{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T19:23:39Z","timestamp":1793129019072,"version":"4.5.0"},"reference-count":110,"publisher":"Springer Science and Business Media LLC","issue":"11","license":[{"start":{"date-parts":[[2021,9,21]],"date-time":"2021-09-21T00:00:00Z","timestamp":1632182400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.springer.com\/tdm"},{"start":{"date-parts":[[2021,9,21]],"date-time":"2021-09-21T00:00:00Z","timestamp":1632182400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.springer.com\/tdm"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Rev Neurol"],"published-print":{"date-parts":[[2021,11]]},"DOI":"10.1038\/s41582-021-00545-1","type":"journal-article","created":{"date-parts":[[2021,9,21]],"date-time":"2021-09-21T10:15:42Z","timestamp":1632219342000},"page":"703-714","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":141,"title":["The case for low-level BACE1 inhibition for the prevention of Alzheimer disease"],"prefix":"10.1038","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6764-3866","authenticated-orcid":false,"given":"Eric","family":"McDade","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iryna","family":"Voytyuk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Aisen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7729-1702","authenticated-orcid":false,"given":"Randall J.","family":"Bateman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3057-2387","authenticated-orcid":false,"given":"Maria C.","family":"Carrillo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bart","family":"De Strooper","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Haass","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0705-3696","authenticated-orcid":false,"given":"Eric M.","family":"Reiman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reisa","family":"Sperling","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6058-8032","authenticated-orcid":false,"given":"Pierre N.","family":"Tariot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riqiang","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colin L.","family":"Masters","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Vassar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan F.","family":"Lichtenthaler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,9,21]]},"reference":[{"key":"545_CR1","doi-asserted-by":"publisher","first-page":"595","DOI":"10.15252\/emmm.201606210","volume":"8","author":"DJ Selkoe","year":"2016","unstructured":"Selkoe, D. J. & Hardy, J. The amyloid hypothesis of Alzheimer\u2019s disease at 25 years. EMBO Mol. Med. 8, 595\u2013608 (2016).","journal-title":"EMBO Mol. Med."},{"key":"545_CR2","doi-asserted-by":"publisher","first-page":"603","DOI":"10.1016\/j.cell.2015.12.056","volume":"164","author":"B De Strooper","year":"2016","unstructured":"De Strooper, B. & Karran, E. The cellular phase of Alzheimer\u2019s disease. Cell 164, 603\u2013615 (2016).","journal-title":"Cell"},{"key":"545_CR3","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1006\/mcne.1999.0811","volume":"14","author":"I Hussain","year":"1999","unstructured":"Hussain, I. et al. Identification of a novel aspartic protease (Asp 2) as beta-secretase. Mol. Cell. Neurosci. 14, 419\u2013427 (1999).","journal-title":"Mol. Cell. Neurosci."},{"key":"545_CR4","doi-asserted-by":"publisher","first-page":"537","DOI":"10.1038\/990114","volume":"402","author":"S Sinha","year":"1999","unstructured":"Sinha, S. et al. Purification and cloning of amyloid precursor protein beta-secretase from human brain. Nature 402, 537\u2013540 (1999).","journal-title":"Nature"},{"key":"545_CR5","doi-asserted-by":"publisher","first-page":"735","DOI":"10.1126\/science.286.5440.735","volume":"286","author":"R Vassar","year":"1999","unstructured":"Vassar, R. et al. Beta-secretase cleavage of Alzheimer\u2019s amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286, 735\u2013741 (1999).","journal-title":"Science"},{"key":"545_CR6","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1038\/990107","volume":"402","author":"R Yan","year":"1999","unstructured":"Yan, R. et al. Membrane-anchored aspartyl protease with Alzheimer\u2019s disease beta-secretase activity. Nature 402, 533\u2013537 (1999).","journal-title":"Nature"},{"key":"545_CR7","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1007\/s40263-019-00613-7","volume":"33","author":"B Das","year":"2019","unstructured":"Das, B. & Yan, R. A close look at BACE1 inhibitors for Alzheimer\u2019s disease treatment. CNS Drugs 33, 251\u2013263 (2019).","journal-title":"CNS Drugs"},{"key":"545_CR8","doi-asserted-by":"publisher","first-page":"1408","DOI":"10.1056\/NEJMoa1812840","volume":"380","author":"MF Egan","year":"2019","unstructured":"Egan, M. F. et al. Randomized trial of verubecestat for prodromal Alzheimer\u2019s disease. N. Engl. J. Med. 380, 1408\u20131420 (2019).","journal-title":"N. Engl. J. Med."},{"key":"545_CR9","doi-asserted-by":"publisher","first-page":"1483","DOI":"10.1056\/NEJMc1813435","volume":"380","author":"D Henley","year":"2019","unstructured":"Henley, D. et al. Preliminary results of a trial of atabecestat in preclinical Alzheimer\u2019s disease. N. Engl. J. Med. 380, 1483\u20131485 (2019).","journal-title":"N. Engl. J. Med."},{"key":"545_CR10","doi-asserted-by":"publisher","first-page":"1476","DOI":"10.1056\/NEJMe1903193","volume":"380","author":"DS Knopman","year":"2019","unstructured":"Knopman, D. S. Lowering of amyloid-beta by beta-secretase inhibitors - some informative failures. N. Engl. J. Med. 380, 1476\u20131478 (2019).","journal-title":"N. Engl. J. Med."