Skip to main content

Critical thinking on amyloid-beta-targeted therapy: challenges and perspectives

Science China Life Sciences volume 64, pages 926–937 (2021)Cite this article

Abstract

Amyloid-beta (Aβ) plays a pivotal role in the pathogenesis of Alzheimer’s disease (AD) and has been regarded as the main therapeutic target for AD. However, most of the Aβ-targeted clinical trials have not succeeded. Therefore, the Aβ-targeted therapeutic strategy on treating this complex disease needs to be re-evaluated. In this review, we analyzed the challenges and critical points of the current anti-Aβ therapeutic strategies. In addition to Aβ, multiple pathological events such as tau hyperphosphorylation, oxidative stress, and neuroinflammation, which are involved in AD pathogenesis and synergistically drive disease progression, could be important targets for AD treatment. Tertiary prevention strategies are needed for the successful management of AD due to its complex and dynamic pathogenesis. Systemic perspective addressing the disease pathogenesis within and outside the brain, as well as the multidomain intervention targeting risk factors and comorbidities, are important approaches for the therapeutic solutions of AD.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

References

  • Alzforum. (2017). High-dose Gantenerumab lowers plaque load. Available from: URL: https://www.alzforum.org/news/conference-coverage/high-dose-gantenerumab-lowers-plaque-load.

    Google Scholar 

  • Alzforum. (2019). Donanemab. Available from: URL: https://www.alzforum.org/therapeutics/donanemab.

    Google Scholar 

  • Alzforum. (2020). In DIAN-TU, Gantenerumab Brings Down Tau. By a Lot. Open Extension Planned. Available from: URL: https://www.alz-forum.org/news/conference-coverage/dian-tu-gantenerumab-brings-down-tau-lot-open-extension-planned.

    Google Scholar 

  • Ancoli-Israel, S., Palmer, B.W., Cooke, J.R., Corey-Bloom, J., Fiorentino, L., Natarajan, L., Liu, L., Ayalon, L., He, F., and Loredo, J.S. (2008). Cognitive effects of treating obstructive sleep apnea in Alzheimer’s disease: A randomized controlled study. J Am Geriatr Soc 56, 2076–2081.

    PubMed  PubMed Central  Google Scholar 

  • Andrade, A.G., Bubu, O.M., Varga, A.W., and Osorio, R.S. (2018). The relationship between obstructive sleep apnea and Alzheimer’s Disease. J Alzheimers Dis 64, S255–S270.

    PubMed  PubMed Central  Google Scholar 

  • Anionic, A., Sena, E.S., Lees, J.S., Wills, T.E., Skeers, P., Batchelor, P.E., Macleod, M.R., and Howells, D.W. (2013). Stem cell transplantation in traumatic spinal cord injury: a systematic review and meta-analysis of animal studies. PLoS Biol 11, e1001738.

    Google Scholar 

  • Ashton, N.J., Leuzy, A., Lim, Y.M., Troakes, C., Hortobagyi, T., Hoglund, K., Aarsland, D., Lovestone, S., Scholl, M., Blennow, K., et al. (2019). Increased plasma neurofilament light chain concentration correlates with severity of post-mortem neurofibrillary tangle pathology and neurodegeneration. Acta Neuropathol Commun 7, {p5}.

  • Barao, S., Moechars, D., Lichtenthaler, S.F., and De Strooper, B. (2016). BACE1 physiological functions may limit its use as therapeutic target for Alzheimer’s disease. Trends Neurosci 39, 158–169.

    CAS  PubMed  Google Scholar 

  • Barnes, D.E., Haight, T.J., Mehta, K.M., Carlson, M.C., Kuller, L.H., and Tager, LB. (2010). Secondhand smoke, vascular disease, and dementia incidence: findings from the cardiovascular health cognition study. Am J Epidemiol 171, 292–302.

    PubMed  PubMed Central  Google Scholar 

  • Barnes, D.E., and Yaffe, K. (2011). The projected effect of risk factor reduction on Alzheimer’s disease prevalence. Lancet Neurol 10, 819–828.

    PubMed  PubMed Central  Google Scholar 

  • Bateman, R.J., Xiong, C., Benzinger, T.L.S., Fagan, A.M., Goate, A., Fox, N.C., Marcus, D.S., Cairns, N.J., Xie, X., Blazey, T.M., et al. (2012). Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. N Engl J Med 367, 795–804.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bautista-Aguilera, O., Esteban, G., Chioua, M., Nikolic, K., Agbaba, D., Moraleda, I., Iriepa, I., Soriano, E., Samadi, A., Unzeta, M., et al. (2014). evaluation, ADMET, molecular modeling, and QSAR analysis of novel donepezil-pyridyl hybrids. Drug Des Devel Ther 8, 1893–1910.

    PubMed  PubMed Central  Google Scholar 

  • Beyreuther, K., and Masters, C.L. (1991). Amyloid precursor protein (APP) and BZA4 amyloid in the etiology of Alzheimer’s disease: Precursor-product relationships in the derangement of neuronal function. Brain Pathol 1, 241–251.

    CAS  PubMed  Google Scholar 

  • Biogen. (2019). Aducanumab update.

    Google Scholar 

  • Birnbaum, J.H., Wanner, D., Gietl, A.F., Saake, A., Kündig, T.M., Hock, C., Nitsch, R.M., and Tackenberg, C. (2018). Oxidative stress and altered mitochondrial protein expression in the absence of amyloid-p and tau pathology in iPSC-derived neurons from sporadic Alzheimer’s disease patients. Stem Cell Res 27, 121–130.

