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(2016) World Alzheimer Report 2016. Alzheimer's Disease International, London."},{"key":"2","unstructured":"2) Working report from Ministry of Health, Labour and Welfare of Japan (2015) \u201cNihon ni okeru ninchisho no koureisya jinkou no syouraisuikei ni kansuru kenkyuu\u201d (in Japanese)."},{"key":"3","unstructured":"3) Glenner, G.G. and Wong, C.W. (1984) Alzheimer\u2019s disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem. Biophys. Res. Commun. 120, 885\u2013890."},{"key":"4","unstructured":"4) Masters, C.L., Simms, G., Weinman, N.A., Multhaup, G., Mcdonald, B.L. and Beyreuther, K. (1985) Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc. Natl. Acad. Sci. U.S.A. 82, 4245\u20134249."},{"key":"5","unstructured":"5) Kosik, K.S., Joachim, C.L. and Selkoe, D.J. (1986) Microtubule-associated protein tau (tau) is a major antigenic component of paired helical filaments in Alzheimer disease. Proc. Natl. Acad. Sci. U.S.A. 83, 4044\u20134048."},{"key":"6","unstructured":"6) Grundke-Iqbal, I., Iqbal, K., Tung, Y.C., Quinlan, M., Wisniewski, H.M. and Binder, L.I. (1986) Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc. Natl. Acad. Sci. U.S.A. 83, 4913\u20134917."},{"key":"7","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1038\/349704a0","volume":"349","author":"A. Goate","year":"1991","unstructured":"7) Goate, A., Chartier-Harlin, M.C., Mullan, M., Brown, J., Crawford, F., Fidani, L., Giuffra, L., Haynes, A., Irving, N. and James, L. (1991) Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer\u2019s disease. Nature 349, 704\u2013706.","journal-title":"?Nature","ISSN":"https:\/\/id.crossref.org\/issn\/0028-0836","issn-type":"print"},{"key":"8","doi-asserted-by":"publisher","unstructured":"8) Sherrington, R., Rogaev, E.I., Liang, Y., Rogaeva, E.A., Levesque, G., Ikeda, M., Chi, H., Lin, C., Li, G., Holman, K., Tsuda, T., Mar, L., Foncin, J.F., Bruni, A.C., Montesi, M.P., Sorbi, S., Rainero, I., Pinessi, L., Nee, L., Chumakov, I., Pollen, D., Brookes, A., Sanseau, P., Polinsky, R.J., Wasco, W., Da Silva, H.A., Haines, J.L., Perkicak-Vance, M.A., Tanzi, R.E., Roses, A.D., Fraser, P.E., Rommens, J.M. and St George-Hyslop, P.H. (1995) Cloning of a gene bearing missense mutations in early-onset familial Alzheimer\u2019s disease. Nature 375, 754\u2013760.","DOI":"10.1038\/375754a0"},{"key":"9","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1126\/science.1072994","volume":"297","author":"J. Hardy","year":"2002","unstructured":"9) Hardy, J. and Selkoe, D.J. (2002) The amyloid hypothesis of Alzheimer\u2019s disease: progress and problems on the road to therapeutics. Science 297, 353\u2013356.","journal-title":"Science","ISSN":"https:\/\/id.crossref.org\/issn\/0036-8075","issn-type":"print"},{"key":"10","doi-asserted-by":"publisher","unstructured":"10) Suzuki, N., Cheung, T.T., Cai, X.D., Odaka, A., Otvos, L., Eckman, C., Golde, T.E. and Younkin, S.G. (1994) An increased percentage of long amyloid beta protein secreted by familial amyloid beta protein precursor (beta APP717) mutants. Science 264, 1336\u20131340.","DOI":"10.1126\/science.8191290"},{"key":"11","doi-asserted-by":"publisher","unstructured":"11) Iwatsubo, T., Odaka, A., Suzuki, N., Mizusawa, H., Nukina, N. and Ihara, Y. (1994) Visualization of A beta 42(43) and A beta 40 in senile plaques with end-specific A beta monoclonals: evidence that an initially deposited species is A beta 42(43). Neuron 13, 45\u201353.","DOI":"10.1016\/0896-6273(94)90458-8"},{"key":"12","unstructured":"12) Iwatsubo, T., Mann, D.M., Odaka, A., Suzuki, N. and Ihara, Y. (1995) Amyloid beta protein (A beta) deposition: A beta 42(43) precedes A beta 40 in Down syndrome. Ann. Neurol. 37, 294\u2013299."