},{"key":"545_CR11","doi-asserted-by":"publisher","first-page":"341","DOI":"10.1056\/NEJMoa1210951","volume":"369","author":"RS Doody","year":"2013","unstructured":"Doody, R. S. et al. A phase 3 trial of semagacestat for treatment of Alzheimer\u2019s disease. N. Engl. J. Med. 369, 341\u2013350 (2013).","journal-title":"N. Engl. J. Med."},{"key":"545_CR12","doi-asserted-by":"publisher","first-page":"1430","DOI":"10.1001\/archneurol.2012.2194","volume":"69","author":"V Coric","year":"2012","unstructured":"Coric, V. et al. Safety and tolerability of the gamma-secretase inhibitor avagacestat in a phase 2 study of mild to moderate Alzheimer disease. Arch. Neurol. 69, 1430\u20131440 (2012).","journal-title":"Arch. Neurol."},{"key":"545_CR13","doi-asserted-by":"publisher","first-page":"721","DOI":"10.1016\/j.cell.2014.10.016","volume":"159","author":"B De Strooper","year":"2014","unstructured":"De Strooper, B. Lessons from a failed gamma-secretase Alzheimer trial. Cell 159, 721\u2013726 (2014).","journal-title":"Cell"},{"key":"545_CR14","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20202560","volume":"218","author":"D Kevin","year":"2021","unstructured":"Kevin, D. et al. Preclinical validation of a potent \u03b3-secretase modulator for Alzheimer\u2019s disease prevention. J. Exp. Med. 218, e20202560 (2021).","journal-title":"J. Exp. Med."},{"key":"545_CR15","doi-asserted-by":"publisher","DOI":"10.1002\/alz.041140","volume":"16","author":"A Graf","year":"2020","unstructured":"Graf, A. et al. Umibecestat in the API Generation program: worsening in RBANS and\/or CDR on treatment reverses after wash-out. Alzheimers Dement. 16, e041140 (2020).","journal-title":"Alzheimers Dement."},{"key":"545_CR16","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1016\/j.phrs.2018.02.014","volume":"130","author":"H Hampel","year":"2018","unstructured":"Hampel, H. et al. Precision pharmacology for Alzheimer\u2019s disease. Pharmacol. Res. 130, 331\u2013365 (2018).","journal-title":"Pharmacol. Res."},{"key":"545_CR17","doi-asserted-by":"publisher","first-page":"1109","DOI":"10.3233\/JAD-150834","volume":"50","author":"S Eketjall","year":"2016","unstructured":"Eketjall, S. et al. AZD3293: a novel, orally active BACE1 inhibitor with high potency and permeability and markedly slow off-rate kinetics. J. Alzheimers Dis. 50, 1109\u20131123 (2016).","journal-title":"J. Alzheimers Dis."},{"key":"545_CR18","doi-asserted-by":"publisher","first-page":"363ra150","DOI":"10.1126\/scitranslmed.aad9704","volume":"8","author":"ME Kennedy","year":"2016","unstructured":"Kennedy, M. E. et al. The BACE1 inhibitor verubecestat (MK-8931) reduces CNS beta-amyloid in animal models and in Alzheimer\u2019s disease patients. Sci. Transl Med. 8, 363ra150 (2016).","journal-title":"Sci. Transl Med."},{"key":"545_CR19","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.201809316","volume":"10","author":"U Neumann","year":"2018","unstructured":"Neumann, U. et al. The BACE-1 inhibitor CNP520 for prevention trials in Alzheimer\u2019s disease. EMBO Mol. Med. 10, e9316 (2018).","journal-title":"EMBO Mol. Med."},{"key":"545_CR20","doi-asserted-by":"publisher","first-page":"1691","DOI":"10.1056\/NEJMoa1706441","volume":"378","author":"MF Egan","year":"2018","unstructured":"Egan, M. F. et al. Randomized trial of verubecestat for mild-to-moderate Alzheimer\u2019s disease. N. Engl. J. Med. 378, 1691\u20131703 (2018).","journal-title":"N. Engl. J. Med."},{"key":"545_CR21","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1001\/jamaneurol.2019.3988","volume":"77","author":"AM Wessels","year":"2019","unstructured":"Wessels, A. M. et al. Efficacy and safety of lanabecestat for treatment of early and mild Alzheimer disease: the AMARANTH and DAYBREAK-ALZ randomized clinical trials. JAMA Neurol. 77, 199\u2013209 (2019).","journal-title":"JAMA Neurol."},{"key":"545_CR22","doi-asserted-by":"publisher","first-page":"1691","DOI":"10.1056\/NEJMoa2100708","volume":"384","author":"MA Mintun","year":"2021","unstructured":"Mintun, M. A. et al. Donanemab in early Alzheimer\u2019s disease. N. Engl. J. Med. 384, 1691\u20131704 (2021).","journal-title":"N. Engl. J. Med."},{"key":"545_CR23","doi-asserted-by":"publisher","first-page":"1172","DOI":"10.1093\/eurheartj\/ehx566","volume":"39","author":"KC Koskinas","year":"2018","unstructured":"Koskinas, K. C. et al. Effect of statins and non-statin LDL-lowering medications on cardiovascular outcomes in secondary prevention: a meta-analysis of randomized trials. Eur. Heart J. 39, 1172\u20131180 (2018).","journal-title":"Eur. Heart J."},{"key":"545_CR24","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms13042","volume":"7","author":"AM Zuhl","year":"2016","unstructured":"Zuhl, A. M. et al. Chemoproteomic profiling reveals that cathepsin D off-target activity drives ocular toxicity of beta-secretase inhibitors. Nat. Commun. 7, 13042 (2016).","journal-title":"Nat. Commun."},{"key":"545_CR25","doi-asserted-by":"publisher","first-page":"980","DOI":"10.1002\/emmm.201101084","volume":"4","author":"J Cai","year":"2012","unstructured":"Cai, J. et al. \u03b2-Secretase (BACE1) inhibition causes retinal pathology by vascular dysregulation and accumulation of age pigment. EMBO Mol. Med. 4, 980\u2013991 (2012).","journal-title":"EMBO Mol. Med."},{"key":"545_CR26","unstructured":"Eli Lilly & Company. Lilly voluntarily terminates phase II study for LY2886721, a beta secretase inhibitor being investigated as a treatment for Alzheimer\u2019s disease. Lilly https:\/\/investor.lilly.com\/static-files\/32b60234-ea3c-4461-875d-87167528f516 (2013)."},{"key":"545_CR27","doi-asserted-by":"publisher","first-page":"365","DOI":"10.1016\/j.cmet.2011.06.018","volume":"14","author":"D Esterhazy","year":"2011","unstructured":"Esterhazy, D. et al. Bace2 is a beta cell-enriched protease that regulates pancreatic beta cell function and mass. Cell Metab. 