    CAS  PubMed  Google Scholar 

  • Bittner, T., Fuhrmann, M., Burgold, S., Ochs, S.M., Hoffmann, N., Mitteregger, G., Kretzschmar, H., LaFerla, F.M., and Herms, J. (2010). Multiple events lead to dendritic spine loss in triple transgenic Alzheimer’s disease mice. PLoS ONE 5, e15477.

    PubMed  PubMed Central  Google Scholar 

  • Brashear, H.R., Ketter, N., Bogert, J., Di, J., Salloway, S.P., Sperling, R., and Bangen, K. (2018). Clinical evaluation of amyloid-related imaging abnormalities in bapineuzumab phase III studies. J Alzheimers Dis 66, 1409–1424.

    CAS  PubMed  Google Scholar 

  • Bretzner, F., Gilbert, F., Baylis, F., and Brownstone, R.M. (2011). Target populations for first-in-human embryonic stem cell research in spinal cord injury. Cell Stem Cell 8, 468–475.

    CAS  PubMed  Google Scholar 

  • Brothers, H.M., Gosztyla, M.L., and Robinson, S.R. (2018). The physiological roles of amyloid-p peptide hint at new ways to treat Alzheimer’s disease. Front Aging Neurosci 10, 118.

    PubMed  PubMed Central  Google Scholar 

  • Bu, X.L., Jiao, S.S., Lian, Y., and Wang, Y.J. (2016). Perspectives on the tertiary prevention strategy for Alzheimer’s disease. Curr Alzheimer Res 13, 307–316.

    CAS  PubMed  Google Scholar 

  • Bu, X.L., Liu, Y.H., Wang, Q.H., Jiao, S.S., Zeng, F., Yao, X.Q., Gao, D., Chen, J.C., and Wang, Y.J. (2015). Serum amyloid-beta levels are increased in patients with obstructive sleep apnea syndrome. Sci Rep 5, 13917.

    PubMed  PubMed Central  Google Scholar 

  • Busche, M.A., Grienberger, C., Keskin, A.D., Song, B., Neumann, U., Staufenbiel, M., Forstl, H., and Konnerth, A. (2015). Decreased amyloid-p and increased neuronal hyperactivity by immunotherapy in Alzheimer’s models. Nat Neurosci 18, 1725–1727.

    CAS  PubMed  Google Scholar 

  • Calcinotto, A., Kohli, J., Zagato, E., Pellegrini, L., Demaria, M., and Alimonti, A. (2019). Cellular senescence: aging, cancer, and injury. Physiol Rev 99, 1047–1078.

    CAS  PubMed  Google Scholar 

  • Carrillo, M.C., Brashear, H.R., Logovinsky, V., Ryan, J.M., Feldman, H.H., Siemers, E.R., Abushakra, S., Hartley, D.M., Petersen, R.C., Khachaturian, A.S., et al. (2013). Can we prevent Alzheimer’s disease? Secondary “prevention” trials in Alzheimer’s disease. Alzheimers Dement 9, 123–131.e1.

    PubMed  Google Scholar 

  • Caselli, R.J., Knopman, D.S., and Bu, G. (2020). An agnostic reevaluation of the amyloid cascade hypothesis of Alzheimer’s disease pathogenesis: The role of APP homeostasis. Alzheimers Dement doi: 10.1002/alz.12124

    Google Scholar 

  • Chabrier, M.A., Cheng, D., Castello, N.A., Green, K.N., and LaFerla, F.M. (2014). Synergistic effects of amyloid-beta and wild-type human tau on dendritic spine loss in a floxed double transgenic model of Alzheimer’s disease. Neurobiol Dis 64, 107–117.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Cheignon, C., Tomas, M., Bonnefont-Rousselot, D., Faller, P., Hureau, C., and Collin, F. (2018). Oxidative stress and the amyloid beta peptide in Alzheimer’s disease. Redox Biol 14, 450–464.

    CAS  PubMed  Google Scholar 

  • Cheng, G., Huang, C., Deng, H., and Wang, H. (2012). Diabetes as a risk factor for dementia and mild cognitive impairment: a meta-analysis of longitudinal studies. Inter Med J 42, 484–491.

    CAS  Google Scholar 

  • Conference, A.s.A.I. (2018). BAN2401 Phase 2 Data Released at AAIC 2018. Chicago.

    Google Scholar 

  • Cooke, J.R., Ayalon, L., Palmer, B.W., Loredo, J.S., Corey-Bloom, J., Natarajan, L., Liu, L., and Ancoli-Israel, S. (2009). Sustained use of CPAP slows deterioration of cognition, sleep, and mood in patients with Alzheimer’s disease and obstructive sleep apnea: A preliminary study. J Clin Sleep Med 05, 305–309.

    Google Scholar 

  • Coric, V., Salloway, S., van Dyck, C.H., Dubois, B., Andreasen, N., Brody, M., Curtis, C., Soininen, H., Thein, S., Shiovitz, T., et al. (2015). Targeting prodromal Alzheimer disease with avagacestat. JAMA Neurol 72, 1324–1333.

    PubMed  Google Scholar 

  • Coric, V., van Dyck, C.H., Salloway, S., Andreasen, N., Brody, M., Richter, R.W., Soininen, H., Thein, S., Shiovitz, T., Pilcher, G., et al. (2012). Safety and tolerability of the y-secretase inhibitor avagacestat in a phase 2 study of mild to moderate Alzheimer disease. Arch Neurol 69, 1430–1440.

    PubMed  Google Scholar 

  • Desikan, R.S., Fan, C.C., Wang, Y., Schork, A.J., Cabral, H.J., Cupples, L. A., Thompson, W.K., Besser, L., Kukull, W.A., Holland, D., et al. (2017). Genetic assessment of age-associated Alzheimer disease risk: Development and validation of a polygenic hazard score. PLoS Med 14, e1002258.