},{"key":"13","doi-asserted-by":"crossref","unstructured":"13) Qi-Takahara, Y., Morishima-Kawashima, M., Tanimura, Y., Dolios, G., Hirotani, N., Horikoshi, Y., Kametani, F., Maeda, M., Saido, T.C., Wang, R. and Ihara, Y. (2005) Longer forms of amyloid beta protein: implications for the mechanism of intramembrane cleavage by gamma-secretase. J. Neurosci. 25, 436\u2013445.","DOI":"10.1523\/JNEUROSCI.1575-04.2005"},{"key":"14","doi-asserted-by":"crossref","unstructured":"14) Takami, M., Nagashima, Y., Sano, Y., Ishihara, S., Morishima-Kawashima, M., Funamoto, S. and Ihara, Y. (2009) gamma-Secretase: successive tripeptide and tetrapeptide release from the transmembrane domain of beta-carboxyl terminal fragment. J. Neurosci. 29, 13042\u201313052.","DOI":"10.1523\/JNEUROSCI.2362-09.2009"},{"key":"15","doi-asserted-by":"crossref","first-page":"4693","DOI":"10.1021\/bi00069a001","volume":"32","author":"J.T. Jarrett","year":"1993","unstructured":"15) Jarrett, J.T., Berger, E.P. and Lansbury, P.T. (1993) The carboxy terminus of the beta amyloid protein is critical for the seeding of amyloid formation: implications for the pathogenesis of Alzheimer\u2019s disease. Biochemistry 32, 4693\u20134697.","journal-title":"Biochemistry","ISSN":"https:\/\/id.crossref.org\/issn\/0006-2960","issn-type":"print"},{"key":"16","unstructured":"16) Petersen, R.C., Doody, R., Kurz, A., Mohs, R.C., Morris, J.C., Rabins, P.V., Ritchie, K., Rossor, M., Thal, L. and Winblad, B. (2001) Current concepts in mild cognitive impairment. Arch. Neurol. 58, 1985\u20131992."},{"key":"17","doi-asserted-by":"crossref","unstructured":"17) Sperling, R.A., Aisen, P.S., Beckett, L.A., Bennett, D.A., Craft, S., Fagan, A.M., Iwatsubo, T., Jack, C.R., Kaye, J., Montine, T.J., Park, D.C., Reiman, E.M., Rowe, C.C., Siemers, E., Stern, Y., Yaffe, K., Carrillo, M.C., Thies, B., Morrison-Bogorad, M., Wagster, M.V. and Phelps, C.H. (2011) Toward defining the preclinical stages of Alzheimer\u2019s disease: recommendations from the National Institute on Aging-Alzheimer\u2019s Association workgroups on diagnostic guidelines for Alzheimer\u2019s disease. Alzheimers Dement. 7, 280\u2013292.","DOI":"10.1016\/j.jalz.2011.03.003"},{"key":"18","unstructured":"18) Bateman, R.J., Xiong, C., Benzinger, T.L., Fagan, A.M., Goate, A., Fox, N.C., Marcus, D.S., Cairns, N.J., Xie, X., Blazey, T.M., Holtzman, D.M., Santacruz, A., Buckles, V., Oliver, A., Moulder, K., Aisen, P.S., Ghetti, B., Klunk, W.E., Mcdade, E., Martins, R.N., Masters, C.L., Mayeux, R., Ringman, J.M., Rossor, M.N., Schofield, P.R., Sperling, R.A., Salloway, S. and Morris, J.C., for the Dominantly Inherited Alzheimer Network (2012) Clinical and biomarker changes in dominantly inherited Alzheimer\u2019s disease. N. Engl. J. Med. 367, 795\u2013804."},{"key":"19","doi-asserted-by":"crossref","unstructured":"19) Ellis, K.A., Lim, Y.Y., Harrington, K., Ames, D., Bush, A.I., Darby, D., Martins, R.N., Masters, C.L., Rowe, C.C., Savage, G., Szoeke, C., Villemagne, V.L., Maruff, P., and for the AIBL Research Group (2013) Decline in cognitive function over 18 months in healthy older adults with high amyloid-\u03b2. J. Alzheimers Dis. 34, 861\u2013871.","DOI":"10.3233\/JAD-122170"},{"key":"20","doi-asserted-by":"crossref","unstructured":"20) Vos, S.J., Xiong, C., Visser, P.J., Jasielec, M.S., Hassenstab, J., Grant, E.A., Cairns, N.J., Morris, J.C., Holtzman, D.M. and Fagan, A.M. (2013) Preclinical Alzheimer\u2019s disease and its outcome: a longitudinal cohort study. Lancet Neurol. 12, 957\u2013965.","DOI":"10.1016\/S1474-4422(13)70194-7"},{"key":"21","unstructured":"21) Morris, J.C., Roe, C.M., Grant, E.A., Head, D., Storandt, M., Goate, A.M., Fagan, A.M., Holtzman, D.M. and Mintun, M.A. (2009) Pittsburgh compound B imaging and prediction of progression from cognitive normality to symptomatic Alzheimer disease. Arch. Neurol. 66, 1469\u20131475."