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MU Yao, ZHAO Huimin, LIU Haochen, et al. Advances in drug development for Alzheimer’s disease[J]. J China Pharm Univ, 2024, 55(6): 816 − 825. DOI: 10.11665/j.issn.1000-5048.2024010202
Citation: MU Yao, ZHAO Huimin, LIU Haochen, et al. Advances in drug development for Alzheimer’s disease[J]. J China Pharm Univ, 2024, 55(6): 816 − 825. DOI: 10.11665/j.issn.1000-5048.2024010202

Advances in drug development for Alzheimer’s disease

Funds: This study was supported by the National Natural Science Foundation of China(No.81903703)
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  • Received Date: January 01, 2024
  • Alzheimer’s disease (AD) is a neurodegenerative disorder involving multiple pathological processes, clinically characterized by memory loss and cognitive impairment. The pathological processes of AD are complex, and the etiology remains unclear. Currently, there are various hypotheses including β-amyloid (Aβ) deposition, tau protein hyperphosphorylation, neuroinflammation, and synaptic loss, upon which researchers base their drug development efforts. Prior to 2021, drugs approved by the U.S. Food and Drug Administration (FDA) had targeted neurotransmitter modulation, but their efficacy was limited. In recent years, the approval of two anti-Aβ monoclonal antibody drugs has brought some clinical benefits to patients, yet they have not fully met clinical needs, which had highlighted the urgent necessity for exploration of new mechanisms and targets in AD drug development. Presently, research on novel mechanisms and targets for AD drug development focuses primarily on several directions: anti-Aβ drugs, anti-Tau protein drugs, anti-neuroinflammation immunotherapies, mitochondrial function-improving drugs, neurogenesis-promoting drugs, and synapse-protective drugs. This paper provides an overview of AD drugs entering clinical trials in the past decade in these directions, details some representative drugs, and concludes with prospects, integrating findings from our research group.

  • [1]
    Scheltens P, Blennow K, Breteler MM, et al. Alzheimer’s disease[J]. Lancet, 2016, 388(10043): 505-517. doi: 10.1016/S0140-6736(15)01124-1
    [2]
    Audagnotto M, Kengo Lorkowski A, Dal Peraro M. Recruitment of the amyloid precursor protein by γ-secretase at the synaptic plasma membrane[J]. Biochem Biophys Res Commun, 2018, 498(2): 334-341. doi: 10.1016/j.bbrc.2017.10.164
    [3]
    Long JM, Holtzman DM. Alzheimer disease: an update on pathobiology and treatment strategies[J]. Cell, 2019, 179(2): 312-339. doi: 10.1016/j.cell.2019.09.001
    [4]
    Canter RG, Penney J, Tsai LH. The road to restoring neural circuits for the treatment of Alzheimer’s disease[J]. Nature, 2016, 539(7628): 187-196. doi: 10.1038/nature20412
    [5]
    Monteiro KLC, Dos Santos Alcântara MG, Freire NML, et al. BACE-1 inhibitors targeting Alzheimer’s disease[J]. Curr Alzheimer Res, 2023, 20(3): 131-148. doi: 10.2174/1567205020666230612155953
    [6]
    Yang GH, Zhou R, Guo XF, et al. Structural basis of γ-secretase inhibition and modulation by small molecule drugs[J]. Cell, 2021, 184 (2): 521-533. e14.
    [7]
    Burki T. Alzheimer’s disease research: the future of BACE inhibitors[J]. Lancet, 2018, 391(10139): 2486. doi: 10.1016/S0140-6736(18)31425-9
    [8]
    Yiannopoulou KG, Papageorgiou SG. Current and future treatments for Alzheimer’s disease[J]. Ther Adv Neurol Disord, 2013, 6(1): 19-33. doi: 10.1177/1756285612461679
    [9]
    Tolar M, Abushakra S, Sabbagh M. The path forward in Alzheimer’s disease therapeutics: reevaluating the amyloid cascade hypothesis[J]. Alzheimers Dement, 2020, 16(11): 1553-1560. doi: 10.1016/j.jalz.2019.09.075
    [10]
    Knopman DS, Jones DT, Greicius MD. Failure to demonstrate efficacy of aducanumab: an analysis of the EMERGE and ENGAGE trials as reported by biogen, December 2019[J]. Alzheimers Dement, 2021, 17(4): 696-701. doi: 10.1002/alz.12213
    [11]
    Söderberg L, Johannesson M, Nygren P, et al. Lecanemab, aducanumab, and gantenerumab - binding profiles to different forms of amyloid-beta might explain efficacy and side effects in clinical trials for Alzheimer’s disease[J]. Neurotherapeutics, 2023, 20(1): 195-206. doi: 10.1007/s13311-022-01308-6
    [12]
    Iqbal K, Liu F, Gong CX, et al. Tau in Alzheimer disease and related tauopathies[J]. Curr Alzheimer Res, 2010, 7(8): 656-664. doi: 10.2174/156720510793611592
    [13]
    Kaufmann WE, Sprouse J, Rebowe N, et al. ANAVEX®2-73 (blarcamesine), a Sigma-1 receptor agonist, ameliorates neurologic impairments in a mouse model of Rett syndrome[J]. Pharmacol Biochem Behav, 2019, 187: 172796. doi: 10.1016/j.pbb.2019.172796
    [14]
    Harrington CR, Storey JM, Clunas S, et al. Cellular models of aggregation-dependent template-directed proteolysis to characterize tau aggregation inhibitors for treatment of Alzheimer disease[J]. J Biol Chem, 2015, 290(17): 10862-10875. doi: 10.1074/jbc.M114.616029
    [15]
    Panza F, Lozupone M. The challenges of anti-tau therapeutics in Alzheimer disease[J]. Nat Rev Neurol, 2022, 18(10): 577-578. doi: 10.1038/s41582-022-00702-0
    [16]
    Rawat P, Sehar U, Bisht J, et al. Phosphorylated tau in Alzheimer’s disease and other tauopathies[J]. Int J Mol Sci, 2022, 23(21): 12841. doi: 10.3390/ijms232112841
    [17]
    Grüninger F. Invited review: drug development for tauopathies[J]. Neuropathol Appl Neurobiol, 2015, 41(1): 81-96. doi: 10.1111/nan.12192
    [18]
    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]. J Prev Alzheimers Dis, 2019, 6(1): 63-69.
