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Current Pharmaceutical Design

Editor-in-Chief

ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

Review Article

A Chronological Review of Potential Disease-Modifying Therapeutic Strategies for Alzheimer's Disease

Author(s): Miren Ettcheto, Oriol Busquets, Triana Espinosa-Jiménez, Ester Verdaguer , Carme Auladell and Antoni Camins*

Volume 26, Issue 12, 2020

Page: [1286 - 1299] Pages: 14

DOI: 10.2174/1381612826666200211121416

Abstract

Late-onset Alzheimer’s disease (LOAD) is a neurodegenerative disorder that has become a worldwide health problem. This pathology has been classically characterized for its affectation on cognitive function and the presence of depositions of extracellular amyloid β-protein (Aβ) and intracellular neurofibrillary tangles (NFT) composed of hyperphosphorylated Tau protein. To this day, no effective treatment has been developed.

Multiple strategies have been proposed over the years with the aim of finding new therapeutic approaches, such as the sequestration of Aβ in plasma or the administration of anti-inflammatory drugs. Also, given the significant role of the insulin receptor in the brain in the proper maintenance of cognitive function, drugs focused on the amelioration of insulin resistance have been proposed as potentially useful and effective in the treatment of AD. In the present review, taking into account the molecular complexity of the disease, it has been proposed that the most appropriate therapeutic strategy is a combinatory treatment of several drugs that will regulate a wide spectrum of the described altered pathological pathways.

Keywords: Neurodegeneration, Alzheimer's disease, Parkinson's disease, oxidative stress, neuroinflammation, ER stress, glutamate, calcium.

[1]
Alzheimer A, Stelzmann RA, Schnitzlein HN, Murtagh FR. An English translation of Alzheimer’s 1907 paper, “Uber eine eigenartige Erkankung der Hirnrinde”. Clin Anat 1995; 8(6): 429-31.
[http://dx.doi.org/10.1002/ca.980080612] [PMID: 8713166]
[2]
Vishal S, Sourabh A, Harkirat S. Alois Alzheimer (1864-1915) and the Alzheimer syndrome. J Med Biogr 2011; 19(1): 32-3.
[http://dx.doi.org/10.1258/jmb.2010.010037] [PMID: 21350079]
[3]
Querfurth HW, LaFerla FM. Alzheimer’s disease. N Engl J Med 2010; 362(4): 329-44.
[http://dx.doi.org/10.1056/NEJMra0909142] [PMID: 20107219]
[4]
Wilson RS, Segawa E, Boyle PA, Anagnos SE, Hizel LP, Bennett DA. The natural history of cognitive decline in Alzheimer’s disease. Psychol Aging 2012; 27(4): 1008-17.
[http://dx.doi.org/10.1037/a0029857] [PMID: 22946521]
[5]
Belloy ME, Napolioni V, Greicius MD. A quarter century of apoE and Alzheimer’s disease: progress to date and the path forward. Neuron 2019; 101(5): 820-38.
[http://dx.doi.org/10.1016/j.neuron.2019.01.056] [PMID: 30844401]
[6]
Castellano JM, Kim J, Stewart FR, et al. Human apoE isoforms differentially regulate brain amyloid-β peptide clearance. Sci Transl Med 2011; 3(89) 89ra57
[http://dx.doi.org/10.1126/scitranslmed.3002156] [PMID: 21715678]
[7]
Hardy J, Allsop D. Amyloid deposition as the central event in the aetiology of Alzheimer’s disease. Trends Pharmacol Sci 1991; 12(10): 383-8.
[http://dx.doi.org/10.1016/0165-6147(91)90609-V] [PMID: 1763432]
[8]
Reitz C, Mayeux R. Alzheimer disease: epidemiology, diagnostic criteria, risk factors and biomarkers. Biochem Pharmacol 2014; 88(4): 640-51.
[http://dx.doi.org/10.1016/j.bcp.2013.12.024] [PMID: 24398425]
[9]
de la Monte SM, Wands JR. Alzheimer’s disease is type 3 diabetes-evidence reviewed. J Diabetes Sci Technol 2008; 2(6): 1101-13.
[http://dx.doi.org/10.1177/193229680800200619] [PMID: 19885299]
[10]
Forloni G, Balducci C. Alzheimer’s disease, oligomers, and inflammation. J Alzheimers Dis 2018; 62(3): 1261-76.
[http://dx.doi.org/10.3233/JAD-170819] [PMID: 29562537]
[11]
Balducci C, Forloni G. Novel targets in Alzheimer’s disease: A special focus on microglia. Pharmacol Res 2018; 130: 402-13.
[http://dx.doi.org/10.1016/j.phrs.2018.01.017] [PMID: 29391235]
[12]
Hampel H, Mesulam MM, Cuello AC, et al. The cholinergic system in the pathophysiology and treatment of Alzheimer’s disease. Brain 2018; 141(7): 1917-33.
[http://dx.doi.org/10.1093/brain/awy132] [PMID: 29850777]
[13]
Saxena M, Dubey R. Target enzyme in alzheimer’s disease: acetylcholinesterase inhibitors. Curr Top Med Chem 2019; 19(4): 264-75.
[http://dx.doi.org/10.2174/1568026619666190128125912] [PMID: 30706815]
[14]
Hardy JA, Higgins GA. Alzheimer’s disease: the amyloid cascade hypothesis. Science 1992; 256(5054): 184-5.