    PubMed  PubMed Central  Google Scholar 

  • Doody, R.S., Raman, R., Farlow, M., Iwatsubo, T., Vellas, B., Joffe, S., Kieburtz, K., He, F., Sun, X., Thomas, R.G., et al. (2013). A phase 3 trial of semagacestat for treatment of Alzheimer’s disease. N Engl J Med 369, 341–350.

    CAS  PubMed  Google Scholar 

  • Dotson, V.M., Beydoun, M.A., and Zonderman, A.B. (2010). Recurrent depressive symptoms and the incidence of dementia and mild cognitive impairment. Neurology 75, 27–34.

    PubMed  PubMed Central  Google Scholar 

  • Espuny-Camacho, I., Arranz, A.M., Fiers, M., Snellinx, A., Ando, K., Munck, S., Bonnefont, J., Lambot, L., Corthout, N., Omodho, L., et al. (2017). Hallmarks of Alzheimer’s disease in stem-cell-derived human neurons transplanted into mouse brain. Neuron 93, 1066–1081.e8.

    CAS  PubMed  Google Scholar 

  • Esquerda-Canals, G., Montoliu-Gaya, L., Güell-Bosch, J., and Villegas, S. (2017). Mouse models of Alzheimer’s disease. J Alzheimers Dis 57, 1171–1183.

    CAS  PubMed  Google Scholar 

  • Fagan, T. (2017). Monomeric seeds and oligomeric clouds—Proteopathy news from AAIC. In: Alzheimer’s Association International Conference 2017. London.

    Google Scholar 

  • Fan, D.Y., and Wang, Y.J. (2020). Early intervention in Alzheimer’s disease: How early is early enough? Neurosci Bull 36, 195–197.

    CAS  PubMed  Google Scholar 

  • Fladby, T., and Maehlen, J. (1999). The amyloid and tau hypothesis in degenerative dementia. Tidsskr Nor Laegeforen 119, 976–979.

    CAS  PubMed  Google Scholar 

  • Fleisher, A.S., Chen, K., Quiroz, Y.T., Jakimovich, L.J., Gomez, M.G., Langois, C.M., Langbaum, J.B., Ayutyanont, N., Roontiva, A., Thiyyagura, P., et al. (2012). Florbetapir PET analysis of amyloid-p deposition in the presenilin 1 E280A autosomal dominant Alzheimer’s disease kindred: a cross-sectional study. Lancet Neurol 11, 1057–1065.

    CAS  PubMed  Google Scholar 

  • Fuhrmann, M., Bittner, T., Jung, C.K.E., Burgold, S., Page, R.M., Mitteregger, G., Haass, C., LaFerla, F.M., Kretzschmar, H., and Herms, J. (2010). Microglial Cx3crl knockout prevents neuron loss in a mouse model of Alzheimer’s disease. Nat Neurosci 13, 411–413.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gamage, K.K., and Kumar, S. (2017). Aducanumab therapy ameliorates calcium overload in a mouse model of Alzheimer’s disease. J Neurosci 37, 4430–4432.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Giacobini, E., and Gold, G. (2013). Alzheimer disease therapy—moving from amyloid-p to tau. Nat Rev Neurol 9, 677–686.

    CAS  Google Scholar 

  • Glenner, G.G., and Wong, C.W. (1984a). Alzheimer’s disease and Down’s syndrome: Sharing of a unique cerebrovascular amyloid fibril protein. Biochem Biophys Res Commun 122, 1131–1135.

    CAS  PubMed  Google Scholar 

  • Glenner, G.G., and Wong, C.W. (1984b). Alzheimer’s disease: Initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun 120, 885–890.

    CAS  PubMed  Google Scholar 

  • Gotz, J., Schild, A., Hoerndli, F., and Pennanen, L. (2004). Amyloid-induced neurofibrillary tangle formation in Alzheimer’s disease: insight from transgenic mouse and tissue-culture models. Int J Dev Neurosci 22, 453–465.

    PubMed  Google Scholar 

  • Green, R.C., Schneider, L.S., Amato, D.A., Beelen, A.P., Wilcock, G., Swabb, E.A., Zavitz, K.H., and Tarenflurbil Phase 3 Study, G. (2009). Effect of tarenflurbil on cognitive decline and activities of daily living in patients with mild Alzheimer disease: A randomized controlled trial. JAMA 302, 2557–2564.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hardy, J., and Allsop, D. (1991). Amyloid deposition as the central event in the aetiology of Alzheimer’s disease. Trends Pharmacol Sci 12, 383–388.

    CAS  PubMed  Google Scholar 

  • Hardy, J., Duff, K., Hardy, K.G., Perez-Tur, J., and Hutton, M. (1998). Genetic dissection of Alzheimer’s disease and related dementias: amyloid and its relationship to tau. Nat Neurosci 1, 355–358.

    CAS  PubMed  Google Scholar 

  • Haston, K.M., and Finkbeiner, S. (2016). Clinical trials in a dish: The potential of pluripotent stem cells to develop therapies for neurodegenerative diseases. Annu Rev Pharmacol Toxicol 56, 489–510.

    CAS  PubMed  Google Scholar 

  • Heneka, M.T., Nadrigny, F., Regen, T., Martinez-Hernandez, A., Dumitrescu-Ozimek, L., Terwel, D., Jardanhazi-Kurutz, D., Walter, J., Kirchhoff, F., Hanisch, U.K., et al. (2010). Locus ceruleus controls Alzheimer’s disease pathology by modulating microglial functions through norepinephrine. Proc Natl Acad Sci USA 107, 6058–6063.

