Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by memory impairment and cognitive decline. The obvious pathological features of AD are still amyloid plaques and neurofibrillary tangles. Development of disease-modifying treatments for AD has been challenging, with almost all drugs aborted. The amyloid cascade concept has been questioned due to the failures of various amyloid-targeting prospects. Despite this, targeting amyloid-β (Aβ) active immunotherapy provided some positive results to support this hypothesis and clinical trials of these candidates are ongoing. In this review, we describe the latest advance in therapeutic strategies based on amyloidogenic processing and evaluate the pros and cons of each treatment strategy. We also highlight the current status of the hottest immunotherapy and discuss the future development direction.
Keywords: Alzheimer’s disease, amyloid beta, clinical research, immunotherapy, and drug development, neurodegenerative disorder.
Graphical Abstract
[http://dx.doi.org/10.1016/S0140-6736(15)01124-1] [PMID: 26921134]
[http://dx.doi.org/10.1016/j.jalz.2018.06.3063] [PMID: 30243772]
[http://dx.doi.org/10.1016/j.cell.2019.09.001] [PMID: 31564456]
[http://dx.doi.org/10.3233/JAD-190507] [PMID: 31476157]
[http://dx.doi.org/10.3233/JAD-179941] [PMID: 29843241]
[http://dx.doi.org/10.1007/s40265-020-01268-1] [PMID: 32020555]
[http://dx.doi.org/10.1016/j.ejphar.2020.173554] [PMID: 32941929]
[http://dx.doi.org/10.3233/JAD-181300] [PMID: 30814363]
[http://dx.doi.org/10.1080/17460441.2020.1793755] [PMID: 32686970]
[http://dx.doi.org/10.1016/j.bcp.2018.09.026] [PMID: 30273553]
[http://dx.doi.org/10.1001/jama.2021.3854] [PMID: 33783469]
[http://dx.doi.org/10.1126/science.1072994] [PMID: 12130773]
[http://dx.doi.org/10.1016/j.phrs.2017.03.020] [PMID: 28351757]
[http://dx.doi.org/10.1074/jbc.M803159200] [PMID: 18694930]
[http://dx.doi.org/10.3389/fncel.2015.00191] [PMID: 26074767]
[http://dx.doi.org/10.3233/JAD-2012-129031] [PMID: 22710920]
[http://dx.doi.org/10.1126/science.abi6401] [PMID: 34353940]
[http://dx.doi.org/10.1016/j.ejmech.2018.02.035] [PMID: 29477076]
[http://dx.doi.org/10.3233/JAD-201027] [PMID: 33749645]
[http://dx.doi.org/10.1016/j.biopsych.2020.02.001] [PMID: 32223911]
[http://dx.doi.org/10.1523/JNEUROSCI.3647-11.2011] [PMID: 22090477]
[http://dx.doi.org/10.1016/j.tins.2016.01.003] [PMID: 26833257]
[http://dx.doi.org/10.1523/JNEUROSCI.4129-14.2015] [PMID: 25609634]
[http://dx.doi.org/10.1016/j.jalz.2013.08.244]
[http://dx.doi.org/10.1080/14737175.2018.1531706] [PMID: 30277096]
[http://dx.doi.org/10.1002/med.21622] [PMID: 31347728]
[http://dx.doi.org/10.15252/emmm.201809717] [PMID: 30322841]
[http://dx.doi.org/10.15252/emmm.201809316] [PMID: 30224383]
[http://dx.doi.org/10.1016/j.trci.2019.02.005] [PMID: 31211217]
[http://dx.doi.org/10.1074/jbc.M707103200] [PMID: 18024430]