[http://dx.doi.org/10.1126/science.1566067] [PMID: 1566067]
[15]
Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 2002; 297(5580): 353-6.
[http://dx.doi.org/10.1126/science.1072994] [PMID: 12130773]
[16]
Viola KL, Klein WL. Amyloid β oligomers in Alzheimer’s disease pathogenesis, treatment, and diagnosis. Acta Neuropathol 2015; 129(2): 183-206.
[http://dx.doi.org/10.1007/s00401-015-1386-3] [PMID: 25604547]
[17]
De Felice FG, Vieira MN, Bomfim TR, et al. Protection of synapses against Alzheimer’s-linked toxins: insulin signaling prevents the pathogenic binding of Abeta oligomers. Proc Natl Acad Sci USA 2009; 106(6): 1971-6.
[http://dx.doi.org/10.1073/pnas.0809158106] [PMID: 19188609]
[18]
Lacor PN, Buniel MC, Furlow PW, et al. Abeta oligomer-induced aberrations in synapse composition, shape, and density provide a molecular basis for loss of connectivity in Alzheimer’s disease. J Neurosci 2007; 27(4): 796-807.
[http://dx.doi.org/10.1523/JNEUROSCI.3501-06.2007] [PMID: 17251419]
[19]
Viola KL, Velasco PT, Klein WL. Why Alzheimer’s is a disease of memory: the attack on synapses by A beta oligomers (ADDLs). J Nutr Health Aging 2008; 12(1): 51S-7S.
[http://dx.doi.org/10.1007/BF02982587] [PMID: 18165846]
[20]
Walsh DM, Selkoe DJ. A beta oligomers - a decade of discovery. J Neurochem 2007; 101(5): 1172-84.
[http://dx.doi.org/10.1111/j.1471-4159.2006.04426.x] [PMID: 17286590]
[21]
Soejitno A, Tjan A, Purwata TE. Alzheimer’s disease: lessons learned from amyloidocentric Clinical Trials. CNS Drugs 2015; 29(6): 487-502.
[http://dx.doi.org/10.1007/s40263-015-0257-8] [PMID: 26187557]
[22]
Winblad B, Amouyel P, Andrieu S, et al. Defeating Alzheimer’s disease and other dementias: a priority for European science and society. Lancet Neurol 2016; 15(5): 455-532.
[http://dx.doi.org/10.1016/S1474-4422(16)00062-4] [PMID: 26987701]
[23]
Selkoe DJ, Hardy J. The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol Med 2016; 8(6): 595-608.
[http://dx.doi.org/10.15252/emmm.201606210] [PMID: 27025652]
[24]
Panza F, Solfrizzi V, Seripa D, et al. TAU-centric targets and drugs in clinical development for the treatment of Alzheimer’s disease. BioMed Res Int 2016; 2016 3245935
[http://dx.doi.org/10.1155/2016/3245935] [PMID: 27429978]
[25]
Panza F, Imbimbo BP, Lozupone M, et al. Disease-modifying therapies for tauopathies: agents in the pipeline. Expert Rev Neurother 2019; 19(5): 397-408.
[http://dx.doi.org/10.1080/14737175.2019.1606715] [PMID: 30973276]
[26]
Kametani F, Hasegawa M. Reconsideration of amyloid hypothesis and tau hypothesis in Alzheimer’s disease. Front Neurosci 2018. 30; 12: 25-5
[http://dx.doi.org/10.3389/fnins.2018.00025]
[27]
Arendt T, Stieler JT, Holzer M. Tau and tauopathies. Brain Res Bull 2016; 126(Pt 3): 238-92.
[http://dx.doi.org/10.1016/j.brainresbull.2016.08.018] [PMID: 27615390]
[28]
Paouri E, Georgopoulos S. Systemic and CNS inflammation crosstalk: implications for Alzheimer’s disease. Curr Alzheimer Res 2019; 16(6): 559-74.
[http://dx.doi.org/10.2174/1567205016666190321154618] [PMID: 30907316]
[29]
Selles MC, Oliveira MM, Ferreira ST. Brain inflammation connects cognitive and non-cognitive symptoms in Alzheimer’s disease. J Alzheimers Dis 2018; 64(s1): S313-27.
[http://dx.doi.org/10.3233/JAD-179925] [PMID: 29710716]
[30]
Ekert JO, Gould RL, Reynolds G, Howard RJ. TNF alpha inhibitors in Alzheimer’s disease: A systematic review. Int J Geriatr Psychiatry 2018; 33(5): 688-94.
[http://dx.doi.org/10.1002/gps.4871] [PMID: 29516540]
[31]
Hoyer S. Senile dementia and Alzheimer’s disease. Brain blood flow and metabolism. Prog Neuropsychopharmacol Biol Psychiatry 1986; 10(3-5): 447-78.
[http://dx.doi.org/10.1016/0278-5846(86)90018-7] [PMID: 3541046]
[32]
Hoyer S, Oesterreich K, Wagner O. Glucose metabolism as the site of the primary abnormality in early-onset dementia of Alzheimer type? J Neurol 1988; 235(3): 143-8.
[http://dx.doi.org/10.1007/BF00314304] [PMID: 3367161]
[33]
Hoyer S. Causes and consequences of disturbances of cerebral glucose metabolism in sporadic Alzheimer disease: therapeutic implications. Adv Exp Med Biol 2004; 541: 135-52.
