brain barrier and is not eliminated by P-glycoprotein. Neurodegener. Dis.,  2012, 10(1-4), 224-228.
[http://dx.doi.org/10.1159/000334300] [PMID: 22301853] 
[171] 
Endres, K.; Fahrenholz, F.; Lotz, J. Increased CSF APPs-α levels in patients with Alzheimer disease treated with acitretin. Neurology,  2014, 83(21), 1930-1935.
[http://dx.doi.org/10.1212/WNL.0000000000001017] 
[172] 
O’Hare, E.; Jeggo, R.; Kim, E.M.; Barbour, B.; Walczak, J.S.; Palmer, P.; Lyons, T.; Page, D.; Hanna, D.; Meara, J.R.; Spanswick, D.; Guo, J.P.; McGeer, E.G.; McGeer, P.L.; Hobson, P. Lack of support for bexarotene as a treatment for Alzheimer’s disease. Neuropharmacology,  2016, 100, 124-130.
[http://dx.doi.org/10.1016/j.neuropharm.2015.04.020] [PMID: 26025659] 
[173] 
Velayudhan, L.; Ffytche, D.; Ballard, C.; Aarsland, D. New therapeutic strategies for Lewy body dementias. Curr. Neurol. Neurosci. Rep.,  2017, 17(9), 68.
[http://dx.doi.org/10.1007/s11910-017-0778-2] [PMID: 28741230] 
[174] 
Takamura, Y.; Ono, K.; Matsumoto, J.; Yamada, M.; Nishijo, H. Effects of the neurotrophic agent T-817MA on oligomeric amyloid-β-induced deficits in long-term potentiation in the hippocampal CA1 subfield. Neurobiol. Aging,  2014, 35(3), 532-536.
[http://dx.doi.org/10.1016/j.neurobiolaging.2013.08.037] [PMID: 24112791] 
[175] 
Grundman, M.; Morgan, R.; Lickliter, J.D.; Schneider, L.S.; DeKosky, S.; Izzo, N.J.; Guttendorf, R.; Higgin, M.; Pribyl, J.; Mozzoni, K.; Safferstein, H.; Catalano, S.M. A phase 1 clinical trial of the sigma-2 receptor complex allosteric antagonist CT1812, a novel therapeutic candidate for Alzheimer’s disease. Alzheimers Dement. (N. Y.),  2019, 5, 20-26.
[http://dx.doi.org/10.1016/j.trci.2018.11.001] [PMID: 30723776] 
[176] 
Polis, B.; Samson, A.O. Arginase as a Potential Target in the Treatment of Alzheimer’s Disease. Adv. Alzheimer Dis.,  2018, 7, 119-140.
[http://dx.doi.org/10.4236/aad.2018.74009] 
[177] 
Nygaard, H.B.; Wagner, A.F.; Bowen, G.S.; Good, S.P.; MacAvoy, M.G.; Strittmatter, K.A.; Kaufman, A.C.; Rosenberg, B.J.; Sekine-Konno, T.; Varma, P.; Chen, K.; Koleske, A.J.; Reiman, E.M.; Strittmatter, S.M.; van Dyck, C.H. A phase Ib multiple ascending dose study of the safety, tolerability, and central nervous system availability of AZD0530 (saracatinib) in Alzheimer’s disease. Alzheimers Res. Ther.,  2015, 7(1), 35.
[http://dx.doi.org/10.1186/s13195-015-0119-0] [PMID: 25874001] 
[178] 
Hannon, R.A.; Clack, G.; Rimmer, M.; Swaisland, A.; Lockton, J.A.; Finkelman, R.D.; Eastell, R. Effects of the Src kinase inhibitor saracatinib (AZD0530) on bone turnover in healthy men: a randomized, double-blind, placebo-controlled, multiple-ascending-dose phase I trial. J. Bone Miner. Res.,  2010, 25(3), 463-471.
