{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T04:47:28Z","timestamp":1793249248891,"version":"4.5.0"},"reference-count":101,"publisher":"Springer Science and Business Media LLC","issue":"4","license":[{"start":{"date-parts":[[2024,4,19]],"date-time":"2024-04-19T00:00:00Z","timestamp":1713484800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"},{"start":{"date-parts":[[2024,4,19]],"date-time":"2024-04-19T00:00:00Z","timestamp":1713484800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Aging"],"DOI":"10.1038\/s43587-024-00611-5","type":"journal-article","created":{"date-parts":[[2024,4,21]],"date-time":"2024-04-21T22:09:16Z","timestamp":1713737356000},"page":"453-463","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":48,"title":["The advent of Alzheimer treatments will change the trajectory of human aging"],"prefix":"10.1038","volume":"4","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8846-9767","authenticated-orcid":false,"given":"Dennis J.","family":"Selkoe","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,4,19]]},"reference":[{"key":"611_CR1","doi-asserted-by":"publisher","first-page":"733","DOI":"10.1038\/325733a0","volume":"325","author":"J Kang","year":"1987","unstructured":"Kang, J. et al. The precursor of Alzheimer\u2019s disease amyloid A4 protein resembles a cell-surface receptor. Nature 325, 733\u2013736 (1987).","journal-title":"Nature"},{"key":"611_CR2","doi-asserted-by":"publisher","first-page":"10758","DOI":"10.1073\/pnas.89.22.10758","volume":"89","author":"W Wasco","year":"1992","unstructured":"Wasco, W. et al. Identification of a mouse brain cDNA that encodes a protein related to the Alzheimer disease-associated amyloid \u03b2 protein precursor. Proc. Natl Acad. Sci. USA 89, 10758\u201310762 (1992).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"611_CR3","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1038\/ng0993-95","volume":"5","author":"W Wasco","year":"1993","unstructured":"Wasco, W. et al. Isolation and characterization of APLP2 encoding a homologue of the Alzheimer\u2019s associated amyloid \u03b2 protein precursor. Nat. Genet. 5, 95\u2013100 (1993).","journal-title":"Nat. Genet."},{"key":"611_CR4","doi-asserted-by":"publisher","first-page":"754","DOI":"10.1038\/375754a0","volume":"375","author":"R Sherrington","year":"1995","unstructured":"Sherrington, R. et al. Cloning of a novel gene bearing missense mutations in early onset familial Alzheimer disease. Nature 375, 754\u2013760 (1995).","journal-title":"Nature"},{"key":"611_CR5","doi-asserted-by":"publisher","first-page":"775","DOI":"10.1038\/376775a0","volume":"376","author":"EI Rogaev","year":"1995","unstructured":"Rogaev, E. I. et al. Familial Alzheimer\u2019s disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer\u2019s disease type 3 gene. Nature 376, 775\u2013778 (1995).","journal-title":"Nature"},{"key":"611_CR6","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":"611_CR7","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":"611_CR8","doi-asserted-by":"publisher","first-page":"3522","DOI":"10.1021\/ja000300g","volume":"122","author":"AK Ghosh","year":"2000","unstructured":"Ghosh, A. K. et al. Design of potent inhibitors for human brain memapsin 2 (beta-secretase). J. Am. Chem. Soc. 122, 3522\u20133523 (2000).","journal-title":"J. Am. Chem. Soc."},{"key":"611_CR9","doi-asserted-by":"publisher","first-page":"513","DOI":"10.1038\/19077","volume":"398","author":"MS Wolfe","year":"1999","unstructured":"Wolfe, M. S. et al. Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and \u03b3-secretase activity. Nature 398, 513\u2013517 (1999).","journal-title":"Nature"},{"key":"611_CR10","doi-asserted-by":"publisher","first-page":"522","DOI":"10.1038\/19091","volume":"398","author":"G Struhl","year":"1999","unstructured":"Struhl, G. & Greenwald, I. Presenilin is required for activity and nuclear access of Notch in Drosophila. Nature 398, 522\u2013525 (1999).","journal-title":"Nature"},{"key":"611_CR11","doi-asserted-by":"publisher","first-page":"518","DOI":"10.1038\/19083","volume":"398","author":"B De Strooper","year":"1999","unstructured":"De Strooper, B. et al. A presenilin-1-dependent \u03b3-secretase-like protease mediates release of Notch intracellular domain. Nature 398, 518\u2013522 (1999).","journal-title":"Nature"},{"key":"611_CR12","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1001\/archneur.1976.00500040001001","volume":"33","author":"R Katzman","year":"1976","unstructured":"Katzman, R. Editorial: the prevalence and malignancy of Alzheimer disease. A major killer. Arch. Neurol. 33, 217\u2013218 (1976).","journal-title":"Arch. Neurol."},{"key":"611_CR13","doi-asserted-by":"publisher","first-page":"1304","DOI":"10.1016\/j.neuron.2022.03.004","volume":"110","author":"YA Martens","year":"2022","unstructured":"Martens, Y. A. et al. ApoE cascade hypothesis in the pathogenesis of Alzheimer\u2019s disease and related dementias. Neuron 110, 1304\u20131317 (2022).","journal-title":"Neuron"},{"key":"611_CR14","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1038\/s41572-021-00269-y","volume":"7","author":"DS Knopman","year":"2021","unstructured":"Knopman, D. S. et al. Alzheimer disease. Nat. Rev. Dis. Prim. 7, 33 (2021).","journal-title":"Nat. Rev. Dis. Prim."},{"key":"611_CR15","doi-asserted-by":"publisher","first-page":"2236","DOI":"10.1016\/j.immuni.2022.10.016","volume":"55","author":"X Chen","year":"2022","unstructured":"Chen, X. & Holtzman, D. M. Emerging roles of innate and adaptive immunity in Alzheimer\u2019s disease. Immunity 55, 2236\u20132254 (2022).","journal-title":"Immunity"},{"key":"611_CR16","first-page":"177","volume":"30","author":"A Alzheimer","year":"1907","unstructured":"Alzheimer, A. Ueber eine eigenartige Erkrankung der Hirnrinde. Centralblatt Nervenheilkd. Psychiatr. 30, 177\u2013179 (1907).","journal-title":"Centralblatt Nervenheilkd. Psychiatr."},{"key":"611_CR17","doi-asserted-by":"publisher","first-page":"1403","DOI":"10.1016\/S0140-6736(76)91936-X","volume":"2","author":"P Davies","year":"1976","unstructured":"Davies, P. & Maloney, A. J. Selective loss of central cholinergic neurons in Alzheimer\u2019s disease. Lancet 2, 1403 (1976).","journal-title":"Lancet"},{"key":"611_CR18","doi-asserted-by":"publisher","first-page":"668","DOI":"10.1016\/S0140-6736(77)92114-6","volume":"1","author":"P White","year":"1977","unstructured":"White, P. et al. Neocortical cholinergic neurons in elderly people. Lancet 1, 668\u2013671 (1977).","journal-title":"Lancet"},{"key":"611_CR19","doi-asserted-by":"publisher","first-page":"885","DOI":"10.1016\/S0006-291X(84)80190-4","volume":"120","author":"GG Glenner","year":"1984","unstructured":"Glenner, G. G. & Wong, C. W. Alzheimer\u2019s disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem. Biophys. Res. Commun. 120, 885\u2013890 (1984).","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"611_CR20","doi-asserted-by":"publisher","first-page":"1131","DOI":"10.1016\/0006-291X(84)91209-9","volume":"122","author":"GG Glenner","year":"1984","unstructured":"Glenner, G. G. & Wong, C. W. Alzheimer\u2019s disease and Down\u2019s syndrome: sharing of a unique cerebrovascular amyloid fibril protein. Biochem. Biophys. Res. Commun. 122, 1131\u20131135 (1984).","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"611_CR21","doi-asserted-by":"publisher","first-page":"4245","DOI":"10.1073\/pnas.82.12.4245","volume":"82","author":"CL Masters","year":"1985","unstructured":"Masters, C. L. et al. Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc. Natl Acad. Sci. USA 82, 4245\u20134249 (1985).