[http://dx.doi.org/10.1007/978-1-4419-8969-7_8] [PMID: 14977212]
[34]
Blass JP, Gibson GE, Hoyer S. The role of the metabolic lesion in Alzheimer’s disease. J Alzheimers Dis 2002; 4(3): 225-32.
[http://dx.doi.org/10.3233/JAD-2002-4312] [PMID: 12226541]
[35]
Hoyer S. The aging brain. Changes in the neuronal insulin/insulin receptor signal transduction cascade trigger late-onset sporadic Alzheimer disease (SAD). A mini-review. J Neural Transm (Vienna) 2002; 109(7-8): 991-1002.
[http://dx.doi.org/10.1007/s007020200082] [PMID: 12111436]
[36]
de la Monte SM, Tong M, Wands JR. The 20-Year Voyage Aboard the Journal of Alzheimer’s Disease: Docking at ‘Type 3 Diabetes’, Environmental/Exposure Factors, Pathogenic Mechanisms, and Potential Treatments. J Alzheimers Dis 2018; 62(3): 1381-90.
[http://dx.doi.org/10.3233/JAD-170829] [PMID: 29562538]
[37]
de la Monte SM. Insulin resistance and neurodegeneration: progress towards the development of new therapeutics for Alzheimer’s disease. Drugs 2017; 77(1): 47-65.
[http://dx.doi.org/10.1007/s40265-016-0674-0] [PMID: 27988872]
[38]
Benedict C, Grillo CA. Insulin resistance as a therapeutic target in the treatment of Alzheimer’s disease: a state-of-the-art review. Front Neurosci 2018; 12: 215.
[http://dx.doi.org/10.3389/fnins.2018.00215] [PMID: 29743868]
[39]
Grillo CA, Woodruff JL, Macht VA, Reagan LP. Insulin resistance and hippocampal dysfunction: Disentangling peripheral and brain causes from consequences. Exp Neurol 2019; 318: 71-7.
[http://dx.doi.org/10.1016/j.expneurol.2019.04.012] [PMID: 31028829]
[40]
Grillo CA, Piroli GG, Lawrence RC, et al. Hippocampal insulin resistance impairs spatial learning and synaptic plasticity. Diabetes 2015; 64(11): 3927-36.
[http://dx.doi.org/10.2337/db15-0596] [PMID: 26216852]
[41]
Plaschke K, Kopitz J, Siegelin M, et al. Insulin-resistant brain state after intracerebroventricular streptozotocin injection exacerbates Alzheimer-like changes in Tg2576 AbetaPP-overexpressing mice. J Alzheimers Dis 2010; 19(2): 691-704.
[http://dx.doi.org/10.3233/JAD-2010-1270] [PMID: 20110613]
[42]
Salkovic-Petrisic M, Knezovic A, Hoyer S, Riederer P. What have we learned from the streptozotocin-induced animal model of sporadic Alzheimer’s disease, about the therapeutic strategies in Alzheimer’s research. J Neural Transm (Vienna) 2013; 120(1): 233-52.
[http://dx.doi.org/10.1007/s00702-012-0877-9] [PMID: 22886150]
[43]
Bomfim TR, Forny-Germano L, Sathler LB, et al. An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer’s disease- associated Aβ oligomers. J Clin Invest 2012; 122(4): 1339-53.
[http://dx.doi.org/10.1172/JCI57256] [PMID: 22476196]
[44]
Talbot K, Wang HY, Kazi H, et al. Demonstrated brain insulin resistance in Alzheimer’s disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. J Clin Invest 2012; 122(4): 1316-38.
[http://dx.doi.org/10.1172/JCI59903] [PMID: 22476197]
[45]
Singh-Manoux A, Dugravot A, Shipley M, et al. Obesity trajectories and risk of dementia: 28 years of follow-up in the Whitehall II Study. Alzheimers Dement 2018; 14(2): 178-86.
[http://dx.doi.org/10.1016/j.jalz.2017.06.2637] [PMID: 28943197]
[46]
Kivimäki M, Luukkonen R, Batty GD, et al. Body mass index and risk of dementia: Analysis of individual-level data from 1.3 million individuals. Alzheimers Dement 2018; 14(5): 601-9.
[http://dx.doi.org/10.1016/j.jalz.2017.09.016] [PMID: 29169013]
[47]
Pedditzi E, Peters R, Beckett N. The risk of overweight/obesity in mid-life and late life for the development of dementia: a systematic review and meta-analysis of longitudinal studies. Age Ageing 2016; 45(1): 14-21.
[http://dx.doi.org/10.1093/ageing/afv151] [PMID: 26764391]
[48]
Cirrito JR, Deane R, Fagan AM, et al. P-glycoprotein deficiency at the blood-brain barrier increases amyloid-beta deposition in an Alzheimer disease mouse model. J Clin Invest 2005; 115(11): 3285-90.
[http://dx.doi.org/10.1172/JCI25247] [PMID: 16239972]
[49]
Deo AK, Borson S, Link JM, et al. Activity of P-glycoprotein, a β-amyloid transporter at the blood-brain barrier, is compromised in patients with mild alzheimer disease. J Nucl Med 2014; 55(7): 1106-11.