[http://dx.doi.org/10.1359/jbmr.090830] [PMID: 19775203] 
[179] 
Butchart, J.; Brook, L.; Hopkins, V.; Teeling, J.; Püntener, U.; Culliford, D.; Sharples, R.; Sharif, S.; McFarlane, B.; Raybould, R.; Thomas, R.; Passmore, P.; Perry, V.H.; Holmes, C. Etanercept in Alzheimer disease: A randomized, placebo-controlled, double-blind, phase 2 trial. Neurology,  2015, 84(21), 2161-2168.
[http://dx.doi.org/10.1212/WNL.0000000000001617] [PMID: 25934853] 
[180] 
Park, S.J.; Jung, J.M.; Lee, H.E.; Lee, Y.W.; Kim, D.H.; Kim, J.M.; Hong, J.G.; Lee, C.H.; Jung, I.H.; Cho, Y.B.; Jang, D.S.; Ryu, J.H. The memory ameliorating effects of INM-176, an ethanolic extract of Angelica gigas, against scopolamine- or Aβ(1-42)-induced cognitive dysfunction in mice. J. Ethnopharmacol.,  2012, 143(2), 611-620.
[http://dx.doi.org/10.1016/j.jep.2012.07.019] [PMID: 22846435] 
[181] 
García-Colunga, J.; Godoy-García, U.; Vázquez-Gómez, E. Interaction of bupropion and zinc with neuronal nicotinic acetylcholine receptors. Neuropharmacology,  2011, 61(8), 1202-1209.
[http://dx.doi.org/10.1016/j.neuropharm.2011.07.009] [PMID: 21791218] 
[182] 
Willis, B.A.; Sundell, K.; Lachno, D.R.; Ferguson-Sells, L.R.; Case, M.G.; Holdridge, K.; DeMattos, R.B.; Raskin, J.; Siemers, E.R.; Dean, R.A. Central pharmacodynamic activity of solanezumab in mild Alzheimer’s disease dementia. Alzheimers Dement. (N. Y.),  2018, 4, 652-660.
[http://dx.doi.org/10.1016/j.trci.2018.10.001] [PMID: 30511011] 
[183] 
Wang, X.; Sun, G.; Feng, T.; Zhang, J.; Huang, X.; Wang, T.; Xie, Z.; Chu, X.; Yang, J.; Wang, H.; Chang, S.; Gong, Y.; Ruan, L.; Zhang, G.; Yan, S.; Lian, W.; Du, C.; Yang, D.; Zhang, Q.; Lin, F.; Liu, J.; Zhang, H.; Ge, C.; Xiao, S.; Ding, J.; Geng, M. Sodium oligomannate therapeutically remodels gut microbiota and suppresses gut bacterial amino acids-shaped neuroinflammation to inhibit Alzheimer’s disease progression. Cell Res.,  2019, 29(10), 787-803.
[http://dx.doi.org/10.1038/s41422-019-0216-x] [PMID: 31488882] 
[184] 
Kennelly, S.P.; Abdullah, L.; Paris, D.; Parish, J.; Mathura, V.; Mullan, M.; Crawford, F.; Lawlor, B.A.; Kenny, R.A. Demonstration of safety in Alzheimer’s patients for intervention with an anti-hypertensive drug Nilvadipine: results from a 6-week open label study. Int. J. Geriatr. Psychiatry,  2011, 26(10), 1038-1045.
[http://dx.doi.org/10.1002/gps.2638] [PMID: 21905098] 
[185] 
Cummings, J.L.; Lyketsos, C.G.; Peskind, E.R.; Porsteinsson, A.P.; Mintzer, J.E.; Scharre, D.W.; De La Gandara, J.E.; Agronin, M.; Davis, C.S.; Nguyen, U.; Shin, P.; Tariot, P.N.; Siffert, J. Effect of dextromethorphan-quinidine on agitation in patients with Alzheimer disease dementia: a randomized clinical trial. JAMA,  2015, 314(12), 1242-1254.