[http://dx.doi.org/10.1517/14656560903044982] [PMID: 19527190]
[http://dx.doi.org/10.1097/01.wnf.0000167360.27670.29] [PMID: 15965311]
[http://dx.doi.org/10.1001/archneur.65.8.1031] [PMID: 18695053]
[http://dx.doi.org/10.1056/NEJMoa1210951] [PMID: 23883379]
[http://dx.doi.org/10.1016/j.cell.2014.10.016] [PMID: 25417150]
[http://dx.doi.org/10.1124/jpet.112.199356] [PMID: 23275065]
[http://dx.doi.org/10.1001/jamaneurol.2015.0607] [PMID: 26414022]
[http://dx.doi.org/10.1002/trc2.12050] [PMID: 32695874]
[http://dx.doi.org/10.1021/acs.jmedchem.5b01960] [PMID: 27007185]
[http://dx.doi.org/10.3109/10717544.2014.954165] [PMID: 25182481]
[http://dx.doi.org/10.1001/jama.2009.1866] [PMID: 20009055]
[http://dx.doi.org/10.1097/WAD.0b013e3182622ace] [PMID: 22922591]
[http://dx.doi.org/10.1172/JCI21746] [PMID: 15146234]
[http://dx.doi.org/10.1002/j.2055-2335.2012.tb00133.x]
[http://dx.doi.org/10.1016/S1474-4422(10)70119-8] [PMID: 20610346]
[http://dx.doi.org/10.1111/j.1471-4159.2008.05396.x] [PMID: 18397369]
[http://dx.doi.org/10.1016/j.ejphar.2010.02.036] [PMID: 20223232]
[http://dx.doi.org/10.2174/156720511795256053] [PMID: 21222604]
[http://dx.doi.org/10.1159/000334300] [PMID: 22301853]
[http://dx.doi.org/10.1212/WNL.0000000000001017] [PMID: 25344383]
[http://dx.doi.org/10.1038/nature07767] [PMID: 19225519]
[http://dx.doi.org/10.1124/jpet.106.112102] [PMID: 17003227]
[http://dx.doi.org/10.1016/j.trci.2017.12.001] [PMID: 29955650]
[http://dx.doi.org/10.1586/1744666X.2014.883921] [PMID: 24490853]
[http://dx.doi.org/10.1212/01.WNL.0000073623.84147.A8] [PMID: 12847155]
[http://dx.doi.org/10.1523/JNEUROSCI.0293-11.2011] [PMID: 21697382]
[http://dx.doi.org/10.1021/acs.chemrev.9b00472] [PMID: 31804810]
[http://dx.doi.org/10.1523/JNEUROSCI.4672-12.2013] [PMID: 23486963]
[http://dx.doi.org/10.1016/j.trci.2016.12.003] [PMID: 29067316]
[http://dx.doi.org/10.1186/s13195-015-0108-3] [PMID: 25918556]
[http://dx.doi.org/10.1016/j.vaccine.2007.01.031] [PMID: 17287052]
[http://dx.doi.org/10.1016/j.trci.2017.03.005] [PMID: 29067332]
[http://dx.doi.org/10.1177/1179573520907397] [PMID: 32165850]
[http://dx.doi.org/10.3233/JAD-170163] [PMID: 28453491]
[http://dx.doi.org/10.1186/s13195-018-0340-8] [PMID: 29378651]
[http://dx.doi.org/10.1007/s12272-013-0036-3] [PMID: 23435942]
[http://dx.doi.org/10.1016/j.biopsych.2017.08.010] [PMID: 28967385]
[http://dx.doi.org/10.1016/j.jalz.2011.09.224] [PMID: 22672770]
[http://dx.doi.org/10.1016/j.jalz.2015.06.1893] [PMID: 26238576]
[http://dx.doi.org/10.1097/WAD.0000000000000151] [PMID: 27213625]
[http://dx.doi.org/10.1074/jbc.M117.801514] [PMID: 28924036]
[http://dx.doi.org/10.1523/JNEUROSCI.4742-11.2012] [PMID: 22787053]
[http://dx.doi.org/10.1186/s13195-018-0424-5] [PMID: 30231896]
[http://dx.doi.org/10.1212/WNL.0000000000005550] [PMID: 29695589]
[http://dx.doi.org/10.1016/j.nicl.2021.102749] [PMID: 34252876]