[http://dx.doi.org/10.2967/jnumed.113.130161] [PMID: 24842892]
[50]
van Assema DM, Lubberink M, Bauer M, et al. Blood-brain barrier P-glycoprotein function in Alzheimer’s disease. Brain 2012; 135(Pt 1): 181-9.
[http://dx.doi.org/10.1093/brain/awr298] [PMID: 22120145]
[51]
He JT, Zhao X, Xu L, Mao CY. Vascular risk factors and alzheimer’s disease: blood-brain barrier disruption, metabolic syndromes, and molecular links. J Alzheimers Dis 2019; 73(1): 39-58.
[http://dx.doi.org/10.3233/JAD-190764] [PMID: 31815697]
[52]
Cummings J, Lee G, Ritter A, Sabbagh M, Zhong K. Alzheimer’s disease drug development pipeline: 2019. Alzheimers Dement (N Y) 2019; 5: 272-93.
[http://dx.doi.org/10.1016/j.trci.2019.05.008] [PMID: 31334330]
[53]
2019 Alzheimer’s disease facts and figures. Alzheimers Dement 2019; 15: 321-87.
[http://dx.doi.org/10.1016/j.jalz.2019.01.010]
[54]
Cline EN, Bicca MA, Viola KL, Klein WL. The Amyloid-β Oligomer hypothesis: beginning of the third decade. J Alzheimers Dis 2018; 64(s1): S567-610.
[http://dx.doi.org/10.3233/JAD-179941] [PMID: 29843241]
[55]
Hsiao CC, Rombouts F, Gijsen HJM. New evolutions in the BACE1 inhibitor field from 2014 to 2018. Bioorg Med Chem Lett 2019; 29(6): 761-77.
[http://dx.doi.org/10.1016/j.bmcl.2018.12.049] [PMID: 30709653]
[56]
Ghosh AK, Brindisi M, Yen YC, et al. Highly selective and potent human β-secretase 2 (BACE2) inhibitors against type 2 diabetes: design, synthesis, x-ray structure and structure-activity relationship studies. ChemMedChem 2019; 14(5): 545-60.
[http://dx.doi.org/10.1002/cmdc.201900100] [PMID: 30637955]
[57]
Sharma P, Srivastava P, Seth A, Tripathi PN, Banerjee AG, Shrivastava SK. Comprehensive review of mechanisms of pathogenesis involved in Alzheimer’s disease and potential therapeutic strategies. Prog Neurobiol 2019; 174: 53-89.
[http://dx.doi.org/10.1016/j.pneurobio.2018.12.006] [PMID: 30599179]
[58]
Brendel M, Jaworska A, Overhoff F, et al. Efficacy of chronic BACE1 inhibition in PS2APP mice depends on the regional Aβ deposition rate and plaque burden at treatment initiation. Theranostics 2018; 8(18): 4957-68.
[http://dx.doi.org/10.7150/thno.27868] [PMID: 30429879]
[59]
Panza F, Lozupone M, Solfrizzi V, et al. BACE inhibitors in clinical development for the treatment of Alzheimer’s disease. Expert Rev Neurother 2018; 18(11): 847-57.
[http://dx.doi.org/10.1080/14737175.2018.1531706] [PMID: 30277096]
[60]
Burki T. Alzheimer’s disease research: the future of BACE inhibitors. Lancet 2018; 391(10139): 2486.
[http://dx.doi.org/10.1016/S0140-6736(18)31425-9] [PMID: 29976459]
[61]
Yan R, Fan Q, Zhou J, Vassar R. Inhibiting BACE1 to reverse synaptic dysfunctions in Alzheimer’s disease. Neurosci Biobehav Rev 2016; 65: 326-40.
[http://dx.doi.org/10.1016/j.neubiorev.2016.03.025] [PMID: 27044452]
[62]
Zuhl AM, Nolan CE, Brodney MA, et al. Chemoproteomic profiling reveals that cathepsin D off-target activity drives ocular toxicity of β-secretase inhibitors. Nat Commun 2016; 7: 13042.
[http://dx.doi.org/10.1038/ncomms13042] [PMID: 27727204]
[63]
Campagna J, Vadivel K, Jagodzinska B, et al. Evaluation of an Allosteric BACE Inhibitor Peptide to identify mimetics that can interact with the loop F region of the enzyme and prevent APP cleavage. J Mol Biol 2018; 430(11): 1566-76.
[http://dx.doi.org/10.1016/j.jmb.2018.04.002] [PMID: 29649434]
[64]
Kumar D, Ganeshpurkar A, Kumar D, Modi G, Gupta SK, Singh SK. Secretase inhibitors for the treatment of Alzheimer’s disease: Long road ahead. Eur J Med Chem 2018; 148: 436-52.
[http://dx.doi.org/10.1016/j.ejmech.2018.02.035] [PMID: 29477076]
[65]
Zhang L, Chen L, Dutra JK, et al. Identification of a novel positron emission tomography (PET) ligand for imaging β-site amyloid precursor protein cleaving enzyme 1 (BACE-1) in Brain. J Med Chem 2018; 61(8): 3296-308.
[http://dx.doi.org/10.1021/acs.jmedchem.7b01769] [PMID: 29356535]
[66]
Timmers M, Barão S, Van Broeck B, et al. BACE1 dynamics upon inhibition with a bace inhibitor and correlation to downstream alzheimer’s disease markers in elderly healthy participants. J Alzheimers Dis 2017; 56(4): 1437-49.