[http://dx.doi.org/10.1001/jama.2015.10214] [PMID: 26393847] 
[186] 
Singh, C. Trinity Laboratories Inc, assignee. Dextromethorphan hydrochloride. United States patent US,  2011, 623.
[187] 
Vandenberghe, C.; St-Pierre, V.; Pierotti, T.; Fortier, M.; Castellano, C.A.; Cunnane, S.C. Tricaprylin alone increases plasma Ketone response more than coconut oil or other medium-chain triglycerides: an acute crossover study in healthy adults. Curr. Dev. Nutr.,  2017, 1(4), 
e000257.
[http://dx.doi.org/10.3945/cdn.116.000257] [PMID: 29955698] 
[188] 
Passmore, M.J. The cannabinoid receptor agonist nabilone for the treatment of dementia-related agitation. Int. J. Geriatr. Psychiatry,  2008, 23(1), 116-117.
[http://dx.doi.org/10.1002/gps.1828] [PMID: 18081000] 
[189] 
Musiek, E.S.; Xiong, D.D.; Holtzman, D.M. Sleep, circadian rhythms, and the pathogenesis of Alzheimer disease. Exp. Mol. Med.,  2015, 47(3), 
e148.
[http://dx.doi.org/10.1038/emm.2014.121] [PMID: 25766617] 
[190] 
Li, F.; Gong, Q.; Dong, H.; Shi, J. Resveratrol, a neuroprotective supplement for Alzheimer’s disease. Curr. Pharm. Des.,  2012, 18(1), 27-33.
[http://dx.doi.org/10.2174/138161212798919075] [PMID: 22211686] 
[191] 
Pasinetti, G.M.; Wang, J.; Ho, L.; Zhao, W.; Dubner, L. Roles of resveratrol and other grape-derived polyphenols in Alzheimer’s disease prevention and treatment. Biochim. Biophys. Acta,  2015, 1852(6), 1202-1208.
[http://dx.doi.org/10.1016/j.bbadis.2014.10.006] [PMID: 25315300] 
[192] 
Du, K.; Liu, M.; Zhong, X.; Yao, W.; Xiao, Q.; Wen, Q.; Yang, B.; Wei, M. Epigallocatechin Gallate Reduces Amyloid β-Induced Neurotoxicity via Inhibiting Endoplasmic Reticulum Stress-Mediated Apoptosis. Mol. Nutr. Food Res.,  2018, 62(8), 
e1700890.
[http://dx.doi.org/10.1002/mnfr.201700890] [PMID: 29446867] 
[193] 
Gugliandolo, A.; Bramanti, P.; Mazzon, E. Role of vitamin E in the treatment of Alzheimer’s disease: Evidence from animal models. Int. J. Mol. Sci.,  2017, 18(12), 2504.
[http://dx.doi.org/10.3390/ijms18122504] [PMID: 29168797] 
[194] 
Seo, J.S.; Baek, I.S.; Leem, Y.H.; Kim, T.K.; Cho, Y.; Lee, S.M.; Park, Y.H.; Han, P.L. SK-PC-B70M alleviates neurologic symptoms in G93A-SOD1 amyotrophic lateral sclerosis mice. Brain Res.,  2011, 1368, 299-307.
[http://dx.doi.org/10.1016/j.brainres.2010.10.048] [PMID: 20971081] 
[195] 
Valles, S.L.; Dolz-Gaiton, P.; Gambini, J.; Borras, C.; Lloret, A.; Pallardo, F.V.; Viña, J. Estradiol or genistein prevent Alzheimer’s disease-associated inflammation correlating with an increase PPAR γ expression in cultured astrocytes. Brain Res.,  2010, 1312, 138-144.
[http://dx.doi.org/10.1016/j.brainres.2009.11.044] [PMID: 19948157] 
[196] 
Correll, C.U.; Skuban, A.; Ouyang, J.; Hobart, M.; Pfister, S.; McQuade, R.D.; Nyilas, M.; Carson, W.H.; Sanchez, R.; Eriksson, H. Efficacy and safety of brexpiprazole for the treatment of acute schizophrenia: a 6-week randomized, double-blind, placebo-controlled trial. Am. J. Psychiatry,  2015, 172(9), 870-880.