14, 365\u2013377 (2011).","journal-title":"Cell Metab."},{"key":"545_CR28","doi-asserted-by":"publisher","first-page":"10536","DOI":"10.1074\/jbc.M112.444703","volume":"288","author":"I Stutzer","year":"2013","unstructured":"Stutzer, I. et al. Systematic proteomic analysis identifies beta-site amyloid precursor protein cleaving enzyme 2 and 1 (BACE2 and BACE1) substrates in pancreatic beta-cells. J. Biol. Chem. 288, 10536\u201310547 (2013).","journal-title":"J. Biol. Chem."},{"key":"545_CR29","doi-asserted-by":"publisher","DOI":"10.26508\/lsa.201800026","volume":"1","author":"I Voytyuk","year":"2018","unstructured":"Voytyuk, I. et al. BACE2 distribution in major brain cell types and identification of novel substrates. Life Sci. Alliance 1, e201800026 (2018).","journal-title":"Life Sci. Alliance"},{"key":"545_CR30","doi-asserted-by":"publisher","first-page":"9712","DOI":"10.1073\/pnas.160115697","volume":"97","author":"M Farzan","year":"2000","unstructured":"Farzan, M., Schnitzler, C. E., Vasilieva, N., Leung, D. & Choe, H. BACE2, a beta -secretase homolog, cleaves at the beta site and within the amyloid-beta region of the amyloid-beta precursor protein. Proc. Natl Acad. Sci. USA 97, 9712\u20139717 (2000).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"545_CR31","doi-asserted-by":"publisher","first-page":"34019","DOI":"10.1074\/jbc.M105583200","volume":"276","author":"R Yan","year":"2001","unstructured":"Yan, R., Munzner, J. B., Shuck, M. E. & Bienkowski, M. J. BACE2 functions as an alternative alpha-secretase in cells. J. Biol. Chem. 276, 34019\u201334027 (2001).","journal-title":"J. Biol. Chem."},{"key":"545_CR32","doi-asserted-by":"publisher","first-page":"10658","DOI":"10.1073\/pnas.1220748110","volume":"110","author":"L Rochin","year":"2013","unstructured":"Rochin, L. et al. BACE2 processes PMEL to form the melanosome amyloid matrix in pigment cells. Proc. Natl Acad. Sci. USA 110, 10658\u201310663 (2013).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"545_CR33","first-page":"202","volume":"3","author":"G Cebers","year":"2016","unstructured":"Cebers, G. et al. Reversible and species-specific depigmentation effects of AZD3293, a BACE inhibitor for the treatment of Alzheimer\u2019s disease, are related to BACE2 inhibition and confined to epidermis and hair. J. Prev. Alzheimers Dis. 3, 202\u2013218 (2016).","journal-title":"J. Prev. Alzheimers Dis."},{"key":"545_CR34","doi-asserted-by":"publisher","DOI":"10.1038\/srep21917","volume":"6","author":"DR Shimshek","year":"2016","unstructured":"Shimshek, D. R. et al. Pharmacological BACE1 and BACE2 inhibition induces hair depigmentation by inhibiting PMEL17 processing in mice. Sci. Rep. 6, 21917 (2016).","journal-title":"Sci. Rep."},{"key":"545_CR35","doi-asserted-by":"publisher","first-page":"3157","DOI":"10.1038\/emboj.2012.173","volume":"31","author":"PH Kuhn","year":"2012","unstructured":"Kuhn, P. H. et al. Secretome protein enrichment identifies physiological BACE1 protease substrates in neurons. EMBO J. 31, 3157\u20133168 (2012).","journal-title":"EMBO J."},{"key":"545_CR36","doi-asserted-by":"publisher","first-page":"25927","DOI":"10.1074\/jbc.M112.377465","volume":"287","author":"L Zhou","year":"2012","unstructured":"Zhou, L. et al. The neural cell adhesion molecules L1 and CHL1 are cleaved by BACE1 protease in vivo. J. Biol. Chem. 287, 25927\u201325940 (2012).","journal-title":"J. Biol. Chem."},{"key":"545_CR37","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0008477","volume":"4","author":"ML Hemming","year":"2009","unstructured":"Hemming, M. L., Elias, J. E., Gygi, S. P. & Selkoe, D. J. Identification of beta-secretase (BACE1) substrates using quantitative proteomics. PLoS ONE 4, e8477 (2009).","journal-title":"PLoS ONE"},{"key":"545_CR38","doi-asserted-by":"publisher","DOI":"10.15252\/embj.2020105693","volume":"39","author":"J T\u00fcshaus","year":"2020","unstructured":"T\u00fcshaus, J. et al. An optimized quantitative proteomics method establishes the cell type-resolved mouse brain secretome. EMBO J. 39, e105693 (2020).","journal-title":"EMBO J."},{"key":"545_CR39","unstructured":"Rogers, M. B. Bump in the road or disaster? BACE inhibitors worsen cognition. AlzForum https:\/\/www.alzforum.org\/news\/conference-coverage\/bump-road-or-disaster-bace-inhibitors-worsen-cognition (2018)."},{"key":"545_CR40","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1186\/s13195-019-0520-1","volume":"11","author":"MF Egan","year":"2019","unstructured":"Egan, M. F. et al. Further analyses of the safety of verubecestat in the phase 3 EPOCH trial of mild-to-moderate Alzheimer\u2019s disease. Alzheimers Res. Ther. 11, 68 (2019).","journal-title":"Alzheimers Res. Ther."},{"key":"545_CR41","doi-asserted-by":"publisher","first-page":"216","DOI":"10.1016\/j.trci.2019.02.005","volume":"5","author":"C Lopez Lopez","year":"2019","unstructured":"Lopez Lopez, C. et al. The Alzheimer\u2019s Prevention Initiative Generation Program: study design of two randomized controlled trials for individuals at risk for clinical onset of Alzheimer\u2019s disease. Alzheimers Dement. 5, 216\u2013227 (2019).","journal-title":"Alzheimers Dement."},{"key":"545_CR42","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1001\/jamaneurol.2020.4857","volume":"78","author":"R Sperling","year":"2021","unstructured":"Sperling, R. et al. Findings of efficacy, safety, and biomarker outcomes of atabecestat in preclinical Alzheimer disease: a truncated randomized phase 2b\/3 clinical trial. JAMA Neurol. 78, 293\u2013301 (2021).","journal-title":"JAMA Neurol."