[http://dx.doi.org/10.3233/JAD-160829] [PMID: 28157093]
[67]
Kennedy ME, Stamford AW, Chen X, et al. The BACE1 inhibitor verubecestat (MK-8931) reduces CNS β-amyloid in animal models and in Alzheimer’s disease patients. Sci Transl Med 2016; 8(363) 363ra150
[http://dx.doi.org/10.1126/scitranslmed.aad9704] [PMID: 27807285]
[68]
Egan MF, Kost J, Voss T, et al. Randomized Trial of Verubecestat for Prodromal Alzheimer’s Disease. N Engl J Med 2019; 380(15): 1408-20.
[http://dx.doi.org/10.1056/NEJMoa1812840] [PMID: 30970186]
[69]
Egan MF, Kost J, Tariot PN, et al. Randomized trial of verubecestat for mild-to-moderate Alzheimer’s disease. N Engl J Med 2018; 378(18): 1691-703.
[http://dx.doi.org/10.1056/NEJMoa1706441] [PMID: 29719179]
[70]
Sims JR, Selzler KJ, Downing AM, et al. Development review of the bace1 inhibitor lanabecestat (AZD3293/LY3314814). J Prev Alzheimers Dis 2017; 4(4): 247-54.
[PMID: 29181490]
[71]
Sakamoto K, Matsuki S, Matsuguma K, et al. 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): 1460-71.
[http://dx.doi.org/10.1002/jcph.950] [PMID: 28618005]
[72]
Ye N, Monk SA, Daga P, et al. 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): 233-43.
[http://dx.doi.org/10.1002/cpdd.422] [PMID: 29319935]
[73]
Timmers M, Streffer JR, Russu A, et al. 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]
[74]
Henley D, Raghavan N, Sperling R, Aisen P, Raman R, Romano G. Preliminary results of a trial of atabecestat in preclinical alzheimer’s disease. N Engl J Med 2019; 380(15): 1483-5.
[http://dx.doi.org/10.1056/NEJMc1813435] [PMID: 30970197]
[75]
Neumann U, Ufer M, Jacobson LH, et al. The BACE-1 inhibitor CNP520 for prevention trials in Alzheimer’s disease. EMBO Mol Med 2018; 10(11) pii: e9316
[76]
Lopez Lopez C, Caputo A, Liu F, et al. The Alzheimer’s prevention initiative generation program: evaluating cnp520 efficacy in the prevention of Alzheimer’s disease. J Prev Alzheimers Dis 2017; 4(4): 242-6.
[PMID: 29181489]
[77]
O’Neill BT, Beck EM, Butler CR, et al. 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): 4476-504.
[http://dx.doi.org/10.1021/acs.jmedchem.8b00246] [PMID: 29613789]
[78]
Qiu R, Ahn JE, Alexander R, et al. Safety, tolerability, pharmacokinetics, and pharmacodynamic effects of PF-06751979, a potent and selective oral bace1 inhibitor: results from phase i studies in healthy adults and healthy older subjects. J Alzheimers Dis 2019; 71(2): 581-95.
[http://dx.doi.org/10.3233/JAD-190228] [PMID: 31424395]
[79]
Boada M, López O, Núñez L, et al. Plasma exchange for Alzheimer’s disease Management by Albumin Replacement (AMBAR) trial: Study design and progress. Alzheimers Dement (N Y) 2019; 5: 61-9.
[http://dx.doi.org/10.1016/j.trci.2019.01.001] [PMID: 30859122]
[80]
Boada M, Ramos-Fernández E, Guivernau B, et al. Treatment of Alzheimer disease using combination therapy with plasma exchange and haemapheresis with albumin and intravenous immunoglobulin: Rationale and treatment approach of the AMBAR (Alzheimer Management By Albumin Replacement) study. Neurologia 2016; 31(7): 473-81.
[http://dx.doi.org/10.1016/j.nrl.2014.02.003] [PMID: 25023458]
[81]
Panza F, Lozupone M, Dibello V, et al. Are antibodies directed against amyloid-β (Aβ) oligomers the last call for the Aβ hypothesis of Alzheimer’s disease? Immunotherapy 2019; 11(1): 3-6.
[http://dx.doi.org/10.2217/imt-2018-0119] [PMID: 30702009]
[82]
Panza F, Seripa D, Solfrizzi V, et al. Emerging drugs to reduce abnormal β-amyloid protein in Alzheimer’s disease patients. Expert Opin Emerg Drugs 2016; 21(4): 377-91.
[http://dx.doi.org/10.1080/14728214.2016.1241232] [PMID: 27678025]
[83]
Kastanenka KV, Bussiere T, Shakerdge N, et al. Immunotherapy with Aducanumab Restores Calcium Homeostasis in Tg2576 Mice. J Neurosci 2016; 36(50): 12549-58.
[http://dx.doi.org/10.1523/JNEUROSCI.2080-16.2016] [PMID: 27810931]
[84]
Ferrero J, Williams L, Stella H, et al. First-in-human, double-blind, placebo-controlled, single-dose escalation study of aducanumab (BIIB037) in mild-to-moderate Alzheimer’s disease. Alzheimers Dement (N Y) 2016; 2(3): 169-76.