[http://dx.doi.org/10.1176/appi.ajp.2015.14101275] [PMID: 25882325] 
[197] 
Diefenderfer, L.A.; Iuppa, C. Brexpiprazole: A review of a new treatment option for schizophrenia and major depressive disorder. Ment Health Clin,  2018, 7(5), 207-212.
[http://dx.doi.org/10.9740/mhc.2017.09.207] [PMID: 29955525] 
[198] 
Atri, A.; Frölich, L.; Ballard, C.; Tariot, P.N.; Molinuevo, J.L.; Boneva, N.; Windfeld, K.; Raket, L.L.; Cummings, J.L. Effect of idalopirdine as adjunct to cholinesterase inhibitors on change in cognition in patients with Alzheimer disease: three randomized clinical trials. JAMA,  2018, 319(2), 130-142.
[http://dx.doi.org/10.1001/jama.2017.20373] [PMID: 29318278] 
[199] 
McKeith, I.G.; Aarsland, D.; Friedhoff, L. A Multnational study evaluating the safety and efficacy of intepirdine (RVT-101) in dementia with lewy bodies. Alzheimers Dement.,  2017, 13(7), 936.
[http://dx.doi.org/10.1016/j.jalz.2017.06.1830] 
[200] 
Yi, X.Y.; Ni, S.F.; Ghadami, M.R.; Meng, H.Q.; Chen, M.Y.; Kuang, L.; Zhang, Y.Q.; Zhang, L.; Zhou, X.Y. Trazodone for the treatment of insomnia: a meta-analysis of randomized placebo-controlled trials. Sleep Med.,  2018, 45, 25-32.
[http://dx.doi.org/10.1016/j.sleep.2018.01.010] [PMID: 29680424] 
[201] 
Zhao, L.; Zhu, L.; Guo, X. Valproic acid attenuates Aβ25-35-induced neurotoxicity in PC12 cells through suppression of mitochondria-mediated apoptotic pathway. Biomed. Pharmacother.,  2018, 106, 77-82.
[http://dx.doi.org/10.1016/j.biopha.2018.06.080] [PMID: 29957469] 
[202] 
Wang, J.; Ono, K.; Dickstein, D.L.; Arrieta-Cruz, I.; Zhao, W.; Qian, X.; Lamparello, A.; Subnani, R.; Ferruzzi, M.; Pavlides, C.; Ho, L.; Hof, P.R.; Teplow, D.B.; Pasinetti, G.M. Carvedilol as a potential novel agent for the treatment of Alzheimer’s disease. Neurobiol. Aging,  2011, 32(12), 2321.e1-2321.e12.
[http://dx.doi.org/10.1016/j.neurobiolaging.2010.05.004] [PMID: 20579773] 
[203] 
Landolfi, C.; Soldo, L.; Polenzani, L.; Apicella, C.; Capezzone de Joannon, A.; Coletta, I.; Di Cesare, F.; Brufani, M.; Pinza, M.; Milanese, C. Inflammatory molecule release by β-amyloid-treated T98G astrocytoma cells: role of prostaglandins and modulation by paracetamol. Eur. J. Pharmacol.,  1998, 360(1), 55-64.
[http://dx.doi.org/10.1016/S0014-2999(98)00663-3] [PMID: 9845273] 
[204] 
Barak, Y.; Plopski, I.; Tadger, S.; Paleacu, D. Escitalopram versus risperidone for the treatment of behavioral and psychotic symptoms associated with Alzheimer’s disease: a randomized double-blind pilot study. Int. Psychogeriatr.,  2011, 23(9), 1515-1519.