},{"key":"22","doi-asserted-by":"crossref","unstructured":"22) Knopman, D.S., Jack, C.R., Wiste, H.J., Weigand, S.D., Vemuri, P., Lowe, V., Kantarci, K., Gunter, J.L., Senjem, M.L., Ivnik, R.J., Roberts, R.O., Boeve, B.F. and Petersen, R.C. (2012) Short-term clinical outcomes for stages of NIA-AA preclinical Alzheimer disease. Neurology 78, 1576\u20131582.","DOI":"10.1212\/WNL.0b013e3182563bbe"},{"key":"23","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1038\/22124","volume":"400","author":"D. 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Neurology 64, 1553\u20131562.","DOI":"10.1212\/01.WNL.0000159740.16984.3C"},{"key":"25","doi-asserted-by":"publisher","unstructured":"25) Holmes, C., Boche, D., Wilkinson, D., Yadegarfar, G., Hopkins, V., Bayer, A., Jones, R.W., Bullock, R., Love, S., Neal, J.W., Zotova, E. and Nicoll, J.A. (2008) Long-term effects of Abeta42 immunisation in Alzheimer\u2019s disease: follow-up of a randomised, placebo-controlled phase I trial. Lancet 372, 216\u2013223.","DOI":"10.1016\/S0140-6736(08)61075-2"},{"key":"26","doi-asserted-by":"crossref","unstructured":"26) Winblad, B., Andreasen, N., Minthon, L., Floesser, A., Imbert, G., Dumortier, T., Maguire, R.P., Blennow, K., Lundmark, J., Staufenbiel, M., Orgogozo, J.M. and Graf, A. (2012) Safety, tolerability, and antibody response of active A\u03b2 immunotherapy with CAD106 in patients with Alzheimer\u2019s disease: randomised, double-blind, placebo-controlled, first-in-human study. Lancet Neurol. 11, 597\u2013604.","DOI":"10.1016\/S1474-4422(12)70140-0"},{"key":"27","unstructured":"27) Farlow, M.R., Andreasen, N., Riviere, M.E., Vostiar, I., Vitaliti, A., Sovago, J., Caputo, A., Winblad, B. and Graf, A. (2015) Long-term treatment with active A\u03b2 immunotherapy with CAD106 in mild Alzheimer\u2019s disease. Alzheimers Res. Ther. 7, 23."},{"key":"28","unstructured":"28) Muhs, A., Hickman, D.T., Pihlgren, M., Chuard, N., Giriens, V., Meerschman, C., Van Der Auwera, I., Van Leuven, F., Sugawara, M., Weingertner, M.C., Bechinger, B., Greferath, R., Kolonko, N., Nagel-Steger, L., Riesner, D., Brady, R.O., Pfeifer, A. and Nicolau, C. (2007) Liposomal vaccines with conformation-specific amyloid peptide antigens define immune response and efficacy in APP transgenic mice. Proc. Natl. Acad. Sci. U.S.A. 104, 9810\u20139815."},{"key":"29","unstructured":"29) Bard, F., Cannon, C., Barbour, R., Burke, R.L., Games, D., Grajeda, H., Guido, T., Hu, K., Huang, J., Johnson-Wood, K., Khan, K., Kholodenko, D., Lee, M., Lieberburg, I., Motter, R., Nguyen, M., Soriano, F., Vasquez, N., Weiss, K., Welch, B., Seubert, P., Schenk, D. and Yednock, T. (2000) Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat. Med. 6, 916\u2013919."},{"key":"30","unstructured":"30) Demattos, R.B., Bales, K.R., Cummins, D.J., Dodart, J.C., Paul, S.M. and Holtzman, D.M. (2001) Peripheral anti-A beta antibody alters CNS and plasma A beta clearance and decreases brain A beta burden in a mouse model of Alzheimer\u2019s disease. Proc. Natl. Acad. Sci. U.S.A. 98, 8850\u20138855."},{"key":"31","doi-asserted-by":"crossref","unstructured":"31) Vasilevko, V., Xu, F., Previti, M.L., Van Nostrand, W.E. and Cribbs, D.H. (2007) Experimental investigation of antibody-mediated clearance mechanisms of amyloid-beta in CNS of Tg-SwDI transgenic mice. J. Neurosci. 27, 13376\u201313383.","DOI":"10.1523\/JNEUROSCI.2788-07.2007"},{"key":"32","doi-asserted-by":"crossref","unstructured":"32) Yamada, K., Yabuki, C., Seubert, P., Schenk, D., Hori, Y., Ohtsuki, S., Terasaki, T., Hashimoto, T. and Iwatsubo, T. (2009) Abeta immunotherapy: intracerebral sequestration of Abeta by an anti-Abeta monoclonal antibody 266 with high affinity to soluble Abeta. J. Neurosci. 29, 11393\u201311398.","DOI":"10.1523\/JNEUROSCI.2021-09.2009"},{"key":"33","doi-asserted-by":"crossref","unstructured":"33) Deane, R., Sagare, A., Hamm, K., Parisi, M., Larue, B., Guo, H., Wu, Z., Holtzman, D.M. and Zlokovic, B.V. (2005) IgG-assisted age-dependent clearance of Alzheimer\u2019s amyloid beta peptide by the blood-brain barrier neonatal Fc receptor. J. Neurosci. 