    CAS  PubMed  Google Scholar 

  • Herrup, K., Carrillo, M.C., Schenk, D., Cacace, A., DeSanti, S., Fremeau, R., Bhat, R., Glicksman, M., May, P., Swerdlow, R., et al. (2013). Beyond amyloid: Getting real about nonamyloid targets in Alzheimer’s disease. Alzheimers Dement 9, 452–458.el.

    PubMed  PubMed Central  Google Scholar 

  • Hu, X., He, W., Diaconu, C., Tang, X., Kidd, G.J., Macklin, W.B., Trapp, B.D., and Yan, R. (2008). Genetic deletion of BACE1 in mice affects remyelination of sciatic nerves. FASEB J 22, 2970–2980.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hunsberger, J.G., Rao, M., Kurtzberg, J., Bulte, J.W.M., Atala, A., LaFerla, F.M., Greely, H.T., Sawa, A., Gandy, S., Schneider, L.S., et al. (2016). Accelerating stem cell trials for Alzheimer’s disease. Lancet Neurol 15, 219–230.

    PubMed  Google Scholar 

  • Hutton, M., Lendon, C.L., Rizzu, P., Baker, M., Froelich, S., Houlden, H., Pickering-Brown, S., Chakraverty, S., Isaacs, A., Grover, A., et al. (1998). Association of missense and 5’-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 393, 702–705.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Jack Jr, C.R., Knopman, D.S., Jagust, W.J., Petersen, R.C., Weiner, M.W., Aisen, PS., Shaw, L.M., Vemuri, P., Wiste, H.J., Weigand, S.D., et al. (2013). Tracking pathophysiological processes in Alzheimer’s disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol 12, 207–216.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Jin, W.S., Bu, X.L., Wang, Y.R., Li, L., Li, W.W., Liu, Y.H., Zhu, C., Yao, X.Q., Chen, Y., Gao, C.Y., et al. (2017a). Reduced cardiovascular functions in patients with Alzheimer’s disease. J Alzheimers Dis 58, 919–925.

    CAS  PubMed  Google Scholar 

  • Jin, W.S., Shen, L.L., Bu, X.L., Zhang, W.W., Chen, S.H., Huang, Z.L., Xiong, J.X., Gao, C.Y., Dong, Z., He, Y.N., et al. (2017b). Peritoneal dialysis reduces amyloid-beta plasma levels in humans and attenuates Alzheimer-associated phenotypes in an APP/PS1 mouse model. Acta Neuropathol 134, 207–220.

    CAS  PubMed  Google Scholar 

  • Jonsson, T., Atwal, J.K., Steinberg, S., Snaedal, J., Jonsson, P.V., Bjornsson, S., Stefansson, H., Sulem, P., Gudbjartsson, D., Maloney, J., et al. (2012). A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline. Nature 488, 96–99.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kandalepas, P.C., Sadleir, K.R., Eimer, W.A., Zhao, J., Nicholson, D.A., and Vassar, R. (2013). The Alzheimer’s p-secretase BACE1 localizes to normal presynaptic terminals and to dystrophic presynaptic terminals surrounding amyloid plaques. Acta Neuropathol 126, 329–352.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kramer, A.F., and Erickson, K.I. (2007). Capitalizing on cortical plasticity: influence of physical activity on cognition and brain function. Trends Cogn Sci 11, 342–348.

    PubMed  Google Scholar 

  • Kunkle, B.W., Grenier-Boley, B., Sims, R., Bis, J.C., Damotte, V., Naj, A. C., Boland, A., Vronskaya, M., van der Lee, S.J., Amlie-Wolf, A., et al. (2019). Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Ap, tau, immunity and lipid processing. Nat Genet 51, 414–430.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lachno, D.R., Evert, B.A., Maloney, K., Willis, B.A., Talbot, J.A., Vandijck, M., and Dean, R.A. (2015). Validation and clinical utility of ELISA methods for quantification of amyloid-p peptides in cerebrospinal fluid specimens from Alzheimer’s disease studies. J Alzheimers Dis 45, 527–542.

    CAS  PubMed  Google Scholar 

  • Lahiri, D.K., Maloney, B., Long, J.M., and Greig, N.H. (2014). Lessons from a BACE1 inhibitor trial: off-site but not off base. Alzheimers Dement 10, S411–S419.

    PubMed  PubMed Central  Google Scholar 

  • Langa, K.M., Larson, E.B., Crimmins, E.M., Faul, J.D., Levine, D.A., Kabeto, M.U., and Weir, D.R. (2017). A comparison of the prevalence of dementia in the United States in 2000 and 2012. JAMA Intern Med 177, 51–58.

    PubMed  PubMed Central  Google Scholar 

  • Lanoiselee, H.M., Nicolas, G., Wallon, D., Rovelet-Lecrux, A., Lacour, M., Rousseau, S., Richard, A.C., Pasquier, F., Rollin-Sillaire, A., Martinaud, O., et al. (2017). APP, PSEN1, and PSEN2 mutations in early-onset Alzheimer disease: A genetic screening study of familial and sporadic cases. PLoS Med 14, e1002270.

    PubMed  PubMed Central  Google Scholar 

  • Larson, E.B., Yaffe, K., and Langa, K.M. (2013). New insights into the dementia epidemic. N Engl J Med 369, 2275–2277.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Levy-Lahad, E., Wasco, W., Poorkaj, P., Romano, D.M., Oshima, J., Pettingell, W.H., Yu, C.E., Jondro, P.D., Schmidt, S.D., Wang, K., et al. (1995). Candidate gene for the chromosome 1 familial Alzheimer’s disease locus. Science 269, 973–977.