[http://dx.doi.org/10.1017/S1041610211000743] [PMID: 21492498] 
[205] 
Bloniecki, V.; Aarsland, D.; Blennow, K.; Cummings, J.; Falahati, F.; Winblad, B.; Freund-Levi, Y. Effects of risperidone and galantamine treatment on Alzheimer’s disease biomarker levels in cerebrospinal fluid. J. Alzheimers Dis.,  2017, 57(2), 387-393.
[http://dx.doi.org/10.3233/JAD-160758] [PMID: 28269767] 
[206] 
Yang, G.; Wang, Y.; Sun, J.; Zhang, K.; Liu, J. Ginkgo biloba for mild cognitive impairment and alzheimer’s disease: a systematic review and meta-analysis of randomized controlled trials. Curr. Top. Med. Chem.,  2016, 16(5), 520-528.
[http://dx.doi.org/10.2174/1568026615666150813143520] [PMID: 26268332] 
[207] 
Soysal, P.; Isik, A.T. Severe hyponatremia due to escitalopram treatment in an elderly adult with Alzheimer’s disease. J. Am. Geriatr. Soc.,  2014, 62(12), 2462-2463.
[http://dx.doi.org/10.1111/jgs.13149] [PMID: 25516055] 
[208] 
Tong, X.K.; Lecrux, C.; Rosa-Neto, P.; Hamel, E. Age-dependent rescue by simvastatin of Alzheimer’s disease cerebrovascular and memory deficits. J. Neurosci.,  2012, 32(14), 4705-4715.
[http://dx.doi.org/10.1523/JNEUROSCI.0169-12.2012] [PMID: 22492027] 
[209] 
Tai, S.Y.; Chen, C.H.; Chien, C.Y.; Yang, Y.H. Cilostazol as an add-on therapy for patients with Alzheimer’s disease in Taiwan: a case control study. BMC Neurol.,  2017, 17(1), 40.
[http://dx.doi.org/10.1186/s12883-017-0800-y] [PMID: 28231822] 
[210] 
Taguchi, A.; Takata, Y.; Ihara, M.; Kasahara, Y.; Tsuji, M.; Nishino, M.; Stern, D.; Okada, M. Cilostazol improves cognitive function in patients with mild cognitive impairment: a retrospective analysis. Psychogeriatrics,  2013, 13(3), 164-169.
[http://dx.doi.org/10.1111/psyg.12021] [PMID: 25707423] 
[211] 
Childress, A.; Sallee, F.R. The use of methylphenidate hydrochloride extended-release oral suspension for the treatment of ADHD. Expert Rev. Neurother.,  2013, 13(9), 979-988.
[http://dx.doi.org/10.1586/14737175.2013.833002] [PMID: 24053342] 
[212] 
Kim, S.H.; Kandiah, N.; Hsu, J.L.; Suthisisang, C.; Udommongkol, C.; Dash, A. Beyond symptomatic effects: potential of donepezil as a neuroprotective agent and disease modifier in Alzheimer’s disease. Br. J. Pharmacol.,  2017, 174(23), 4224-4232.
[http://dx.doi.org/10.1111/bph.14030] [PMID: 28901528] 
[213] 
Park, JJ; Choi, SH; Kim, S Effect of galantamine on attention in patients with Alzheimer's disease combined with cerebrovascular disease. Geriatr Gerontol. Int.,  2017, 17(10), 1661-6-70.
[214] 
Penhasi, A.; Gomberg, M. A specific two-pulse release of rivastigmine using a modified time-controlled delivery system: A proof of concept case study. J. Drug Deliv. Sci. Technol.,  2018, 47, 404-410. http://dx.doi.org/10.1016/j.jddst.2018.08.009
[215] 
Kulkarni, J.; Thomas, N.; Hudaib, A.R.; Gavrilidis, E.; Grigg, J.; Tan, R.; Cheng, J.; Arnold, A.; Gurvich, C. Effect of the glutamate NMDA receptor antagonist memantine as adjunctive treatment in borderline personality disorder: An exploratory, randomised, double-blind, placebo-controlled trial. CNS Drugs,  2018, 32(2), 179-187.