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"611_CR22","doi-asserted-by":"publisher","first-page":"1124","DOI":"10.1126\/science.2111584","volume":"248","author":"E Levy","year":"1990","unstructured":"Levy, E. et al. Mutation of the Alzheimer\u2019s disease amyloid gene in hereditary cerebral hemorrhage, Dutch-type. Science 248, 1124\u20131126 (1990).","journal-title":"Science"},{"key":"611_CR23","doi-asserted-by":"publisher","first-page":"704","DOI":"10.1038\/349704a0","volume":"349","author":"A Goate","year":"1991","unstructured":"Goate, A. et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer\u2019s disease. Nature 349, 704\u2013706 (1991).","journal-title":"Nature"},{"key":"611_CR24","doi-asserted-by":"publisher","first-page":"322","DOI":"10.1038\/359322a0","volume":"359","author":"C Haass","year":"1992","unstructured":"Haass, C. et al. Amyloid \u03b2-peptide is produced by cultured cells during normal metabolism. Nature 359, 322\u2013325 (1992).","journal-title":"Nature"},{"key":"611_CR25","doi-asserted-by":"publisher","first-page":"523","DOI":"10.1038\/373523a0","volume":"373","author":"D Games","year":"1995","unstructured":"Games, D. et al. Alzheimer-type neuropathology in transgenic mice overexpressing V717F \u03b2-amyloid precursor protein. Nature 373, 523\u2013527 (1995).","journal-title":"Nature"},{"key":"611_CR26","first-page":"229","volume":"95","author":"J Brion","year":"1985","unstructured":"Brion, J., Passareiro, E., Nunez, J. & Flament-Durand, J. Mise en evidence immunologique de la protein tau au niveau des lesions de degenerescence neurofibrillaire de la maladie d\u2019Alzheimer. Arch. Biol. 95, 229\u2013235 (1985).","journal-title":"Arch. Biol."},{"key":"611_CR27","doi-asserted-by":"publisher","first-page":"1541","DOI":"10.1093\/oxfordjournals.jbchem.a135625","volume":"99","author":"N Nukina","year":"1986","unstructured":"Nukina, N. & Ihara, Y. One of the antigenic determinants of paired helical filaments is related to tau protein. J. Biochem. 99, 1541\u20131544 (1986).","journal-title":"J. Biochem."},{"key":"611_CR28","doi-asserted-by":"publisher","first-page":"4044","DOI":"10.1073\/pnas.83.11.4044","volume":"83","author":"KS Kosik","year":"1986","unstructured":"Kosik, K. S., Joachim, C. L. & Selkoe, D. J. Microtubule-associated protein, tau, is a major antigenic component of paired helical filaments in Alzheimer\u2019s disease. Proc. Natl Acad. Sci. USA 83, 4044\u20134048 (1986).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"611_CR29","doi-asserted-by":"publisher","first-page":"4913","DOI":"10.1073\/pnas.83.13.4913","volume":"83","author":"I Grundke-Iqbal","year":"1986","unstructured":"Grundke-Iqbal, I. et al. Abnormal phosphorylation of the microtubule-associated protein t (tau) in Alzheimer cytoskeletal pathology. Proc. Natl Acad. Sci. USA 83, 4913\u20134917 (1986).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"611_CR30","doi-asserted-by":"publisher","first-page":"702","DOI":"10.1038\/31508","volume":"393","author":"M Hutton","year":"1998","unstructured":"Hutton, M. et al. Association of missense and 5\u2032-splice-site mutations in tau with the inherited FTDP-17. Nature 393, 702\u2013705 (1998).","journal-title":"Nature"},{"key":"611_CR31","doi-asserted-by":"publisher","first-page":"1977","DOI":"10.1073\/pnas.90.5.1977","volume":"90","author":"WJ Strittmatter","year":"1993","unstructured":"Strittmatter, W. J. et al. Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc. Natl Acad. Sci. USA 90, 1977\u20131981 (1993).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"611_CR32","doi-asserted-by":"publisher","first-page":"1488","DOI":"10.1126\/science.1228541","volume":"337","author":"DJ Selkoe","year":"2012","unstructured":"Selkoe, D. J. Preventing Alzheimer\u2019s disease. Science 337, 1488\u20131492 (2012).","journal-title":"Science"},{"key":"611_CR33","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":"611_CR34","doi-asserted-by":"publisher","first-page":"380","DOI":"10.1002\/ana.410430316","volume":"43","author":"VP Prasher","year":"1998","unstructured":"Prasher, V. P. et al. Molecular mapping of Alzheimer-type dementia in Down\u2019s syndrome. Ann. Neurol. 