25, 11495\u201311503.","DOI":"10.1523\/JNEUROSCI.3697-05.2005"},{"key":"34","doi-asserted-by":"publisher","unstructured":"34) Salloway, S., Sperling, R., Gilman, S., Fox, N.C., Blennow, K., Raskind, M., Sabbagh, M., Honig, L.S., Doody, R., Van Dyck, C.H., Mulnard, R., Barakos, J., Gregg, K.M., Liu, E., Lieberburg, I., Schenk, D., Black, R., Grundman, M., and for the Bapineuzumab 201 Clinical Trial Investigators (2009) A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease. Neurology 73, 2061\u20132070.","DOI":"10.1212\/WNL.0b013e3181c67808"},{"key":"35","doi-asserted-by":"crossref","unstructured":"35) 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., Rodriguez Martinez De Liano, S., Liu, E., Koller, M., Gregg, K.M., Schenk, D., Black, R. and Grundman, M. (2010) 11C-PiB PET assessment of change in fibrillar amyloid-beta load in patients with Alzheimer\u2019s disease treated with bapineuzumab: a phase 2, double-blind, placebo-controlled, ascending-dose study. Lancet Neurol. 9, 363\u2013372.","DOI":"10.1016\/S1474-4422(10)70043-0"},{"key":"36","unstructured":"36) Salloway, S., Sperling, R., Fox, N.C., Blennow, K., Klunk, W., Raskind, M., Sabbagh, M., Honig, L.S., Porsteinsson, A.P., Ferris, S., Reichert, M., Ketter, N., Nejadnik, B., Guenzler, V., Miloslavsky, M., Wang, D., Lu, Y., Lull, J., Tudor, I.C., Liu, E., Grundman, M., Yuen, E., Black, R. and Brashear, H.R., for the Bapineuzumab 301 and 302 Clinical Trial Investigators (2014) Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer\u2019s disease. N. Engl. J. Med. 370, 322\u2013333."},{"key":"37","doi-asserted-by":"crossref","unstructured":"37) Sperling, R.A., Jack, C.R., Black, S.E., Frosch, M.P., Greenberg, S.M., Hyman, B.T., Scheltens, P., Carrillo, M.C., Thies, W., Bednar, M.M., Black, R.S., Brashear, H.R., Grundman, M., Siemers, E.R., Feldman, H.H. and Schindler, R.J. (2011) Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: recommendations from the Alzheimer\u2019s Association Research Roundtable Workgroup. Alzheimers Dement. 7, 367\u2013385.","DOI":"10.1016\/j.jalz.2011.05.2351"},{"key":"38","unstructured":"38) Ostrowitzki, S., Deptula, D., Thurfjell, L., Barkhof, F., Bohrmann, B., Brooks, D.J., Klunk, W.E., Ashford, E., Yoo, K., Xu, Z.X., Loetscher, H. and Santarelli, L. (2012) Mechanism of amyloid removal in patients with Alzheimer disease treated with gantenerumab. Arch. Neurol. 69, 198\u2013207."},{"key":"39","doi-asserted-by":"crossref","unstructured":"39) Lasser, R., Scheltens, P., Dubois, B., Nikolcheva, T., Retout, S., Volz, D., Csilla, C. and Boada, M. (2016) Efficacy, safety and biomarker data from SCarlet RoAD \u2014 a global Phase 3 study of gantenerumab in patients with prodromal AD. Neurology 86, Supplement S1.002.","DOI":"10.1016\/j.jagp.2016.02.034"},{"key":"40","doi-asserted-by":"crossref","unstructured":"40) Farlow, M., Arnold, S.E., Van Dyck, C.H., Aisen, P.S., Snider, B.J., Porsteinsson, A.P., Friedrich, S., Dean, R.A., Gonzales, C., Sethuraman, G., Demattos, R.B., Mohs, R., Paul, S.M. and Siemers, E.R. (2012) Safety and biomarker effects of solanezumab in patients with Alzheimer\u2019s disease. Alzheimers Dement. 8, 261\u2013271.","DOI":"10.1016\/j.jalz.2011.09.224"},{"key":"41","unstructured":"41) Doody, R.S., Thomas, R.G., Farlow, M., Iwatsubo, T., Vellas, B., Joffe, S., Kieburtz, K., Raman, R., Sun, X., and Aisen, P.S. for the Alzheimer\u2019s Disease Cooperative Study Steering Committee; Siemers, E., Liu-Seifert, H. and Mohs, R. for the Solanezumab Study Group (2014) Phase 3 trials of solanezumab for mild-to-moderate Alzheimer\u2019s disease. N. Engl. J. Med. 370, 311\u2013321."