[http://dx.doi.org/10.1186/s13195-017-0318-y] [PMID: 29221491]
[http://dx.doi.org/10.3233/JAD-215065] [PMID: 34366359]
[http://dx.doi.org/10.1038/nature19323] [PMID: 27582220]
[http://dx.doi.org/10.1097/YCO.0000000000000587] [PMID: 32040044]
[http://dx.doi.org/10.1186/s13195-016-0181-2] [PMID: 27048170]
[http://dx.doi.org/10.1186/s13195-021-00813-8] [PMID: 33865446]
[http://dx.doi.org/10.1002/trc2.12112] [PMID: 33614890]
[PMID: 34585215]
[http://dx.doi.org/10.1056/NEJMc2109455] [PMID: 34379933]
[http://dx.doi.org/10.1016/j.bmcl.2016.05.040] [PMID: 27256911]
[http://dx.doi.org/10.3389/fneur.2020.00614] [PMID: 32733362]
[http://dx.doi.org/10.1016/j.neurobiolaging.2006.02.015] [PMID: 16675063]
[http://dx.doi.org/10.1212/01.wnl.0000244346.08950.64] [PMID: 17082468]
[http://dx.doi.org/10.1007/s12603-009-0106-x] [PMID: 19536424]
[http://dx.doi.org/10.1007/s40262-017-0608-3] [PMID: 29063518]
[http://dx.doi.org/10.1007/s40263-017-0434-z] [PMID: 28435985]
[http://dx.doi.org/10.1007/s40263-018-0554-0] [PMID: 30076539]
[http://dx.doi.org/10.1074/jbc.R111.288308] [PMID: 21965666]
[http://dx.doi.org/10.3390/ijms222111791] [PMID: 34769222]
[http://dx.doi.org/10.1186/s13195-018-0431-6] [PMID: 30309389]
[http://dx.doi.org/10.1179/174313206X152483] [PMID: 17427283]
[http://dx.doi.org/10.1038/s41422-019-0216-x] [PMID: 31488882]
[http://dx.doi.org/10.1186/s13195-020-00678-3] [PMID: 32928279]
[http://dx.doi.org/10.1007/s11064-016-1844-x] [PMID: 26869037]
[http://dx.doi.org/10.1073/pnas.1402228111] [PMID: 24591589]
[http://dx.doi.org/10.1002/ptr.6732] [PMID: 32491273]
[http://dx.doi.org/10.1016/j.neuint.2008.10.008] [PMID: 19041676]
[http://dx.doi.org/10.2174/138161212798919075] [PMID: 22211686]
[http://dx.doi.org/10.2174/1567205016666190801153751] [PMID: 31368873]
[http://dx.doi.org/10.1212/WNL.0000000000002035] [PMID: 26362286]
[http://dx.doi.org/10.1016/j.pbb.2014.09.005] [PMID: 25220684]
[http://dx.doi.org/10.1007/s12011-012-9411-z] [PMID: 22528780]
[http://dx.doi.org/10.3390/molecules16032084] [PMID: 21368720]
[http://dx.doi.org/10.3390/biom10010059] [PMID: 31905923]
[http://dx.doi.org/10.1016/j.lfs.2019.03.055] [PMID: 30914316]
[http://dx.doi.org/10.3892/mmr.2017.6704] [PMID: 28586024]
[http://dx.doi.org/10.3233/JAD-170512] [PMID: 29332042]
[http://dx.doi.org/10.3390/ijms21155459] [PMID: 32751716]
[http://dx.doi.org/10.1523/JNEUROSCI.0354-12.2012] [PMID: 22815492]
[http://dx.doi.org/10.1016/j.neurobiolaging.2017.03.016] [PMID: 28438486]
[PMID: 32920628]
[http://dx.doi.org/10.17925/ENR.2012.07.02.92]
[http://dx.doi.org/10.1002/med.21722] [PMID: 32808294]
[http://dx.doi.org/10.14283/jpad.2017.12] [PMID: 29071250]
[http://dx.doi.org/10.1002/trc2.12073] [PMID: 33043108]
[http://dx.doi.org/10.3233/JAD-180766] [PMID: 30689575]
[http://dx.doi.org/10.1038/s41582-018-0116-6] [PMID: 30610216]
[http://dx.doi.org/10.1016/j.jalz.2019.09.075] [PMID: 31706733]