},{"key":"545_CR43","doi-asserted-by":"publisher","first-page":"1483","DOI":"10.1002\/alz.12164","volume":"16","author":"AM Wessels","year":"2020","unstructured":"Wessels, A. M. et al. Cognitive outcomes in trials of two BACE inhibitors in Alzheimer\u2019s disease. Alzheimers Dement. 16, 1483\u20131492 (2020).","journal-title":"Alzheimers Dement."},{"key":"545_CR44","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1186\/s13195-018-0415-6","volume":"10","author":"M Timmers","year":"2018","unstructured":"Timmers, M. et al. Pharmacodynamics of atabecestat (JNJ-54861911), an oral BACE1 inhibitor in patients with early Alzheimer\u2019s disease: randomized, double-blind, placebo-controlled study. Alzheimers Res. Ther. 10, 85 (2018).","journal-title":"Alzheimers Res. Ther."},{"key":"545_CR45","doi-asserted-by":"publisher","first-page":"1623","DOI":"10.1016\/j.jalz.2018.06.3053","volume":"14","author":"SY Lynch","year":"2018","unstructured":"Lynch, S. Y. et al. Elenbecestat, a BACE inhibitor: results from a phase 2 study in subjects with mild cognitive impairment and mild-to-moderate dementia due to Alzheimer\u2019s disease [abstract P4-389]. Alzheimers Dement. 14, 1623 (2018).","journal-title":"Alzheimers Dement."},{"key":"545_CR46","first-page":"418","volume":"12","author":"B Willis","year":"2016","unstructured":"Willis, B. et al. Pharmacokinetics, pharmacodynamics, safety, and tolerability of LY3202626, a novel BACE1 inhibitor, in healthy subjects and patients with Alzheimer\u2019s disease [abstract P1-044]. Alzheimers Dement. 12, 418 (2016).","journal-title":"Alzheimers Dement."},{"key":"545_CR47","unstructured":"Rogers, M. B. Picking through the rubble, field tries to salvage BACE inhibitors. AlzForum https:\/\/www.alzforum.org\/news\/conference-coverage\/picking-through-rubble-field-tries-salvage-bace-inhibitors (2019)."},{"key":"545_CR48","doi-asserted-by":"publisher","DOI":"10.1002\/alz.041142","volume":"16","author":"EM Reiman","year":"2020","unstructured":"Reiman, E. M. et al. The API Generation program: umibecestat treatment and discontinuation effects on hippocampal and whole brain volumes in the overall population and amyloid-negative APOE4 homozygotes. Alzheimers Dement. 16, e041142 (2020).","journal-title":"Alzheimers Dement."},{"key":"545_CR49","doi-asserted-by":"publisher","first-page":"3816","DOI":"10.1093\/brain\/awaa332","volume":"143","author":"C Sur","year":"2020","unstructured":"Sur, C. et al. BACE inhibition causes rapid, regional, and non-progressive volume reduction in Alzheimer\u2019s disease brain. Brain 143, 3816\u20133826 (2020).","journal-title":"Brain"},{"key":"545_CR50","doi-asserted-by":"publisher","first-page":"26326","DOI":"10.1074\/jbc.M611687200","volume":"282","author":"L McConlogue","year":"2007","unstructured":"McConlogue, L. et al. Partial reduction of BACE1 has dramatic effects on Alzheimer plaque and synaptic pathology in APP transgenic mice. J. Biol. Chem. 282, 26326\u201326334 (2007).","journal-title":"J. Biol. Chem."},{"key":"545_CR51","doi-asserted-by":"publisher","DOI":"10.1038\/srep00231","volume":"2","author":"L Cao","year":"2012","unstructured":"Cao, L., Rickenbacher, G. T., Rodriguez, S., Moulia, T. W. & Albers, M. W. The precision of axon targeting of mouse olfactory sensory neurons requires the BACE1 protease. Sci. Rep. 2, 231 (2012).","journal-title":"Sci. Rep."},{"key":"545_CR52","doi-asserted-by":"publisher","first-page":"30797","DOI":"10.1074\/jbc.M505249200","volume":"280","author":"D Dominguez","year":"2005","unstructured":"Dominguez, D. et al. Phenotypic and biochemical analyses of BACE1- and BACE2-deficient mice. J. Biol. Chem. 280, 30797\u201330806 (2005).","journal-title":"J. Biol. Chem."},{"key":"545_CR53","doi-asserted-by":"publisher","first-page":"11693","DOI":"10.1523\/JNEUROSCI.2766-05.2005","volume":"25","author":"FM Laird","year":"2005","unstructured":"Laird, F. M. et al. BACE1, a major determinant of selective vulnerability of the brain to amyloid-beta amyloidogenesis, is essential for cognitive, emotional, and synaptic functions. J. Neurosci. 25, 11693\u201311709 (2005).","journal-title":"J. Neurosci."},{"key":"545_CR54","doi-asserted-by":"publisher","first-page":"927","DOI":"10.1084\/jem.20171831","volume":"215","author":"X Hu","year":"2018","unstructured":"Hu, X., Das, B., Hou, H., He, W. & Yan, R. BACE1 deletion in the adult mouse reverses preformed amyloid deposition and improves cognitive functions. J. Exp. Med. 215, 927\u2013940 (2018).","journal-title":"J. Exp. Med."},{"key":"545_CR55","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-56329-7","volume":"9","author":"S Lombardo","year":"2019","unstructured":"Lombardo, S. et al. BACE1 partial deletion induces synaptic plasticity deficit in adult mice. Sci. Rep. 9, 19877 (2019).","journal-title":"Sci. Rep."},{"key":"545_CR56","doi-asserted-by":"publisher","first-page":"1367","DOI":"10.1016\/j.celrep.2015.07.059","volume":"12","author":"S Barao","year":"2015","unstructured":"Barao, S. et al. Antagonistic effects of BACE1 and APH1B-gamma-secretase control axonal guidance by regulating growth cone collapse. Cell Rep. 12, 1367\u20131376 (2015).","journal-title":"Cell Rep."},{"key":"545_CR57","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1038\/nature11283","volume":"488","author":"T Jonsson","year":"2012","unstructured":"Jonsson, T. et al. A mutation in APP protects against Alzheimer\u2019s disease and age-related cognitive decline. Nature 488, 96\u201399 (2012).","journal-title":"Nature"},{"key":"545_CR58","doi-asserted-by":"publisher","first-page":"128","DOI":"10.1002\/ana.24969","volume":"82","author":"H Martiskainen","year":"2017","unstructured":"Martiskainen, H. et al. Decreased plasma beta-amyloid in the Alzheimer\u2019s disease APP A673T variant carriers. Ann. Neurol. 82, 128\u2013132 (2017).","journal-title":"Ann. Neurol."