[http://dx.doi.org/10.1007/s40263-018-0506-8] [PMID: 29549516] 
[216] 
 Available at: https://www.nia.nih.gov/health/how-alzheimers-disease-treated
[217] 
McKeage, K.; Lyseng-Williamson, K.A. Ginkgo biloba
                         extract EGb 761® in the symptomatic treatment of mild-to-moderate dementia: a profile of its use.
                     Drugs Ther. Perspect.,  2018, 34(8), 358-366.
[http://dx.doi.org/10.1007/s40267-018-0537-8] [PMID: 30546253] 
[218] 
Mendez, M.F. Early-Onset Alzheimer Disease. Neurol. Clin.,  2017, 35(2), 263-281.
[http://dx.doi.org/10.1016/j.ncl.2017.01.005] [PMID: 28410659] 
[219] 
Daubert, E.A.; Condron, B.G. Serotonin: a regulator of neuronal morphology and circuitry. Trends Neurosci.,  2010, 33(9), 424-434.
[http://dx.doi.org/10.1016/j.tins.2010.05.005] [PMID: 20561690] 
[220] 
Rodríguez, J.J.; Noristani, H.N.; Verkhratsky, A. The serotonergic system in ageing and Alzheimer’s disease. Prog. Neurobiol.,  2012, 99(1), 15-41.
[http://dx.doi.org/10.1016/j.pneurobio.2012.06.010] [PMID: 22766041] 
[221] 
Naumenko, V.S.; Popova, N.K.; Lacivita, E.; Leopoldo, M.; Ponimaskin, E.G. Interplay between serotonin 5-HT1A and 5-HT7 receptors in depressive disorders. CNS Neurosci. Ther.,  2014, 20(7), 582-590.
[http://dx.doi.org/10.1111/cns.12247] [PMID: 24935787] 
[222] 
Kandimalla, R.; Reddy, P.H. Therapeutics of neurotransmitters in Alzheimer’s disease. J. Alzheimers Dis.,  2017, 57(4), 1049-1069.
[http://dx.doi.org/10.3233/JAD-161118] [PMID: 28211810] 
[223] 
Song, X.; Jensen, M.Ø.; Jogini, V.; Stein, R.A.; Lee, C.H.; Mchaourab, H.S.; Shaw, D.E.; Gouaux, E. Mechanism of NMDA receptor channel block by MK-801 and memantine. Nature,  2018, 556(7702), 515-519.
[http://dx.doi.org/10.1038/s41586-018-0039-9] [PMID: 29670280] 
[224] 
Hulshof, T.A.; Zuidema, S.U.; van Meer, P.J.K.; Gispen-de Wied, C.C.; Luijendijk, H.J. Baseline imbalances and clinical outcomes of atypical antipsychotics in dementia: A meta-epidemiological study of randomized trials. Int. J. Methods Psychiatr. Res.,  2019, 28(1), 
e1757.
[http://dx.doi.org/10.1002/mpr.1757] [PMID: 30515916] 
[225] 
Bhattacharjee, S.; Patanwala, A.E.; Lo-Ciganic, W.H.; Malone, D.C.; Lee, J.K.; Knapp, S.M.; Warholak, T.; Burke, W.J. Alzheimer’s disease medication and risk of all-cause mortality and all-cause hospitalization: A retrospective cohort study. Alzheimers Dement. (N.Y.),  2019, 5, 294-302.
[http://dx.doi.org/10.1016/j.trci.2019.05.005] [PMID: 31338414] 
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DOI https://dx.doi.org/10.2174/1874467213666200422090135	Print ISSN 1874-4672
Publisher Name Bentham Science Publisher	Online ISSN 1874-4702
Current Molecular Pharmacology

Recent Updates in the Alzheimer’s Disease Etiopathology and Possible Treatment Approaches: A Narrative Review of Current Clinical Trials

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