    CAS  PubMed  Google Scholar 

  • Lewis, J., Dickson, D.W., Lin, W.L., Chisholm, L., Corral, A., Jones, G., Yen, S.H., Sahara, N., Skipper, L., Yager, D., et al. (2001). Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science 293, 1487–1491.

    CAS  PubMed  Google Scholar 

  • Li, W.W., Wang, Z., Fan, D.Y., Shen, Y.Y., Chen, D.W., Li, H.Y., Li, L., Yang, H., Liu, Y.H., Bu, X.L., et al. (2020). Association of polygenic risk score with age at onset and cerebrospinal fluid biomarkers of Alzheimer’s disease in a Chinese cohort. Neurosci Bull 36, 696–704.

    CAS  PubMed  Google Scholar 

  • Liu, Y.H., Bu, X.L., Liang, C.R., Wang, Y.R., Zhang, T., Jiao, S.S., Zeng, F., Yao, X.Q., Zhou, H.D., Deng, J., et al. (2015). An N-terminal antibody promotes the transformation of amyloid fibrils into oligomers and enhances the neurotoxicity of amyloid-beta: the dust-raising effect. J Neuroinflammation 12, 153.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Liu, Y.H., Giunta, B., Zhou, H.D., Tan, J., and Wang, Y.J. (2012). Immunotherapy for Alzheimer disease: the challenge of adverse effects. Nat Rev Neurol 8, 465–469.

    CAS  PubMed  Google Scholar 

  • Livingston, G., Sommerlad, A., Orgeta, V., Costafreda, S.G., Huntley, J., Ames, D., Ballard, C., Banerjee, S., Burns, A., Cohen-Mansfield, J., et al. (2017). Dementia prevention, intervention, and care. Lancet 390, 2673–2734.

    PubMed  Google Scholar 

  • Lunn, J.S., Sakowski, S.A., Hur, J., and Feldman, E.L. (2011). Stem cell technology for neurodegenerative diseases. Ann Neurol 70, 353–361.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lutsey, P.L., Chen, N., Mirabelli, M.C., Lakshminarayan, K., Knopman, D. S., Vossel, K.A., Gottesman, R.F., Mosley, T.H., and Alonso, A. (2019). Impaired lung function, lung disease, and risk of incident dementia. Am J Respir Crit Care Med 199, 1385–1396.

    PubMed  PubMed Central  Google Scholar 

  • Marco-Contelles, J., Unzeta, M., Bolea, I., Esteban, G., Ramsay, R.R., Romero, A., Martinez-Murillo, R., Carreiras, M.C., and Ismaili, L. (2016). ASS234, as a new multi-target directed propargylamine for Alzheimer’s disease therapy. Front Neurosci 10, 294.

    PubMed  PubMed Central  Google Scholar 

  • Marsh, S.E., and Blurton-Jones, M. (2012). Examining the mechanisms that link p-amyloid and a-synuclein pathologies. Alzheimers Res Ther 4, 11.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Masters, C.L., Multhaup, G., Simms, G., Pottgiesser, J., Martins, R.N., and Beyreuther, K. (1985a). Neuronal origin of a cerebral amyloid: neurofibrillary tangles of Alzheimer’s disease contain the same protein as the amyloid of plaque cores and blood vessels. EMBO J 4, 2757–2763.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Masters, C.L., Simms, G., Weinman, N.A., Multhaup, G., McDonald, B.L., and Beyreuther, K. (1985b). Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc Natl Acad Sci USA 82, 4245–4249.

    CAS  PubMed  Google Scholar 

  • Mattsson-Carlgren, N., Andersson, E., Janelidze, S., Ossenkoppele, R., Insel, P., Strandberg, O., Zetterberg, H., Rosen, H.J., Rabinovici, G., Chai, X., et al. (2020). Ap deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease. Sci Adv 6, eaaz2387.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Mattsson, N., Andreasson, U., Zetterberg, H., and Blennow, K. (2017). Association of plasma neurofilament light with neurodegeneration in patients with Alzheimer disease. JAMA Neurol 74, 557–566.

    PubMed  PubMed Central  Google Scholar 

  • May, P.C., Dean, R.A., Lowe, S.L., Martenyi, E., Sheehan, S.M., Boggs, L. N., Monk, S.A., Mathes, B.M., Mergott, D.J., Watson, B.M., et al. (2011). Robust central reduction of amyloid-p in humans with an orally available, non-peptidic p-secretase inhibitor. J Neurosci 31, 16507–16516.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Miller, J.A., Horvath, S., and Geschwind, D.H. (2010). Divergence of human and mouse brain transcriptome highlights Alzheimer disease pathways. Proc Natl Acad Sci USA 107, 12698–12703.

    CAS  PubMed  Google Scholar 

  • Moreno-Jiménez, E.P., Flor-García, M., Terreros-Roncal, J., Rabano, A., Cafini, E., Pallas-Bazarra, N., Ávila, J., and Llorens-Martin, M. (2019). Adult hippocampal neurogenesis is abundant in neurologically healthy subjects and drops sharply in patients with Alzheimer’s disease. Nat Med 25, 554–560.

    PubMed  Google Scholar 

  • Myers, A., Holmans, P., Marshall, H., Kwon, J., Meyer, D., Ramic, D., Shears, S., Booth, J., DeVrieze, F.W., Crook, R., et al. (2000). Susceptibility locus for Alzheimer’s disease on chromosome 10. Science 290, 2304–2305.