},{"key":"545_CR59","doi-asserted-by":"publisher","first-page":"30990","DOI":"10.1074\/jbc.M114.589069","volume":"289","author":"JA Maloney","year":"2014","unstructured":"Maloney, J. A. et al. Molecular mechanisms of Alzheimer disease protection by the A673T allele of amyloid precursor protein. J. Biol. Chem. 289, 30990\u201331000 (2014).","journal-title":"J. Biol. Chem."},{"key":"545_CR60","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1186\/1750-1326-7-39","volume":"7","author":"P Das","year":"2012","unstructured":"Das, P. et al. Transient pharmacologic lowering of Abeta production prior to deposition results in sustained reduction of amyloid plaque pathology. Mol. Neurodegener. 7, 39 (2012).","journal-title":"Mol. Neurodegener."},{"key":"545_CR61","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1016\/j.jalz.2018.02.018","volume":"14","author":"CR Jack","year":"2018","unstructured":"Jack, C. R. et al. NIA-AA research framework: toward a biological definition of Alzheimer\u2019s disease. Alzheimers Dement. 14, 535\u2013562 (2018).","journal-title":"Alzheimers Dement."},{"key":"545_CR62","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1038\/nature19323","volume":"537","author":"J Sevigny","year":"2016","unstructured":"Sevigny, J. et al. The antibody aducanumab reduces Abeta plaques in Alzheimer\u2019s disease. Nature 537, 50\u201356 (2016).","journal-title":"Nature"},{"key":"545_CR63","doi-asserted-by":"publisher","first-page":"737","DOI":"10.1016\/j.neurol.2013.07.017","volume":"169","author":"SM Mills","year":"2013","unstructured":"Mills, S. M. et al. Preclinical trials in autosomal dominant AD: implementation of the DIAN-TU trial. Rev. Neurol. 169, 737\u2013743 (2013).","journal-title":"Rev. Neurol."},{"key":"545_CR64","doi-asserted-by":"publisher","first-page":"321","DOI":"10.3233\/JAD-2011-0059","volume":"26","author":"EM Reiman","year":"2011","unstructured":"Reiman, E. M. et al. Alzheimer\u2019s Prevention Initiative: a plan to accelerate the evaluation of presymptomatic treatments. J. Alzheimers Dis. 26, 321\u2013329 (2011).","journal-title":"J. Alzheimers Dis."},{"key":"545_CR65","doi-asserted-by":"publisher","first-page":"228fs213","DOI":"10.1126\/scitranslmed.3007941","volume":"6","author":"RA Sperling","year":"2014","unstructured":"Sperling, R. A. et al. The A4 study: stopping AD before symptoms begin? Sci. Transl Med. 6, 228fs213 (2014).","journal-title":"Sci. Transl Med."},{"key":"545_CR66","doi-asserted-by":"publisher","DOI":"10.1002\/alz.041139","volume":"16","author":"PN Tariot","year":"2020","unstructured":"Tariot, P. N. et al. The generation program: baseline characteristics of cognitively unimpaired APOE4 carriers recruited for Generation study 1 and Generation study 2. Alzheimers Dement. 16, e041139 (2020).","journal-title":"Alzheimers Dement."},{"key":"545_CR67","doi-asserted-by":"publisher","DOI":"10.1002\/alz.041143","volume":"16","author":"M-L Rouzade-Dominguez","year":"2020","unstructured":"Rouzade-Dominguez, M.-L. et al. The API Generation program: biomarker phenotyping of cognitively unimpaired participants screened in Generation study 1 and Generation study 2. Alzheimers Dement. 16, e041143 (2020).","journal-title":"Alzheimers Dement."},{"key":"545_CR68","doi-asserted-by":"publisher","first-page":"4964","DOI":"10.1523\/JNEUROSCI.4560-08.2009","volume":"29","author":"RA Karlnoski","year":"2009","unstructured":"Karlnoski, R. A. et al. Suppression of amyloid deposition leads to long-term reductions in Alzheimer\u2019s pathologies in Tg2576 mice. J. Neurosci. 29, 4964\u20134971 (2009).","journal-title":"J. Neurosci."},{"key":"545_CR69","doi-asserted-by":"publisher","first-page":"1580","DOI":"10.1038\/s41593-020-00737-w","volume":"23","author":"RE Uhlmann","year":"2020","unstructured":"Uhlmann, R. E. et al. Acute targeting of pre-amyloid seeds in transgenic mice reduces Alzheimer-like pathology later in life. Nat. Neurosci. 23, 1580\u20131588 (2020).","journal-title":"Nat. Neurosci."},{"key":"545_CR70","doi-asserted-by":"publisher","first-page":"468","DOI":"10.1016\/j.jalz.2016.06.2365","volume":"13","author":"M Mortamais","year":"2017","unstructured":"Mortamais, M. et al. Detecting cognitive changes in preclinical Alzheimer\u2019s disease: a review of its feasibility. Alzheimers Dement. 13, 468\u2013492 (2017).","journal-title":"Alzheimers Dement."},{"key":"545_CR71","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1016\/j.atherosclerosissup.2004.08.007","volume":"5","author":"MS Brown","year":"2004","unstructured":"Brown, M. S. & Goldstein, J. L. A tribute to Akira Endo, discoverer of a \u201cpenicillin\u201d for cholesterol. Atheroscler. Suppl. 5, 13\u201316 (2004).","journal-title":"Atheroscler. Suppl."},{"key":"545_CR72","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1016\/j.neuron.2011.01.002","volume":"69","author":"TE Golde","year":"2011","unstructured":"Golde, T. E., Schneider, L. S. & Koo, E. H. Anti-a\u03b2 therapeutics in Alzheimer\u2019s disease: the need for a paradigm shift. Neuron 69, 203\u2013213 (2011).","journal-title":"Neuron"},{"key":"545_CR73","doi-asserted-by":"publisher","first-page":"272","DOI":"10.1016\/j.trci.2019.05.008","volume":"5","author":"J Cummings","year":"2019","unstructured":"Cummings, J., Lee, G., Ritter, A., Sabbagh, M. & Zhong, K. Alzheimer\u2019s disease drug development pipeline: 2019. Alzheimers Dement. 5, 272\u2013293 (2019).","journal-title":"Alzheimers Dement."