    [19]
    Parrocha CMT, Nowick JS. Current peptide vaccine and immunotherapy approaches against Alzheimer’s disease[J]. Pept Sci, 2023, 115(1): e24289. doi: 10.1002/pep2.24289
    [20]
    Stamouli EC, Politis AM. Pro-inflammatory cytokines in Alzheimer’s disease[J]. Psychiatriki, 2016, 27(4): 264-275. doi: 10.22365/jpsych.2016.274.264
    [21]
    Shen ZW, Bao XJ, Wang RZ. Clinical PET imaging of microglial activation: implications for microglial therapeutics in Alzheimer’s disease[J]. Front Aging Neurosci, 2018, 10: 314. doi: 10.3389/fnagi.2018.00314
    [22]
    Hampel H, Caraci F, Cuello AC, et al. A path toward precision medicine for neuroinflammatory mechanisms in Alzheimer’s disease[J]. Front Immunol, 2020, 11: 456. doi: 10.3389/fimmu.2020.00456
    [23]
    Wyss-Coray T, Rogers J. Inflammation in Alzheimer disease-a brief review of the basic science and clinical literature[J]. Cold Spring Harb Perspect Med, 2012, 2(1): a006346.
    [24]
    Song T, Song XP, Zhu C, et al. Mitochondrial dysfunction, oxidative stress, neuroinflammation, and metabolic alterations in the progression of Alzheimer’s disease: a meta-analysis of in vivo magnetic resonance spectroscopy studies[J]. Ageing Res Rev, 2021, 72: 101503. doi: 10.1016/j.arr.2021.101503
    [25]
    Butchart J, Brook L, Hopkins V, et al. Etanercept in Alzheimer disease: a randomized, placebo-controlled, double-blind, phase 2 trial[J]. Neurology, 2015, 84(21): 2161-2168. doi: 10.1212/WNL.0000000000001617
    [26]
    Decourt B, Drumm-Gurnee D, Wilson J, et al. Poor safety and tolerability hamper reaching a potentially therapeutic dose in the use of thalidomide for Alzheimer’s disease: results from a double-blind, placebo-controlled trial[J]. Curr Alzheimer Res, 2017, 14(4): 403-411. doi: 10.2174/1567205014666170117141330
    [27]
    Wang YM, Cella M, Mallinson K, et al. TREM2 lipid sensing sustains the microglial response in an Alzheimer’s disease model[J]. Cell, 2015, 160(6): 1061-1071. doi: 10.1016/j.cell.2015.01.049
    [28]
    Wang ST, Mustafa M, Yuede CM, et al. Anti-human TREM2 induces microglia proliferation and reduces pathology in an Alzheimer’s disease model[J]. J Exp Med, 2020, 217(9): e20200785. doi: 10.1084/jem.20200785
    [29]
    Nguyen TT, Wei SB, Nguyen TH, et al. Mitochondria-associated programmed cell death as a therapeutic target for age-related disease[J]. Exp Mol Med, 2023, 55(8): 1595-1619. doi: 10.1038/s12276-023-01046-5
    [30]
    Han S, Jeong YY, Sheshadri P, et al. Mitophagy regulates integrity of mitochondria at synapses and is critical for synaptic maintenance[J]. EMBO Rep, 2020, 21(9): e49801. doi: 10.15252/embr.201949801
    [31]
    Wang Y, Zou JY, Wang Y, et al. Hydralazine inhibits neuroinflammation and oxidative stress in APP/PS1 mice via TLR4/NF-κB and Nrf2 pathways[J]. Neuropharmacology, 2023, 240: 109706. doi: 10.1016/j.neuropharm.2023.109706
    [32]
    Vasic V, Barth K, Schmidt MHH. Neurodegeneration and neuro-regeneration-Alzheimer’s disease and stem cell therapy[J]. Int J Mol Sci, 2019, 20(17): 4272. doi: 10.3390/ijms20174272
    [33]
    Nakaji-Hirabayashi T, Kato K, Iwata H. In vivo study on the survival of neural stem cells transplanted into the rat brain with a collagen hydrogel that incorporates laminin-derived polypeptides[J]. Bioconjug Chem, 2013, 24(11): 1798-1804. doi: 10.1021/bc400005m
    [34]