    CAS  PubMed  Google Scholar 

  • Ngandu, T., Lehtisalo, J., Solomon, A., Levälahti, E., Ahtiluoto, S., Antikainen, R., Bäckman, L., Hänninen, T., Jula, A., Laatikainen, T., et al. (2015). A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER): a randomised controlled trial. Lancet 385, 2255–2263.

    PubMed  Google Scholar 

  • Nguyen, H.L., Thi Minh Thu, T., Truong, P.M., Lan, P.D., Man, V.H., Nguyen, PH., Tu, L.A., Chen, Y.C., and Li, M.S. (2016). Ap41 aggregates more like Ap40 than like Ap42: in silico and in vitro study. J Phys Chem B 120, 7371–7379.

    CAS  PubMed  Google Scholar 

  • Nho, K., Kueider-Paisley, A., Ahmad, S., MahmoudianDehkordi, S., Arnold, M., Risacher, S.L., Louie, G., Blach, C., Baillie, R., Han, X., et al. (2019). Association of altered liver enzymes with Alzheimer disease diagnosis, cognition, neuroimaging measures, and cerebrospinal fluid biomarkers. JAMA Netw Open 2, e197978.

    PubMed  PubMed Central  Google Scholar 

  • Nicoll, J.A.R., Buckland, G.R., Harrison, C.H., Page, A., Harris, S., Love, S., Neal, J.W., Holmes, C., and Boche, D. (2019). Persistent neuropathological effects 14 years following amyloid-p immunization in Alzheimer’s disease. Brain 142, 2113–2126.

    PubMed  PubMed Central  Google Scholar 

  • Norton, S., Matthews, F.E., Barnes, D.E., Yaffe, K., and Brayne, C. (2014). Potential for primary prevention of Alzheimer’s disease: an analysis of population-based data. Lancet Neurol 13, 788–794.

    PubMed  Google Scholar 

  • Ostrowitzki, S., Lasser, R.A., Dorflinger, E., Scheltens, P., Barkhof, F., Nikolcheva, T., Ashford, E., Retout, S., Hofmann, C., Delmar, P., et al. (2017). A phase III randomized trial of gantenerumab in prodromal Alzheimer’s disease. Alz Res Ther 9, 95.

    Google Scholar 

  • Ou-Yang, M.H., Kurz, J.E., Nomura, T., Popovic, J., Rajapaksha, T.W., Dong, H., Contractor, A., Chetkovich, D.M., Tourtellotte, W.G., and Vassar, R. (2018). Axonal organization defects in the hippocampus of adult conditional BACE1 knockout mice. Sci Transl Med 10, eaao5620.

    PubMed  Google Scholar 

  • Patton, R.L., Kalback, W.M., Esh, C.L., Kokjohn, T.A., Van Vickie, G.D., Luehrs, D.C., Kuo, Y.M., Lopez, J., Brune, D., Ferrer, I., et al. (2006). Amyloid-p peptide remnants in AN-1792-immunized Alzheimer’s disease patients. Am J Pathol 169, 1048–1063.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Pericak-Vance, M.A., Bass, M.P., Yamaoka, L.H., Gaskell, P.C., Scott, W. K., Terwedow, H.A., Menold, M.M., Conneally, P.M., Small, G.W., Vance, J.M., et al. (1997). Complete genomic screen in late-onset familial Alzheimer disease. JAMA 278, 1237–1241.

    CAS  PubMed  Google Scholar 

  • Petrushina, I., Ghochikyan, A., Mktrichyan, M., Mamikonyan, G., Movsesyan, N., Davtyan, H., Patel, A., Head, E., Cribbs, D.H., and Agadjanyan, M.G. (2007). Alzheimer’s disease peptide epitope vaccine reduces insoluble but not soluble/oligomeric Ap species in amyloid precursor protein transgenic mice. J Neurosci 27, 12721–12731.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Piirainen, S., Youssef, A., Song, C., Kalueff, A.V., Landreth, G.E., Malm, T., and Tian, L. (2017). Psychosocial stress on neuroinflammation and cognitive dysfunctions in Alzheimer’s disease: the emerging role for microglia? Neurosci Biobehav Rev 77, 148–164.

    CAS  PubMed  Google Scholar 

  • Polanco, J.C., Li, C., Bodea, L.G., Martinez-Marmol, R., Meunier, F.A., and Gotz, J. (2018). Amyloid-p and tau complexity—towards improved biomarkers and targeted therapies. Nat Rev Neurol 14, 22–39.

    CAS  PubMed  Google Scholar 

  • Pratico, D., Uryu, K., Leight, S., Trojanoswki, J.Q., and Lee, V.M.Y. (2001). Increased lipid peroxidation precedes amyloid plaque formation in an animal model of Alzheimer amyloidosis. J Neurosci 21, 4183–4187.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Preische, O., Schultz, S.A., Apel, A., Kuhle, J., Kaeser, S.A., Barro, C., Gräber, S., Kuder-Buletta, E., LaFougere, C., Laske, C., et al. (2019). Serum neurofilament dynamics predicts neurodegeneration and clinical progression in presymptomatic Alzheimer’s disease. Nat Med 25, 277–283.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Qosa, H., Abuasal, B.S., Romero, I.A., Weksler, B., Couraud, P.O., Keller, J.N., and Kaddoumi, A. (2014). Differences in amyloid-p clearance across mouse and human blood-brain barrier models: Kinetic analysis and mechanistic modeling. Neuropharmacology 79, 668–678.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Quiroz, Y.T., Sperling, R.A., Norton, D.J., Baena, A., Arboleda-Velasquez, J.E., Cosio, D., Schultz, A., Lapoint, M., Guzman-Velez, E., Miller, J.B., et al. (2018). Association between amyloid and tau accumulation in young adults with autosomal dominant Alzheimer disease. JAMA Neurol 75, 548.