},{"key":"545_CR74","doi-asserted-by":"publisher","first-page":"801","DOI":"10.1016\/j.neuron.2020.09.029","volume":"108","author":"JW Lewcock","year":"2020","unstructured":"Lewcock, J. W. et al. Emerging microglia biology defines novel therapeutic approaches for Alzheimer\u2019s disease. Neuron 108, 801\u2013821 (2020).","journal-title":"Neuron"},{"key":"545_CR75","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1038\/s41582-018-0116-6","volume":"15","author":"F Panza","year":"2019","unstructured":"Panza, F., Lozupone, M., Logroscino, G. & Imbimbo, B. P. A critical appraisal of amyloid-\u03b2-targeting therapies for Alzheimer disease. Nat. Rev. Neurol. 15, 73\u201388 (2019).","journal-title":"Nat. Rev. Neurol."},{"key":"545_CR76","doi-asserted-by":"publisher","first-page":"961","DOI":"10.1001\/jamaneurol.2014.803","volume":"71","author":"MC Donohue","year":"2014","unstructured":"Donohue, M. C. et al. The preclinical Alzheimer cognitive composite: measuring amyloid-related decline. JAMA Neurol. 71, 961\u2013970 (2014).","journal-title":"JAMA Neurol."},{"key":"545_CR77","unstructured":"US National Library of Medicine. ClinicalTrials.gov https:\/\/clinicaltrials.gov\/ct2\/show\/NCT02569398 (2020)."},{"key":"545_CR78","doi-asserted-by":"publisher","first-page":"993","DOI":"10.1136\/jnnp-2015-312383","volume":"87","author":"J Wang","year":"2016","unstructured":"Wang, J. et al. ADCOMS: A composite clinical outcome for prodromal Alzheimer\u2019s disease trials. J. Neurol. Neurosurg. Psychiatry 87, 993\u2013999 (2016).","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"545_CR79","unstructured":"US National Library of Medicine. ClinicalTrials.gov https:\/\/clinicaltrials.gov\/ct2\/show\/NCT02956486 (2021)."},{"key":"545_CR80","doi-asserted-by":"publisher","first-page":"S13","DOI":"10.1097\/00002093-199700112-00003","volume":"11","author":"RC Mohs","year":"1997","unstructured":"Mohs, R. C. et al. Development of cognitive instruments for use in clinical trials of antidementia drugs: additions to the Alzheimer\u2019s Disease Assessment Scale that broaden its scope. The Alzheimer\u2019s Disease Cooperative Study. Alzheimer Dis. Assoc. Disord. 11, S13\u2013S21 (1997).","journal-title":"Alzheimer Dis. Assoc. Disord."},{"key":"545_CR81","unstructured":"US National Library of Medicine. ClinicalTrials.gov https:\/\/clinicaltrials.gov\/ct2\/show\/NCT02245737 (2019)."},{"key":"545_CR82","unstructured":"US National Library of Medicine. ClinicalTrials.gov https:\/\/clinicaltrials.gov\/ct2\/show\/NCT02783573 (2019)."},{"key":"545_CR83","doi-asserted-by":"publisher","first-page":"P432","DOI":"10.1016\/j.jalz.2016.06.828","volume":"12","author":"D McKinzie","year":"2016","unstructured":"McKinzie, D. et al. Nonclinical pharmacological characterization of the BACE1 inhibitor LY3202626. Alzheimers Dement. 12, P432\u2013P433 (2016).","journal-title":"Alzheimers Dement."},{"key":"545_CR84","unstructured":"US National Library of Medicine. ClinicalTrials.gov https:\/\/clinicaltrials.gov\/ct2\/show\/NCT02791191 (2021)."},{"key":"545_CR85","unstructured":"US National Library of Medicine. ClinicalTrials.gov https:\/\/clinicaltrials.gov\/ct2\/show\/NCT03367403 (2021)."},{"key":"545_CR86","doi-asserted-by":"publisher","first-page":"761","DOI":"10.1016\/j.bmcl.2018.12.049","volume":"29","author":"CC Hsiao","year":"2019","unstructured":"Hsiao, C. C., Rombouts, F. & Gijsen, H. J. M. New evolutions in the BACE1 inhibitor field from 2014 to 2018. Bioorg. Med. Chem. Lett. 29, 761\u2013777 (2019).","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"545_CR87","unstructured":"US National Library of Medicine. ClinicalTrials.gov https:\/\/clinicaltrials.gov\/ct2\/show\/NCT02565511 (2021)."},{"key":"545_CR88","unstructured":"US National Library of Medicine. ClinicalTrials.gov https:\/\/clinicaltrials.gov\/ct2\/show\/NCT01739348 (2018)."},{"key":"545_CR89","unstructured":"US National Library of Medicine. ClinicalTrials.gov https:\/\/clinicaltrials.gov\/ct2\/show\/NCT01953601 (2019)."},{"key":"545_CR90","doi-asserted-by":"publisher","first-page":"1565","DOI":"10.1016\/j.jalz.2018.06.1353","volume":"14","author":"M Navitsky","year":"2018","unstructured":"Navitsky, M. et al. Standardization of amyloid quantitation with florbetapir standardized uptake value rations to the Centiloid scale. Alzheimers Dement. 14, 1565\u20131571 (2018).","journal-title":"Alzheimers Dement."},{"key":"545_CR91","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1016\/j.semcdb.2020.03.005","volume":"105","author":"L Ch\u00e1vez-Guti\u00e9rrez","year":"2020","unstructured":"Ch\u00e1vez-Guti\u00e9rrez, L. & Szaruga, M. Mechanisms of neurodegeneration - insights from familial Alzheimer\u2019s disease. Semin. Cell Dev. Biol. 105, 75\u201385 (2020).","journal-title":"Semin. Cell Dev. Biol."},{"key":"545_CR92","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/j.semcdb.2020.05.019","volume":"105","author":"G G\u00fcner","year":"2020","unstructured":"G\u00fcner, G. & Lichtenthaler, S. F. The substrate repertoire of \u03b3-secretase\/presenilin. Semin. Cell Dev. Biol. 105, 27\u201342 (2020).","journal-title":"Semin. Cell Dev. Biol."},{"key":"545_CR93","doi-asserted-by":"publisher","DOI":"10.15252\/embj.201899456","volume":"37","author":"SF Lichtenthaler","year":"2018","unstructured":"Lichtenthaler, S. F., Lemberg, M. K. & Fluhrer, R. Proteolytic ectodomain shedding of membrane proteins in mammals-hardware, concepts, and recent developments. EMBO J. 37, e99456 (2018).","journal-title":"EMBO J."},{"key":"545_CR94","doi-asserted-by":"publisher","first-page":"4833","DOI":"10.1523\/JNEUROSCI.5221-09.2010","volume":"30","author":"E Jorissen","year":"2010","unstructured":"Jorissen, E. et al. The disintegrin\/metalloproteinase ADAM10 is essential for the establishment of the brain cortex. J. Neurosci. 30, 4833\u20134844 (2010).","journal-title":"J. Neurosci."},{"key":"545_CR95","doi-asserted-by":"publisher","first-page":"3020","DOI":"10.1038\/emboj.2010.167","volume":"29","author":"PH Kuhn","year":"2010","unstructured":"Kuhn, P. H. et al. ADAM10 is the physiologically relevant, constitutive alpha-secretase of the amyloid precursor protein in primary neurons. EMBO J. 29, 3020\u20133032 (2010).","journal-title":"EMBO J."