},{"key":"42","doi-asserted-by":"publisher","unstructured":"42) Sevigny, J., Chiao, P., Bussi\u00e8re, T., Weinreb, P.H., Williams, L., Maier, M., Dunstan, R., Salloway, S., Chen, T., Ling, Y., O\u2019gorman, J., Qian, F., Arastu, M., Li, M., Chollate, S., Brennan, M.S., Quintero-Monzon, O., Scannevin, R.H., Arnold, H.M., Engber, T., Rhodes, K., Ferrero, J., Hang, Y., Mikulskis, A., Grimm, J., Hock, C., Nitsch, R.M. and Sandrock, A. (2016) The antibody aducanumab reduces A\u03b2 plaques in Alzheimer\u2019s disease. Nature 537, 50\u201356.","DOI":"10.1038\/nature19323"},{"key":"43","unstructured":"43) Doody, R.S., Raman, R., Farlow, M., Iwatsubo, T., Vellas, B., Joffe, S., Kieburtz, K., He, F., Sun, X., Thomas, R.G., Aisen, P.S. for the Alzheimer\u2019s Disease Cooperative Study Steering Committee; and Siemers, E., Sethuraman, G. and Mohs, R., for the Semagacestat Study Group (2013) A phase 3 trial of semagacestat for treatment of Alzheimer\u2019s disease. N. Engl. J. Med. 369, 341\u2013350."},{"key":"44","doi-asserted-by":"crossref","unstructured":"44) Coric, V., Van Dyck, C.H., Salloway, S., Andreasen, N., Brody, M., Richter, R.W., Soininen, H., Thein, S., Shiovitz, T., Pilcher, G., Colby, S., Rollin, L., Dockens, R., Pachai, C., Portelius, E., Andreasson, U., Blennow, K., Soares, H., Albright, C., Feldman, H.H. and Berman, R.M. (2012) Safety and tolerability of the \u03b3-secretase inhibitor avagacestat in a phase 2 study of mild to moderate Alzheimer disease. Arch. Neurol. 69, 1430\u20131440.","DOI":"10.1001\/archneurol.2012.2194"},{"key":"45","doi-asserted-by":"crossref","first-page":"2557","DOI":"10.1001\/jama.2009.1866","volume":"302","author":"R.C. Green","year":"2009","unstructured":"45) Green, R.C., Schneider, L.S., Amato, D.A., Beelen, A.P., Wilcock, G., Swabb, E.A., Zavitz, K.H. for the Tarenflurbil Phase 3 Study Group (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\u20132564.","journal-title":"JAMA The Journal of the American Medical Association","ISSN":"https:\/\/id.crossref.org\/issn\/0098-7484","issn-type":"print"},{"key":"46","unstructured":"46) Hussain, I., Powell, D., Howlett, D.R., Tew, D.G., Meek, T.D., Chapman, C., Gloger, I.S., Murphy, K.E., Southan, C.D., Ryan, D.M., Smith, T.S., Simmons, D.L., Walsh, F.S., Dingwall, C. and Christie, G. (1999) Identification of a novel aspartic protease (Asp 2) as beta-secretase. Mol. Cell. Neurosci. 14, 419\u2013427."},{"key":"47","doi-asserted-by":"publisher","unstructured":"47) Sinha, S., Anderson, J.P., Barbour, R., Basi, G.S., Caccavello, R., Davis, D., Doan, M., Dovey, H.F., Frigon, N., Hong, J., Jacobson-Croak, K., Jewett, N., Keim, P., Knops, J., Lieberburg, I., Power, M., Tan, H., Tatsuno, G., Tung, J., Schenk, D., Seubert, P., Suomensaari, S.M., Wang, S., Walker, D., Zhao, J., Mcconlogue, L. and John, V. (1999) Purification and cloning of amyloid precursor protein beta-secretase from human brain. Nature 402, 537\u2013540.","DOI":"10.1038\/990114"},{"key":"48","doi-asserted-by":"publisher","unstructured":"48) Vassar, R., Bennett, B.D., Babu-Khan, S., Kahn, S., Mendiaz, E.A., Denis, P., Teplow, D.B., Ross, S., Amarante, P., Loeloff, R., Luo, Y., Fisher, S., Fuller, J., Edenson, S., Lile, J., Jarosinski, M.A., Biere, A.L., Curran, E., Burgess, T., Louis, J.C., Collins, F., Treanor, J., Rogers, G. and Citron, M. (1999) Beta-secretase cleavage of Alzheimer\u2019s amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286, 735\u2013741.","DOI":"10.1126\/science.286.5440.735"},{"key":"49","doi-asserted-by":"publisher","unstructured":"49) Yan, R., Bienkowski, M.J., Shuck, M.E., Miao, H., Tory, M.C., Pauley, A.M., Brashier, J.R., Stratman, N.C., Mathews, W.R., Buhl, A.E., Carter, D.B., Tomasselli, A.G., Parodi, L.A., Heinrikson, R.L. and Gurney, M.E. (1999) Membrane-anchored aspartyl protease with Alzheimer\u2019s disease beta-secretase activity. Nature 402, 533\u2013537.","DOI":"10.1038\/990107"},{"key":"50","unstructured":"50) Lin, X., Koelsch, G., Wu, S., Downs, D., Dashti, A. and Tang, J. (2000) Human aspartic protease memapsin 2 cleaves the beta-secretase site of beta-amyloid precursor protein. Proc. Natl. Acad. Sci. U.S.A. 97, 1456\u20131460."