[http://dx.doi.org/10.1016/j.trci.2016.06.002] [PMID: 29067304]
[85]
Sevigny J, Chiao P, Bussière T, et al. The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease. Nature 2016; 537(7618): 50-6.
[http://dx.doi.org/10.1038/nature19323] [PMID: 27582220]
[86]
Selkoe DJ. Alzheimer disease and aducanumab: adjusting our approach. Nat Rev Neurol 2019; 15(7): 365-6.
[http://dx.doi.org/10.1038/s41582-019-0205-1] [PMID: 31138932]
[87]
Budd Haeberlein S, O’Gorman J, Chiao P, et al. Clinical development of aducanumab, an anti-aβ human monoclonal antibody being investigated for the treatment of early Alzheimer’s disease. J Prev Alzheimers Dis 2017; 4(4): 255-63.
[PMID: 29181491]
[88]
Logovinsky V, Satlin A, Lai R, et al. Safety and tolerability of BAN2401--a clinical study in Alzheimer’s disease with a protofibril selective Aβ antibody. Alzheimers Res Ther 2016; 8(1): 14.
[http://dx.doi.org/10.1186/s13195-016-0181-2] [PMID: 27048170]
[89]
Lannfelt L, Möller C, Basun H, et al. Perspectives on future Alzheimer therapies: amyloid-β protofibrils - a new target for immunotherapy with BAN2401 in Alzheimer’s disease. Alzheimers Res Ther 2014; 6(2): 16.
[http://dx.doi.org/10.1186/alzrt246] [PMID: 25031633]
[90]
Satlin A, Wang J, Logovinsky V, et al. Design of a Bayesian adaptive phase 2 proof-of-concept trial for BAN2401, a putative disease-modifying monoclonal antibody for the treatment of Alzheimer’s disease. Alzheimers Dement (N Y) 2016; 2(1): 1-12.
[http://dx.doi.org/10.1016/j.trci.2016.01.001] [PMID: 29067290]
[91]
Salloway S, Honigberg LA, Cho W, et al. Amyloid positron emission tomography and cerebrospinal fluid results from a crenezumab anti-amyloid-beta antibody double-blind, placebo-controlled, randomized phase II study in mild-to-moderate Alzheimer’s disease (BLAZE). Alzheimers Res Ther 2018; 10(1): 96.
[http://dx.doi.org/10.1186/s13195-018-0424-5] [PMID: 30231896]
[92]
Cummings JL, Cohen S, van Dyck CH, et al. ABBY: A phase 2 randomized trial of crenezumab in mild to moderate Alzheimer disease. Neurology 2018; 90(21): e1889-97.
[http://dx.doi.org/10.1212/WNL.0000000000005550] [PMID: 29695589]
[93]
Ostrowitzki S, Lasser RA, Dorflinger E, et al. A phase III randomized trial of gantenerumab in prodromal Alzheimer’s disease. Alzheimers Res Ther 2017; 9(1): 95.
[http://dx.doi.org/10.1186/s13195-017-0318-y] [PMID: 29221491]
[94]
Pradier L, Blanchard-Brégeon V, Bohme A, et al. SAR228810: an antibody for protofibrillar amyloid β peptide designed to reduce the risk of amyloid-related imaging abnormalities (ARIA). Alzheimers Res Ther 2018; 10(1): 117.
[http://dx.doi.org/10.1186/s13195-018-0447-y] [PMID: 30486882]
[95]
Grundman M, Morgan R, Lickliter JD, et al. 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: 20-6.
[http://dx.doi.org/10.1016/j.trci.2018.11.001] [PMID: 30723776]
[96]
Billinton A, Newton P, Lloyd C, et al. Preclinical discovery and development of medi1814, a monoclonal antibody selectively targeting beta-amyloid 42 (aβ42). Alzheimers Dement 2017; 13: 266.
[http://dx.doi.org/10.1016/j.jalz.2017.06.141]
[97]
Pesini P, Lacosta AM, Sarasa M. The deposition of Aβ40 in the brain is pathognomonic for Alzheimer-type dementia in Down syndrome. Alzheimers Dement 2009; 5: 297-8.
[http://dx.doi.org/10.1016/j.jalz.2009.04.434]
[98]
Lacosta AM, Pascual-Lucas M, Pesini P, et al. 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]
[99]
Wang CY, Finstad CL, Walfield AM, et al. Site-specific UBITh amyloid-beta vaccine for immunotherapy of Alzheimer’s disease. Vaccine 2007; 25(16): 3041-52.
[http://dx.doi.org/10.1016/j.vaccine.2007.01.031] [PMID: 17287052]
[100]
Wang CY, Wang PN, Chiu MJ, et al. UB-311, a novel UBITh® amyloid β peptide vaccine for mild Alzheimer’s disease. Alzheimers Dement (N Y) 2017; 3(2): 262-72.
[http://dx.doi.org/10.1016/j.trci.2017.03.005] [PMID: 29067332]
[101]
Näslund J, Schierhorn A, Hellman U, et al. Relative abundance of Alzheimer A β amyloid peptide variants in Alzheimer disease and normal aging. Proc Natl Acad Sci USA 1994; 91(18): 8378-82.
[http://dx.doi.org/10.1073/pnas.91.18.8378] [PMID: 8078890]
[102]
Muhs A, Hickman DT, Pihlgren M, et al. Liposomal vaccines with conformation-specific amyloid peptide antigens define immune response and efficacy in APP transgenic mice. Proc Natl Acad Sci USA 2007; 104(23): 9810-5.