    Mu YL, Gage FH. Adult hippocampal neurogenesis and its role in Alzheimer’s disease[J]. Mol Neurodegener, 2011, 6: 85. doi: 10.1186/1750-1326-6-85
    [35]
    Knudsen LB, Lau J. The discovery and development of liraglutide and semaglutide[J]. Front Endocrinol, 2019, 10: 155. doi: 10.3389/fendo.2019.00155
    [36]
    Du HY, Meng XY, Yao Y, et al. The mechanism and efficacy of GLP-1 receptor agonists in the treatment of Alzheimer’s disease[J]. Front Endocrinol, 2022, 13: 1033479. doi: 10.3389/fendo.2022.1033479
    [37]
    Vargas-Soria M, Carranza-Naval MJ, Del Marco A, et al. Role of liraglutide in Alzheimer’s disease pathology[J]. Alzheimers Res Ther, 2021, 13(1): 112. doi: 10.1186/s13195-021-00853-0
    [38]
    Femminella GD, Frangou E, Love SB, et al. Evaluating the effects of the novel GLP-1 analogue liraglutide in Alzheimer’s disease: study protocol for a randomised controlled trial (ELAD study)[J]. Trials, 2019, 20(1): 191. doi: 10.1186/s13063-019-3259-x
    [39]
    Briyal S, Nguyen C, Leonard M, et al. Stimulation of endothelin B receptors by IRL-1620 decreases the progression of Alzheimer’s disease[J]. Neuroscience, 2015, 301: 1-11. doi: 10.1016/j.neuroscience.2015.05.044
    [40]
    Irwin RW, Brinton RD. Allopregnanolone as regenerative therapeutic for Alzheimer’s disease: translational development and clinical promise[J]. Prog Neurobiol, 2014, 113: 40-55. doi: 10.1016/j.pneurobio.2013.08.004
    [41]
    Hernandez GD, Solinsky CM, Mack WJ, et al. Safety, tolerability, and pharmacokinetics of allopregnanolone as a regenerative therapeutic for Alzheimer’s disease: a single and multiple ascending dose phase 1b/2a clinical trial[J]. Alzheimers Dement, 2020, 6(1): e12107.
    [42]
    Zhao HM, Wei J, Du YN, et al. Improved cognitive impairments by silencing DMP1 via enhancing the proliferation of neural progenitor cell in Alzheimer-like mice[J]. Aging Cell, 2022, 21(5): e13601. doi: 10.1111/acel.13601
    [43]
    Mecca AP, O’dell RS, Sharp ES, et al. Synaptic density and cognitive performance in Alzheimer’s disease: a PET imaging study with[11 C]UCB-J[J]. Alzheimers Dement, 2022, 18(12): 2527-2536. doi: 10.1002/alz.12582
    [44]
    Scheff SW, Price DA. Alzheimer’s disease-related alterations in synaptic density: neocortex and hippocampus[J]. J Alzheimers Dis, 2006, 9 (3 Suppl): 101-115.
    [45]
    Laurén J, Gimbel DA, Nygaard HB, et al. Cellular prion protein mediates impairment of synaptic plasticity by amyloid-beta oligomers[J]. Nature, 2009, 457(7233): 1128-1132. doi: 10.1038/nature07761
    [46]
    Griffiths J, Grant SGN. Synapse pathology in Alzheimer’s disease[J]. Semin Cell Dev Biol, 2023, 139: 13-23. doi: 10.1016/j.semcdb.2022.05.028
    [47]
    Um JW, Nygaard HB, Heiss JK, et al. Alzheimer amyloid-β oligomer bound to postsynaptic prion protein activates Fyn to impair neurons[J]. Nat Neurosci, 2012, 15(9): 1227-1235. doi: 10.1038/nn.3178
    [48]
    Nygaard HB. Targeting Fyn kinase in Alzheimer’s disease[J]. Biol Psychiatry, 2018, 83(4): 369-376. doi: 10.1016/j.biopsych.2017.06.004
    [49]
    Chen PP, Wei J, Liu XQ, et al. Dihydroergotamine ameliorates synaptic atrophy in Alzheimer’s disease states and its effect on cognitive function[J]. J China Pharm Univ (中国药科大学学报), 2023, 54(4): 501-510.
    [50]
    Serrano ME, Kim E, Petrinovic MM, et al. Imaging synaptic density: the next holy grail of neuroscience [J]? Front Neurosci, 2022, 16 : 796129.
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