},{"key":"51","doi-asserted-by":"crossref","unstructured":"51) Di Fede, G., Catania, M., Morbin, M., Rossi, G., Suardi, S., Mazzoleni, G., Merlin, M., Giovagnoli, A.R., Prioni, S., Erbetta, A., Falcone, C., Gobbi, M., Colombo, L., Bastone, A., Beeg, M., Manzoni, C., Francescucci, B., Spagnoli, A., Cant\u00f9, L., Del Favero, E., Levy, E., Salmona, M. and Tagliavini, F. (2009) A recessive mutation in the APP gene with dominant-negative effect on amyloidogenesis. Science 323, 1473\u20131477.","DOI":"10.1126\/science.1168979"},{"key":"52","unstructured":"52) Mullan, M., Crawford, F., Axelman, K., Houlden, H., Lilius, L., Winblad, B. and Lannfelt, L. (1992) A pathogenic mutation for probable Alzheimer\u2019s disease in the APP gene at the N-terminus of beta-amyloid. Nat. Genet. 1, 345\u2013347."},{"key":"53","doi-asserted-by":"publisher","unstructured":"53) Jonsson, T., Atwal, J.K., Steinberg, S., Snaedal, J., Jonsson, P.V., Bjornsson, S., Stefansson, H., Sulem, P., Gudbjartsson, D., Maloney, J., Hoyte, K., Gustafson, A., Liu, Y., Lu, Y., Bhangale, T., Graham, R.R., Huttenlocher, J., Bjornsdottir, G., Andreassen, O.A., J\u00f6nsson, E.G., Palotie, A., Behrens, T.W., Magnusson, O.T., Kong, A., Thorsteinsdottir, U., Watts, R.J. and Stefansson, K. (2012) A mutation in APP protects against Alzheimer\u2019s disease and age-related cognitive decline. Nature 488, 96\u201399.","DOI":"10.1038\/nature11283"},{"key":"54","unstructured":"54) Luo, Y., Bolon, B., Kahn, S., Bennett, B.D., Babu-Khan, S., Denis, P., Fan, W., Kha, H., Zhang, J., Gong, Y., Martin, L., Louis, J.C., Yan, Q., Richards, W.G., Citron, M. and Vassar, R. (2001) Mice deficient in BACE1, the Alzheimer\u2019s beta-secretase, have normal phenotype and abolished beta-amyloid generation. Nat. Neurosci. 4, 231\u2013232."},{"key":"55","doi-asserted-by":"crossref","unstructured":"55) Yan, R. and Vassar, R. (2014) Targeting the \u03b2 secretase BACE1 for Alzheimer\u2019s disease therapy. Lancet Neurol. 13, 319\u2013329.","DOI":"10.1016\/S1474-4422(13)70276-X"},{"key":"56","doi-asserted-by":"crossref","unstructured":"56) Kennedy, M.E., Stamford, A.W., Chen, X., Cox, K., Cumming, J.N., Dockendorf, M.F., Egan, M., Ereshefsky, L., Hodgson, R.A., Hyde, L.A., Jhee, S., Kleijn, H.J., Kuvelkar, R., Li, W., Mattson, B.A., Mei, H., Palcza, J., Scott, J.D., Tanen, M., Troyer, M.D., Tseng, J.L., Stone, J.A., Parker, E.M. and Forman, M.S. (2016) The BACE1 inhibitor verubecestat (MK-8931) reduces CNS \u03b2-amyloid in animal models and in Alzheimer\u2019s disease patients. Sci. Transl. Med. 8, 363ra150.","DOI":"10.1126\/scitranslmed.aad9704"},{"key":"57","doi-asserted-by":"crossref","unstructured":"57) Eketj\u00e4ll, S., Janson, J., Kaspersson, K., Bogstedt, A., Jeppsson, F., F\u00e4lting, J., Haeberlein, S.B., Kugler, A.R., Alexander, R.C. and Cebers, G. (2016) AZD3293: A novel, orally active BACE1 inhibitor with high potency and permeability and markedly slow off-rate kinetics. J. Alzheimers Dis. 50, 1109\u20131123.","DOI":"10.3233\/JAD-150834"},{"key":"58","doi-asserted-by":"crossref","unstructured":"58) Cebers, G., Alexander, R.C., Haeberlein, S.B., Han, D., Goldwater, R., Ereshefsky, L., Olsson, T., Ye, N., Rosen, L., Russell, M., Maltby, J., Eketj\u00e4ll, S. and Kugler, A.R. (2017) AZD3293: Pharmacokinetic and pharmacodynamic effects in healthy subjects and patients with Alzheimer\u2019s disease. J. Alzheimers Dis. 55, 1039\u20131053.","DOI":"10.3233\/JAD-160701"},{"key":"59","doi-asserted-by":"crossref","unstructured":"59) Braak, H., Zetterberg, H., Del Tredici, K. and Blennow, K. (2013) Intraneuronal tau aggregation precedes diffuse plaque deposition, but amyloid-\u03b2 changes occur before increases of tau in cerebrospinal fluid. Acta Neuropathol. 