[http://dx.doi.org/10.1073/pnas.0703137104] [PMID: 17517595]
[103]
Hickman DT, López-Deber MP, Ndao DM, et al. Sequence-independent control of peptide conformation in liposomal vaccines for targeting protein misfolding diseases. J Biol Chem 2011; 286(16): 13966-76.
[http://dx.doi.org/10.1074/jbc.M110.186338] [PMID: 21343310]
[104]
Khan A, Corbett A, Ballard C. Emerging amyloid and tau targeting treatments for Alzheimer’s diseaseExpert Rev Neurother 2017; 17(7): 697-711. l.
[http://dx.doi.org/10.1080/14737175.2017.1326819] [PMID: 28490214]
[105]
Wischik CM, Harrington CR, Storey JM. Tau-aggregation inhibitor therapy for Alzheimer’s disease. Biochem Pharmacol 2014; 88(4): 529-39.
[http://dx.doi.org/10.1016/j.bcp.2013.12.008] [PMID: 24361915]
[106]
Gauthier S, Feldman HH, Schneider LS, et al. Efficacy and safety of tau-aggregation inhibitor therapy in patients with mild or moderate Alzheimer’s disease: a randomised, controlled, double-blind, parallel-arm, phase 3 trial. Lancet 2016; 388(10062): 2873-84.
[http://dx.doi.org/10.1016/S0140-6736(16)31275-2] [PMID: 27863809]
[107]
Atamna H, Kumar R. Protective role of methylene blue in Alzheimer’s disease via mitochondria and cytochrome c oxidase. J Alzheimers Dis 2010; 20(Suppl. 2): S439-52.
[http://dx.doi.org/10.3233/JAD-2010-100414] [PMID: 20463399]
[108]
Novak P, Schmidt R, Kontsekova E, et al. 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): 123-34.
[http://dx.doi.org/10.1016/S1474-4422(16)30331-3] [PMID: 27955995]
[109]
Novak P, Zilka N, Zilkova M, et al. AADvac1, an Active Immunotherapy for Alzheimer’s disease and non Alzheimer tauopathies: an overview of preclinical and clinical development. J Prev Alzheimers Dis 2019; 6(1): 63-9.
[PMID: 30569088]
[110]
Novak P, Schmidt R, Kontsekova E, et al. FUNDAMANT: an interventional 72-week phase 1 follow-up study of AADvac1, an active immunotherapy against tau protein pathology in Alzheimer’s disease. Alzheimers Res Ther 2018; 10(1): 108.
[http://dx.doi.org/10.1186/s13195-018-0436-1] [PMID: 30355322]
[111]
Kontsekova E, Zilka N, Kovacech B, Novak P, Novak M. First-in-man tau vaccine targeting structural determinants essential for pathological tau-tau interaction reduces tau oligomerisation and neurofibrillary degeneration in an Alzheimer’s disease model. Alzheimers Res Ther 2014; 6(4): 44.
[http://dx.doi.org/10.1186/alzrt278] [PMID: 25478017]
[112]
West T, Hu Y, Verghese PB, et al. Preclinical and Clinical Development of ABBV-8E12, a Humanized anti-tau antibody, for treatment of Alzheimer’s disease and other tauopathies. J Prev Alzheimers Dis 2017; 4(4): 236-41.
[PMID: 29181488]
[113]
Doody R. Developing disease-modifying treatments in alzheimer’s disease - a perspective from roche and genentech. J Prev Alzheimers Dis 2017; 4(4): 264-72.
[PMID: 29181492]
[114]
Alam R, Driver D, Wu S, et al. Preclinical characterization of an antibody [ly3303560] targeting aggregated TAU Alzheimer’s Dement 2017. 13: 592-3
[115]
Calsolaro V, Edison P. Neuroinflammation in Alzheimer’s disease: Current evidence and future directions. Alzheimers Dement 2016; 12(6): 719-32.
[http://dx.doi.org/10.1016/j.jalz.2016.02.010] [PMID: 27179961]
[116]
Zhang C, Griciuc A, Hudry E, et al. Cromolyn reduces levels of the alzheimer’s disease-associated amyloid β-protein by promoting microglial phagocytosis. Sci Rep 2018; 8(1): 1144.
[http://dx.doi.org/10.1038/s41598-018-19641-2] [PMID: 29348604]
[117]
Ettcheto M, Sánchez-López E, Pons L, et al. Dexibuprofen prevents neurodegeneration and cognitive decline in APPswe/PS1dE9 through multiple signaling pathways. Redox Biol 2017; 13: 345-52.
[http://dx.doi.org/10.1016/j.redox.2017.06.003] [PMID: 28646794]
[118]
Wilcock GK, Black SE, Hendrix SB, Zavitz KH, Swabb EA, Laughlin MA. Tarenflurbil Phase II Study investigators. Efficacy and safety of tarenflurbil in mild to moderate Alzheimer’s disease: a randomized phase II trial. Lancet Neurol 2008; 7: 483-93.
[http://dx.doi.org/10.1016/S1474-4422(08)70090-5] [PMID: 18450517]
[119]
Green RC, Schneider LS, Amato DA, et al. Effect of tarenflurbil on cognitive decline and activities of daily living in patients with mild Alzheimer disease: a randomized controlled trial. JAMA 2009; 302(23): 2557-64.