},{"key":"545_CR96","doi-asserted-by":"publisher","first-page":"3922","DOI":"10.1073\/pnas.96.7.3922","volume":"96","author":"S Lammich","year":"1999","unstructured":"Lammich, S. et al. Constitutive and regulated alpha-secretase cleavage of Alzheimer\u2019s amyloid precursor protein by a disintegrin metalloprotease. Proc. Natl Acad. Sci. USA 96, 3922\u20133927 (1999).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"545_CR97","doi-asserted-by":"publisher","first-page":"443","DOI":"10.1038\/nature14864","volume":"526","author":"M Willem","year":"2015","unstructured":"Willem, M. et al. \u03b7-Secretase processing of APP inhibits neuronal activity in the hippocampus. Nature 526, 443\u2013447 (2015).","journal-title":"Nature"},{"key":"545_CR98","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms9762","volume":"6","author":"Z Zhang","year":"2015","unstructured":"Zhang, Z. et al. Delta-secretase cleaves amyloid precursor protein and regulates the pathogenesis in Alzheimer\u2019s disease. Nat. Commun. 6, 8762 (2015).","journal-title":"Nat. Commun."},{"key":"545_CR99","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.pneurobio.2015.10.003","volume":"135","author":"P Saftig","year":"2015","unstructured":"Saftig, P. & Lichtenthaler, S. P. The alpha secretase ADAM10: a metalloprotease with multiple functions in the brain. Prog. Neurobiol. 135, 1\u201320 (2015).","journal-title":"Prog. Neurobiol."},{"key":"545_CR100","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aao5620","volume":"10","author":"MH Ou-Yang","year":"2018","unstructured":"Ou-Yang, M. H. et al. Axonal organization defects in the hippocampus of adult conditional BACE1 knockout mice. Sci. Transl Med. 10, e5620 (2018).","journal-title":"Sci. Transl Med."},{"key":"545_CR101","doi-asserted-by":"publisher","first-page":"2015","DOI":"10.1038\/emboj.2013.146","volume":"32","author":"C Cheret","year":"2013","unstructured":"Cheret, C. et al. Bace1 and neuregulin-1 cooperate to control formation and maintenance of muscle spindles. EMBO J. 32, 2015\u20132028 (2013).","journal-title":"EMBO J."},{"key":"545_CR102","doi-asserted-by":"publisher","first-page":"7856","DOI":"10.1523\/JNEUROSCI.3372-12.2013","volume":"33","author":"D Fleck","year":"2013","unstructured":"Fleck, D. et al. Dual cleavage of neuregulin 1 type III by BACE1 and ADAM17 liberates its EGF-like domain and allows paracrine signaling. J. Neurosci. 33, 7856\u20137869 (2013).","journal-title":"J. Neurosci."},{"key":"545_CR103","doi-asserted-by":"publisher","first-page":"664","DOI":"10.1126\/science.1132341","volume":"314","author":"M Willem","year":"2006","unstructured":"Willem, M. et al. Control of peripheral nerve myelination by the beta-secretase BACE1. Science 314, 664\u2013666 (2006).","journal-title":"Science"},{"key":"545_CR104","doi-asserted-by":"publisher","first-page":"1520","DOI":"10.1038\/nn1797","volume":"9","author":"X Hu","year":"2006","unstructured":"Hu, X. et al. Bace1 modulates myelination in the central and peripheral nervous system. Nat. Neurosci. 9, 1520\u20131525 (2006).","journal-title":"Nat. Neurosci."},{"key":"545_CR105","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1016\/j.celrep.2013.06.005","volume":"4","author":"X Hu","year":"2013","unstructured":"Hu, X., He, W., Luo, X., Tsubota, K. E. & Yan, R. BACE1 regulates hippocampal astrogenesis via the Jagged1-Notch pathway. Cell Rep. 4, 40\u201349 (2013).","journal-title":"Cell Rep."},{"key":"545_CR106","doi-asserted-by":"publisher","first-page":"428","DOI":"10.1016\/j.biopsych.2016.12.023","volume":"83","author":"K Zhu","year":"2018","unstructured":"Zhu, K. et al. Beta-site amyloid precursor protein cleaving enzyme 1 inhibition impairs synaptic plasticity via seizure protein 6. Biol. Psychiatry 83, 428\u2013437 (2018).","journal-title":"Biol. Psychiatry"},{"key":"545_CR107","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1186\/s13024-016-0134-z","volume":"11","author":"M Pigoni","year":"2016","unstructured":"Pigoni, M. et al. Seizure protein 6 and its homolog seizure 6-like protein are physiological substrates of BACE1 in neurons. Mol. Neurodegener. 11, 67 (2016).","journal-title":"Mol. Neurodegener."},{"key":"545_CR108","doi-asserted-by":"publisher","first-page":"38408","DOI":"10.1074\/jbc.M112.415505","volume":"287","author":"B Hitt","year":"2012","unstructured":"Hitt, B. et al. beta-Site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1)-deficient mice exhibit a close homolog of L1 (CHL1) loss-of-function phenotype involving axon guidance defects. J. Biol. Chem. 287, 38408\u201338425 (2012).","journal-title":"J. Biol. Chem."},{"key":"545_CR109","doi-asserted-by":"publisher","DOI":"10.15252\/embj.201798858","volume":"37","author":"T Muller","year":"2018","unstructured":"Muller, T. et al. Neuregulin 3 promotes excitatory synapse formation on hippocampal interneurons. EMBO J. 37, e98858 (2018).","journal-title":"EMBO J."