126, 631\u2013641.","DOI":"10.1007\/s00401-013-1139-0"},{"key":"60","doi-asserted-by":"crossref","unstructured":"60) Braak, H. and Del Tredici, K. (2011) The pathological process underlying Alzheimer\u2019s disease in individuals under thirty. Acta Neuropathol. 121, 171\u2013181.","DOI":"10.1007\/s00401-010-0789-4"},{"key":"61","unstructured":"61) Wischik, C.M., Edwards, P.C., Lai, R.Y., Roth, M. and Harrington, C.R. (1996) Selective inhibition of Alzheimer disease-like tau aggregation by phenothiazines. Proc. Natl. Acad. Sci. U.S.A. 93, 11213\u201311218."},{"key":"62","unstructured":"62) Taniguchi, S., Suzuki, N., Masuda, M., Hisanaga, S., Iwatsubo, T., Goedert, M. and Hasegawa, M. (2005) Inhibition of heparin-induced tau filament formation by phenothiazines, polyphenols, and porphyrins. J. Biol. Chem. 280, 7614\u20137623."},{"key":"63","doi-asserted-by":"crossref","unstructured":"63) Wischik, C.M., Staff, R.T., Wischik, D.J., Bentham, P., Murray, A.D., Storey, J.M., Kook, K.A. and Harrington, C.R. (2015) Tau aggregation inhibitor therapy: an exploratory phase 2 study in mild or moderate Alzheimer\u2019s disease. J. Alzheimers Dis. 44, 705\u2013720.","DOI":"10.3233\/JAD-142874"},{"key":"64","doi-asserted-by":"crossref","unstructured":"64) Gauthier, S., Feldman, H.H., Schneider, L.S., Wilcock, G.K., Frisoni, G.B., Hardlund, J.H., Moebius, H.J., Bentham, P., Kook, K.A., Wischik, D.J., Schelter, B.O., Davis, C.S., Staff, R.T., Bracoud, L., Shamsi, K., Storey, J.M., Harrington, C.R. and Wischik, C.M. (2016) Efficacy and safety of tau-aggregation inhibitor therapy in patients with mild or moderate Alzheimer\u2019s disease: a randomised, controlled, double-blind, parallel-arm, phase 3 trial. Lancet 388, 2873\u20132884.","DOI":"10.1016\/S0140-6736(16)31275-2"},{"key":"65","doi-asserted-by":"crossref","unstructured":"65) Lovestone, S., Boada, M., Dubois, B., H\u00fcll, M., Rinne, J.O., Huppertz, H.J., Calero, M., Andr\u00e9s, M.V., G\u00f3mez-Carrillo, B., Le\u00f3n, T., Del Ser, T.; ARGO investigators (2015) A phase II trial of tideglusib in Alzheimer\u2019s disease. J. Alzheimers Dis. 45, 75\u201388.","DOI":"10.3233\/JAD-141959"},{"key":"66","unstructured":"66) Hampel, H., Ewers, M., B\u00fcrger, K., Annas, P., M\u00f6rtberg, A., Bogstedt, A., Fr\u00f6lich, L., Schr\u00f6der, J., Sch\u00f6nknecht, P., Riepe, M.W., Kraft, I., Gasser, T., Leyhe, T., M\u00f6ller, H.J., Kurz, A. and Basun, H. (2009) Lithium trial in Alzheimer\u2019s disease: a randomized, single-blind, placebo-controlled, multicenter 10-week study. J. Clin. Psychiatry 70, 922\u2013931."},{"key":"67","doi-asserted-by":"crossref","unstructured":"67) Kontsekova, E., Zilka, N., Kovacech, B., Novak, P. and Novak, M. (2014) First-in-man tau vaccine targeting structural determinants essential for pathological tau-tau interaction reduces tau oligomerisation and neurofibrillary degeneration in an Alzheimer\u2019s disease model. Alzheimers Res. Ther. 6, 44.","DOI":"10.1186\/alzrt278"},{"key":"68","doi-asserted-by":"crossref","unstructured":"68) Novak, P., Schmidt, R., Kontsekova, E., Zilka, N., Kovacech, B., Skrabana, R., Vince-Kazmerova, Z., Katina, S., Fialova, L., Prcina, M., Parrak, V., Dal-Bianco, P., Brunner, M., Staffen, W., Rainer, M., Ondrus, M., Ropele, S., Smisek, M., Sivak, R., Winblad, B. and Novak, M. (2017) Safety and immunogenicity of the tau vaccine AADvac1 in patients with Alzheimer\u2019s disease: a randomised, double-blind, placebo-controlled, phase 1 trial. Lancet Neurol. 16, 123\u2013134.","DOI":"10.1016\/S1474-4422(16)30331-3"},{"key":"69","unstructured":"69) Theunis, C., Crespo-Biel, N., Gafner, V., Pihlgren, M., L\u00f3pez-Deber, M.P., Reis, P., Hickman, D.T., Adolfsson, O., Chuard, N., Ndao, D.M., Borghgraef, P., Devijver, H., Van Leuven, F., Pfeifer, A. and Muhs, A. (2013) Efficacy and safety of a liposome-based vaccine against protein Tau, assessed in tau.P301L mice that model tauopathy. PLoS One 8, e72301."