[http://dx.doi.org/10.1001/jama.2009.1866] [PMID: 20009055]
[120]
Brazier D, Perry R, Keane J, Barrett K, Elmaleh DR. Pharmacokinetics of cromolyn and ibuprofen in healthy elderly volunteers. Clin Drug Investig 2017; 37(11): 1025-34.
[http://dx.doi.org/10.1007/s40261-017-0549-5] [PMID: 28856569]
[121]
De Felice FG. Alzheimer’s disease and insulin resistance: translating basic science into clinical applications. J Clin Invest 2013; 123(2): 531-9.
[http://dx.doi.org/10.1172/JCI64595] [PMID: 23485579]
[122]
De Felice FG, Ferreira ST. Inflammation, defective insulin signaling, and mitochondrial dysfunction as common molecular denominators connecting type 2 diabetes to Alzheimer disease. Diabetes 2014; 63(7): 2262-72.
[http://dx.doi.org/10.2337/db13-1954] [PMID: 24931033]
[123]
Hsu CC, Wahlqvist ML, Lee MS, Tsai HN. Incidence of dementia is increased in type 2 diabetes and reduced by the use of sulfonylureas and metformin. J Alzheimers Dis 2011; 24(3): 485-93.
[http://dx.doi.org/10.3233/JAD-2011-101524] [PMID: 21297276]
[124]
Boccardi V, Murasecco I, Mecocci P. Diabetes drugs in the fight against Alzheimer’s disease. Ageing Res Rev 2019; 54: 100936
[http://dx.doi.org/10.1016/j.arr.2019.100936] [PMID: 31330313]
[125]
McClean PL, Parthsarathy V, Faivre E, Hölscher C. The diabetes drug liraglutide prevents degenerative processes in a mouse model of Alzheimer’s disease. J Neurosci 2011; 31(17): 6587-94.
[http://dx.doi.org/10.1523/JNEUROSCI.0529-11.2011] [PMID: 21525299]
[126]
Gejl M, Gjedde A, Egefjord L, et al. In Alzheimer’s disease, 6-month treatment with GLP-1 analog prevents decline of brain glucose metabolism: randomized, placebo-controlled, double-blind clinical trial. Front Aging Neurosci 2016; 8: 108.
[http://dx.doi.org/10.3389/fnagi.2016.00108] [PMID: 27252647]
[127]
Patrick S, Corrigan R, Grizzanti J, et al. Neuroprotective effects of the amylin analog, pramlintide, on alzheimer’s disease are associated with oxidative stress regulation mechanisms. J Alzheimers Dis 2019; 69(1): 157-68.
[http://dx.doi.org/10.3233/JAD-180421] [PMID: 30958347]
[128]
Landreth GE, Heneka MT. Anti-inflammatory actions of peroxisome proliferator-activated receptor gamma agonists in Alzheimer’s disease. Neurobiol Aging 2001; 22(6): 937-44.
[http://dx.doi.org/10.1016/S0197-4580(01)00296-2] [PMID: 11755002]
[129]
Vandal M, White PJ, Tremblay C, et al. Insulin reverses the high-fat diet-induced increase in brain Aβ and improves memory in an animal model of Alzheimer disease. Diabetes 2014; 63(12): 4291-301.
[http://dx.doi.org/10.2337/db14-0375] [PMID: 25008180]
[130]
Chapman CD, Schiöth HB, Grillo CA, Benedict C. Intranasal insulin in Alzheimer’s disease: food for thought Neuropharmacology 2018; 136(Pt B): 196-201.
[http://dx.doi.org/10.1016/j.neuropharm.2017.11.037] [PMID: 29180222]
[131]
McDade E, Bateman RJ. Stop Alzheimer’s before it starts. Nature 2017; 547(7662): 153-5.
[http://dx.doi.org/10.1038/547153a] [PMID: 28703214]
[132]
Balakrishnan K, Verdile G, Mehta PD, et al. Plasma Abeta42 correlates positively with increased body fat in healthy individuals. J Alzheimers Dis 2005; 8(3): 269-82.
[http://dx.doi.org/10.3233/JAD-2005-8305] [PMID: 16340084]
[133]
Fish PV, Steadman D, Bayle ED, Whiting P. New approaches for the treatment of Alzheimer’s disease. Bioorg Med Chem Lett 2019; 29(2): 125-33.
[http://dx.doi.org/10.1016/j.bmcl.2018.11.034] [PMID: 30501965]
[134]
Godyń J, Jończyk J, Panek D, Malawska B. Therapeutic strategies for Alzheimer’s disease in clinical trials. Pharmacol Rep 2016; 68(1): 127-38.
[http://dx.doi.org/10.1016/j.pharep.2015.07.006] [PMID: 26721364]
[135]
Cummings JL, Tong G, Ballard C. Treatment combinations for Alzheimer ’s disease: current and future pharmacotherapy options. J Alzheimers Dis 2019; 67(3): 779-94.
[http://dx.doi.org/10.3233/JAD-180766] [PMID: 30689575]
[136]
Fessel J. Prevention of Alzheimer’s disease by treating mild cognitive impairment with combinations chosen from eight available drugs. Alzheimers Dement (N Y) 2019; 5: 780-8.
[http://dx.doi.org/10.1016/j.trci.2019.09.019] [PMID: 31763432]

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