    PubMed  PubMed Central  Google Scholar 

  • Reitz, C., and Mayeux, R. (2014). Alzheimer disease: epidemiology, diagnostic criteria, risk factors and biomarkers. Biochem Pharmacol 88, 640–651.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Rinne, J.O., Brooks, D.J., Rossor, M.N., Fox, N.C., Bullock, R., Klunk, W. E., Mathis, C.A., Blennow, K., Barakos, J., Okello, A.A., et al. (2010). HC-PiB PET assessment of change in fibrillar amyloid-p load in patients with Alzheimer’s disease treated with bapineuzumab: a phase 2, double-blind, placebo-controlled, ascending-dose study. Lancet Neurol 9, 363–372.

    CAS  PubMed  Google Scholar 

  • Sakai, K., Senda, T., Hata, R., Kuroda, M., Hasegawa, M., Kato, M., Abe, M., Kawaguchi, K., Nakai, S., Hiki, Y., et al. (2016). Patients that have undergone hemodialysis exhibit lower amyloid deposition in the brain: Evidence supporting a therapeutic strategy for Alzheimer’s disease by removal of blood amyloid. J Alzheimers Dis 51, 997–1002.

    CAS  PubMed  Google Scholar 

  • Satizabal, C.L., Beiser, A.S., Chouraki, V., Chene, G., Dufouil, C., and Seshadri, S. (2016). Incidence of dementia over three decades in the framingham heart study. N Engl J Med 374, 523–532.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Scheuner, D., Eckman, C., Jensen, M., Song, X., Citron, M., Suzuki, N., Bird, T.D., Hardy, J., Hutton, M., Kukull, W., et al. (1996). Secreted amyloid p-protein similar to that in the senile plaques of Alzheimer’s disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer’s disease. Nat Med 2, 864–870.

    CAS  PubMed  Google Scholar 

  • Selkoe, D.J. (2000). The genetics and molecular pathology of Alzheimer’s disease. Neurol Clin 18, 903–921.

    CAS  PubMed  Google Scholar 

  • Selkoe, D.J., and Hardy, J. (2016). The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol Med 8, 595–608.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sevigny, J., Chiao, P., Bussiere, T., Weinreb, P.H., Williams, L., Maier, M., Dunstan, R., Salloway, S., Chen, T., Ling, Y., et al. (2016). The antibody aducanumab reduces Ap plaques in Alzheimer’s disease. Nature 537, 50–56.

    CAS  PubMed  Google Scholar 

  • Siemers, E.R., Quinn, J.F., Kaye, J., Farlow, M.R., Porsteinsson, A., Tariot, P., Zoulnouni, P., Galvin, J.E., Holtzman, D.M., Knopman, D.S., et al. (2006). Effects of a gamma-secretase inhibitor in a randomized study of patients with Alzheimer disease. Neurology 66, 602–604.

    CAS  PubMed  Google Scholar 

  • Sorrells, S.E., Paredes, M.E., Cebrian-Silla, A., Sandoval, K., Qi, D., Kelley, K.W., James, D., Mayer, S., Chang, J., Auguste, K.I., et al. (2018). Human hippocampal neurogenesis drops sharply in children to undetectable levels in adults. Nature 555, 377–381.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sperling, R.A., Jack Jr., C.R., Black, S.E., Frosch, M.P., Greenberg, S.M., Hyman, B.T., Scheltens, P., Carrillo, M.C., Thies, W., Bednar, M.M., et al. (2011). Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: Recommendations from the Alzheimer’s Association Research Roundtable Workgroup. Alzheimers Dement 7, 367–385.

    PubMed  PubMed Central  Google Scholar 

  • Sun, B.L., Li, W.W., Zhu, C., Jin, W.S., Zeng, F., Liu, Y.H., Bu, X.L., Zhu, J., Yao, X.Q., and Wang, Y.J. (2018). Clinical research on Alzheimer’s disease: progress and perspectives. Neurosci Bull 34, 1111–1118.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Swahn, B.M., Kolmodin, K., Karlström, S., von Berg, S., Söderman, P., Holenz, J., Berg, S., Lindstrom, J., Sundstrom, M., Rurek, D., et al. (2012). Design and synthesis of β-site amyloid precursor protein cleaving enzyme (BACR1) inhibitors with in vivo brain reduction of p-amyloid peptides. J Med Chem 55, 9346–9361.

    CAS  PubMed  Google Scholar 

  • Ran, C.H., Fan, C.C., Mormino, R.C., Sugrue, L.P., Broce, I.J., Hess, C.P., Dillon, W.P., Bonham, L.W., Yokoyama, J.S., Karch, C.M., et al. (2018). Polygenic hazard score: an enrichment marker for Alzheimer’s associated amyloid and tau deposition. Acta Neuropathol 135, 85–93.

    Google Scholar 

  • Rharp, W.G., and Sarkar, I. (2013). Origins of amyloid-p. BMC Genomics 14, 290.

    Google Scholar 

  • Ronnies, E., and Rrushina, E. (2017). Oxidative stress, synaptic dysfunction, and Alzheimer’s disease. J Alzheimers Dis 57, 1105–1121.

    Google Scholar 

  • Vassar, R., Bennett, B.D., Babu-Khan, S., Kahn, S., Mendiaz, E.A., Denis, P., Replow, D.B., Ross, S., Amarante, P., Loeloff, R., et al. (1999). Beta-secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286, 735–741.