},{"key":"545_CR110","doi-asserted-by":"publisher","first-page":"2508","DOI":"10.1073\/pnas.1716322115","volume":"115","author":"YN Wang","year":"2018","unstructured":"Wang, Y. N. et al. Controlling of glutamate release by neuregulin3 via inhibiting the assembly of the SNARE complex. Proc. Natl Acad. Sci. USA 115, 2508\u20132513 (2018).","journal-title":"Proc. Natl Acad. Sci. USA"}],"container-title":["Nature Reviews Neurology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41582-021-00545-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41582-021-00545-1","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41582-021-00545-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,10,27]],"date-time":"2021-10-27T09:07:42Z","timestamp":1635325662000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41582-021-00545-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,21]]},"references-count":110,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2021,11]]}},"alternative-id":["545"],"URL":"https:\/\/doi.org\/10.1038\/s41582-021-00545-1","relation":{},"ISSN":["1759-4758","1759-4766"],"issn-type":[{"value":"1759-4758","type":"print"},{"value":"1759-4766","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,21]]},"assertion":[{"value":"23 July 2021","order":1,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 September 2021","order":2,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"There were no sources of funding that directly supported this work. E.M. reports serving on a data safety committee for Eli Lilly and Company, personal honoraria for continuing medical education activities for Eisai and Eli Lilly and Company and UpToDate, and institutional grant support from Eli Lilly and Company, Hoffman-La Roche and Janssen. P.A. has research grants from Eisai, Eli Lilly and Company and Janssen pharmaceuticals, and has received consulting fees from Biogen, Hoffman-La Roche, ImmunoBrain Checkpoint, Merck & Co. and Samus. R.J.B. serves as the principal investigator of the Dominantly Inherited Alzheimer Network Trial Unit (DIAN-TU), which is supported by the Alzheimer\u2019s Association, the GHR Foundation, an anonymous organization and the DIAN-TU Pharma Consortium (active: Biogen, Eisai, Eli Lilly and Company\/Avid Radiopharmaceuticals, Hoffman-La Roche\/Genentech, Janssen and United Neuroscience; previously: Abbvie, Amgen, AstraZeneca, Forum, Mithridion, Novartis, Pfizer and Sanofi). The DIAN-TU-001 clinical trial is supported by pharmaceutical partners Eli Lilly and Company, Hoffman-La Roche and Janssen, the Alzheimer\u2019s Association, Avid Radiopharmaceuticals, the GHR Foundation, US National Institutes of Health (NIH) project U01AG042791, NIH project U01AG42791-S1 (Foundation for the National Institutes of Health Accelerating Medicines Partnership), NIH project R01AG046179, NIH project R56AG053267, NIH project R01AG053267, NIH project R01AG053267-S1, NIH project R01AG053267-S2, NIH project U01AG059798 and an anonymous organization. In-kind support has been received from Bracket and CogState for DIAN-TU-001. R.J.B. has received honoraria as a speaker and\/or consultant and\/or advisory board member from Amgen, AC Immune, Eisai, Hoffman-LaRoche, Janssen and Pfizer and reimbursement of travel expenses from AC Immune, Hoffman-La Roche and Janssen. R.J.B. receives laboratory research funding from the Alzheimer\u2019s Association, the Association for Frontotemporal Degeneration, the BrightFocus Foundation, the Cure Alzheimer\u2019s Fund, Centene Corporation, the NIH, the Rainwater Foundation Tau Consortium, the Tau SILK Consortium (AbbVie, Biogen and Eli Lilly and Company) and an anonymous foundation. R.J.B. is a cofounder of and serves on the scientific advisory board for C2N Diagnostics LLC. Washington University also holds equity in C2N Diagnostics. C2N Diagnostics has licensed certain anti-tau antibodies to AbbVie for therapeutic development. Washington University, R.J.B. and D. Holtzman have equity ownership interest in C2N Diagnostics and receive royalty income based on technology (stable isotope labelling kinetics and blood plasma assay) licensed by Washington University to C2N Diagnostics. R.J.B. receives income from C2N Diagnostics for serving on the scientific advisory board. Washington University, with R.J.B. as a co-inventor, has submitted the US non-provisional patent application \u201cMethods for measuring the metabolism of CNS derived biomolecules in vivo\u201d and the provisional patent application \u201cPlasma based methods for detecting CNS amyloid deposition\u201d. B.D.S. has received research support from Esai and Janssen pharmaceuticals. C.H. reports collaborations with Denali Therapeutics Inc., has participated in one advisory board meeting of Biogen and has received a speaker honorarium from Novartis and Roche. C.H. is the chief adviser to ISAR Bioscience. E.M.R. is one of the leaders of the Alzheimer\u2019s Prevention Initiative, which worked closely with Amgen and Novartis in Alzheimer\u2019s Prevention Initiative Generation Study 1 and Generation Study 2. These trials were funded by Amgen, the US National Institute on Aging, Novartis and philanthropy. E.M.R. is an unpaid scientific adviser to Avid Radiopharmaceuticals, a subsidiary of Eli Lilly and Company. R.S. has research grants from Eli Lilly and Company, Eisai and Janssen pharmaceuticals. P.N.T. has received consulting fees from Acadia, AC Immune, Axsome, BioXcel, Boehringer-Ingelheim, Brain Test Inc., Eisai, eNOVA, the Gerontological Society of America, Otuska & Astex and Syneos, consulting fees and research support from Abbvie, Avanir, Biogen, Cortexyme, Genentech, Eli Lilly and Company, Merck & Co. and Roche and research support from Novartis and has stock ownership in Adamas Pharmaceuticals, which has no past, current or known future involvement in any \u03b2-site amyloid precursor protein (APP)-cleaving enzyme (BACE) inhibitor-related therapies or clinical trials. R.V. has stock options in Alector given for his service on the scientific advisory board. R.V.\u2019s advisory relationship with Alector does not involve BACE1 inhibition as a therapeutic strategy. R.V. has consulted for Eisai and Novartis in the past, but is not doing so currently. S.F.L. reports research funding from Novartis and Shionogi. The other authors report no relevant disclosures.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}