},{"key":"70","doi-asserted-by":"crossref","unstructured":"70) Donohue, M.C., Sperling, R.A., Salmon, D.P., Rentz, D.M., Raman, R., Thomas, R.G., Weiner, M. Aisen, P.S.; for the Australian Imaging, Biomarkers, and Lifestyle Flagship Study of Ageing; the Alzheimer\u2019s Disease Neuroimaging Initiative; and the Alzheimer\u2019s Disease Cooperative Study (2014) The preclinical Alzheimer cognitive composite: measuring amyloid-related decline. JAMA Neurol. 71, 961\u2013970.","DOI":"10.1001\/jamaneurol.2014.803"},{"key":"71","doi-asserted-by":"crossref","unstructured":"71) Mormino, E.C., Papp, K.V., Rentz, D.M., Donohue, M.C., Amariglio, R., Quiroz, Y.T., Chhatwal, J., Marshall, G.A., Donovan, N., Jackson, J., Gatchel, J.R., Hanseeuw, B.J., Schultz, A.P., Aisen, P.S., Johnson, K.A. and Sperling, R.A. (2017) Early and late change on the preclinical Alzheimer\u2019s cognitive composite in clinically normal older individuals with elevated amyloid \u03b2. Alzheimers Dement. 13, 1004\u20131012.","DOI":"10.1016\/j.jalz.2017.01.018"},{"key":"72","doi-asserted-by":"crossref","unstructured":"72) Mueller, S.G., Weiner, M.W., Thal, L.J., Petersen, R.C., Jack, C.R., Jagust, W., Trojanowski, J.Q., Toga, A.W. and Beckett, L. (2005) Ways toward an early diagnosis in Alzheimer\u2019s disease: the Alzheimer\u2019s Disease Neuroimaging Initiative (ADNI). Alzheimers Dement. 1, 55\u201366.","DOI":"10.1016\/j.jalz.2005.06.003"},{"key":"73","doi-asserted-by":"crossref","unstructured":"73) Ellis, K.A., Bush, A.I., Darby, D., De Fazio, D., Foster, J., Hudson, P., Lautenschlager, N.T., Lenzo, N., Martins, R.N., Maruff, P., Masters, C., Milner, A., Pike, K., Rowe, C., Savage, G., Szoeke, C., Taddei, K., Villemagne, V., Woodward, M., Ames, D., and the AIBL Research Group (2009) The Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging: methodology and baseline characteristics of 1112 individuals recruited for a longitudinal study of Alzheimer\u2019s disease. Int. Psychogeriatr. 21, 672\u2013687.","DOI":"10.1017\/S1041610209009405"},{"key":"74","doi-asserted-by":"crossref","unstructured":"74) Iwatsubo, T. (2010) Japanese Alzheimer\u2019s Disease Neuroimaging Initiative: present status and future. Alzheimers Dement. 6, 297\u2013299.","DOI":"10.1016\/j.jalz.2010.03.011"},{"key":"75","doi-asserted-by":"crossref","unstructured":"75) Toga, A.W., Neu, S.C., Bhatt, P., Crawford, K.L. and Ashish, N. (2016) The global Alzheimer\u2019s association interactive network. Alzheimers Dement. 12, 49\u201354.","DOI":"10.1016\/j.jalz.2015.06.1896"},{"key":"76","doi-asserted-by":"crossref","unstructured":"76) Cummings, J., Aisen, P., Barton, R., Bork, J., Doody, R., Dwyer, J., Egan, J.C., Feldman, H., Lappin, D., Truyen, L., Salloway, S., Sperling, R. and Vradenburg, G. (2016) Re-engineering Alzheimer clinical trials: Global Alzheimer\u2019s Platform network. J. Prev. Alzheimer\u2019s Dis. 3, 114\u2013120.","DOI":"10.14283\/jpad.2016.93"},{"key":"77","doi-asserted-by":"crossref","unstructured":"77) Ritchie, C.W., Molinuevo, J.L., Truyen, L., Satlin, A., Van Der Geyten, S. and Lovestone, S. (2015) Development of interventions for the secondary prevention of Alzheimer\u2019s dementia: the European Prevention of Alzheimer\u2019s Dementia (EPAD) project. Lancet Psychiatry 3, 179\u2013186.","DOI":"10.1016\/S2215-0366(15)00454-X"},{"key":"78","unstructured":"78) Sakurai, T., Arai, H. and Toba, K. (2016) Japan\u2019s challenge of early detection of persons with cognitive decline. J. Am. Med. Dir. Assoc. 17, 451\u2013452."},{"key":"79","doi-asserted-by":"crossref","unstructured":"79) Matsuda, H., Mizusawa, H., Maikusa, N., Imabayashi, E., Ogawa, M., Toba, K., Shimada, H. and Suzuki, K. (2016) Online registry for the prevention of dementia in Japan. 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