    CAS  PubMed  Google Scholar 

  • Wang, J., Gu, B.J., Masters, C.L., and Wang, Y.J. (2017). A systemic view of Alzheimer disease—insights from amyloid-p metabolism beyond the brain. Nat Rev Neurol 13, 612–623.

    CAS  PubMed  Google Scholar 

  • Wang, L., Esteban, G., Ojima, M., Bautista-Aguilera, O.M., Inokuchi, T., Moraleda, I., Iriepa, I., Samadi, A., Youdim, M.B.H., Romero, A., et al. (2014). Donepezil+propargylamine+8-hydroxyquinoline hybrids as new multifunctional metal-chelators, ChE and MAO inhibitors for the potential treatment of Alzheimer’s disease. Eur J Med Chem 80, 543–561.

    CAS  PubMed  Google Scholar 

  • Wang, X., Sun, G., Feng, T., Zhang, J., Huang, X., Wang, T., Xie, Z., Chu, X., Yang, J., Wang, H., et al. (2019). Sodium oligomannate therapeutically remodels gut microbiota and suppresses gut bacterial amino acids-shaped neuroinflammation to inhibit Alzheimer’s disease progression. Cell Res 29, 787–803.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wang, Y.J. (2014). Lessons from immunotherapy for Alzheimer disease. Nat Rev Neurol 10, 188–189.

    CAS  PubMed  Google Scholar 

  • Willem, M., Garratt, A.N., Novak, B., Citron, M., Kaufmann, S., Rittger, A., DeStrooper, B., Saftig, P., Birchmeier, C., and Haass, C. (2006). Control of peripheral nerve myelination by the beta-secretase BACE1. Science 314, 664–666.

    CAS  PubMed  Google Scholar 

  • Wu, S.C., Cao, Z.S., Chang, K.M., and Juang, J.L. (2017). Intestinal microbial dysbiosis aggravates the progression of Alzheimer’s disease in Drosophila. Nat Commun 8, 24.

    PubMed  PubMed Central  Google Scholar 

  • Wu, Y.T., Fratiglioni, L., Matthews, F.E., Lobo, A., Breteler, M.M.B., Skoog, I., and Brayne, C. (2016). Dementia in western Europe: epidemiological evidence and implications for policy making. Lancet Neurol 15, 116–124.

    CAS  PubMed  Google Scholar 

  • Xiang, Y., Bu, X.L., Liu, Y.H., Zhu, C., Shen, L.L., Jiao, S.S., Zhu, X.Y., Giunta, B., Ran, J., Song, W.H., et al. (2015). Physiological amyloid-beta clearance in the periphery and its therapeutic potential for Alzheimer’s disease. Acta Neuropathol 130, 487–499.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yang, A.J., Chandswangbhuvana, D., Shu, T., Henschen, A., and Glabe, C. G. (1999). Intracellular accumulation of insoluble, newly synthesized Apn-42 in amyloid precursor protein-transfected cells that have been treated with Aβl-42. J Biol Chem 274, 20650–20656.

    CAS  PubMed  Google Scholar 

  • Zhang, J., He, Y., Jiang, X., Jiang, H., and Shen, J. (2019). Nature brings new avenues to the therapy of central nervous system diseases—an overview of possible treatments derived from natural products. Sci China Life Sci 62, 1332–1367.

    PubMed  Google Scholar 

  • Zhao, J., Fu, Y., Yasvoina, M., Shao, P., Hitt, B., O’Connor, T., Logan, S., Maus, E., Citron, M., Berry, R., et al. (2007). Beta-site amyloid precursor protein cleaving enzyme 1 levels become elevated in neurons around amyloid plaques: implications for Alzheimer’s disease pathogenesis. J Neurosci 27, 3639–3649.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhuang, Z.Q., Shen, L.L., Li, W.W., Fu, X., Zeng, F., Gui, L., Lu, Y., Cai, M., Zhu, C., Ran, Y.L., et al. (2018). Gut microbiota is altered in patients with Alzheimer’s disease. J Alzheimers Dis 63, 1337–1346.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Natural Science Foundation of China (91749206, 81930028, 81625007, 81870860, 31921003).

Author information

Author notes

  1. Contributed equally to this work

Affiliations

  1. Department of Neurology and Center for Clinical Neuroscience, Daping Hospital, Third Military Medical University, Chongqing, 400042, China

    Bin-lu Sun, Yang Chen, Dong-yu Fan, Chi Zhu, Fan Zeng & Yan-jiang Wang

  2. Chongqing Key Laboratory of Ageing and Brain Diseases, Chongqing, 400042, China

    Bin-lu Sun, Yang Chen, Dong-yu Fan, Chi Zhu, Fan Zeng & Yan-jiang Wang

  3. Institute of Brain and Intelligence, Third Military Medical University, Chongqing, 400042, China

    Bin-lu Sun, Yang Chen, Dong-yu Fan, Chi Zhu, Fan Zeng & Yan-jiang Wang

Authors
  1. Bin-lu Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yang Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dong-yu Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chi Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Fan Zeng
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yan-jiang Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Fan Zeng or Yan-jiang Wang.

Additional information

Compliance and ethics

The author(s) declare that they have no conflict of interest.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Sun, Bl., Chen, Y., Fan, Dy. et al. Critical thinking on amyloid-beta-targeted therapy: challenges and perspectives. Sci. China Life Sci. 64, 926–937 (2021). https://doi.org/10.1007/s11427-020-1810-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11427-020-1810-y

Keywords

  • Alzheimer’s disease
  • amyloid β
  • immunotherapy
  • β-secretase
  • γ-secretase
  • enzyme inhibitor
  • multi-target therapy
  • tertiary prevention strategy