43, 380\u2013383 (1998).","journal-title":"Ann. Neurol."},{"key":"611_CR35","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1006\/nbdi.1996.0003","volume":"3","author":"CA Lemere","year":"1996","unstructured":"Lemere, C. A. et al. Sequence of deposition of heterogeneous amyloid \u03b2-peptides and Apo E in Down syndrome: implications for initial events in amyloid plaque formation. Neurobiol. Dis. 3, 16\u201332 (1996).","journal-title":"Neurobiol. Dis."},{"key":"611_CR36","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1006\/neur.1996.0017","volume":"5","author":"DM Mann","year":"1996","unstructured":"Mann, D. M. & Iwatsubo, T. Diffuse plaques in the cerebellum and corpus striatum in Down\u2019s syndrome contain amyloid beta protein (A\u03b2) only in the form of A\u03b242(43). Neurodegeneration 5, 115\u2013120 (1996).","journal-title":"Neurodegeneration"},{"key":"611_CR37","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1038\/ng1718","volume":"38","author":"A Rovelet-Lecrux","year":"2006","unstructured":"Rovelet-Lecrux, A. et al. APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy. Nat. Genet. 38, 24\u201326 (2006).","journal-title":"Nat. Genet."},{"key":"611_CR38","doi-asserted-by":"publisher","first-page":"921","DOI":"10.1126\/science.8346443","volume":"261","author":"EH Corder","year":"1993","unstructured":"Corder, E. H. et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer\u2019s disease in late onset families. Science 261, 921\u2013923 (1993).","journal-title":"Science"},{"key":"611_CR39","doi-asserted-by":"publisher","first-page":"89ra57","DOI":"10.1126\/scitranslmed.3002156","volume":"3","author":"JM Castellano","year":"2011","unstructured":"Castellano, J. M. et al. Human apoE isoforms differentially regulate brain amyloid-\u03b2 peptide clearance. Sci. Transl. Med. 3, 89ra57 (2011).","journal-title":"Sci. Transl. Med."},{"key":"611_CR40","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-18534-1","volume":"11","author":"Q Zhang","year":"2020","unstructured":"Zhang, Q. et al. Risk prediction of late-onset Alzheimer\u2019s disease implies an oligogenic architecture. Nat. Commun. 11, 4799 (2020).","journal-title":"Nat. Commun."},{"key":"611_CR41","doi-asserted-by":"publisher","first-page":"1276","DOI":"10.1038\/s41588-021-00921-z","volume":"53","author":"DP Wightman","year":"2021","unstructured":"Wightman, D. P. et al. A genome-wide association study with 1,126,563 individuals identifies new risk loci for Alzheimer\u2019s disease. Nat. Genet. 53, 1276\u20131282 (2021).","journal-title":"Nat. Genet."},{"key":"611_CR42","doi-asserted-by":"publisher","first-page":"1323","DOI":"10.1016\/j.ajpath.2020.02.009","volume":"190","author":"N Kakuda","year":"2020","unstructured":"Kakuda, N. et al. \u03b3-Secretase activity is associated with braak senile plaque stages. Am. J. Pathol. 190, 1323\u20131331 (2020).","journal-title":"Am. J. Pathol."},{"key":"611_CR43","doi-asserted-by":"publisher","first-page":"344","DOI":"10.1002\/emmm.201200214","volume":"4","author":"N Kakuda","year":"2012","unstructured":"Kakuda, N. et al. Altered gamma-secretase activity in mild cognitive impairment and Alzheimer\u2019s disease. EMBO Mol. Med. 4, 344\u2013352 (2012).","journal-title":"EMBO Mol. Med."},{"key":"611_CR44","doi-asserted-by":"publisher","unstructured":"Huang, Z. et al. Proteomics of resilience to Alzheimer\u2019s disease identifies brain regional soluble A\u03b2 levels, actin filament processes, and response to injury. Preprint at bioRxiv https:\/\/doi.org\/10.1101\/2022.10.09.511430 (2022).","DOI":"10.1101\/2022.10.09.511430"},{"key":"611_CR45","doi-asserted-by":"publisher","first-page":"1283","DOI":"10.1056\/NEJM198006053022305","volume":"302","author":"GG Glenner","year":"1980","unstructured":"Glenner, G. G. Amyloid deposits and amyloidosis: the beta-fibrilloses (first of two parts). N. Engl. J. Med. 302, 1283\u20131292 (1980).","journal-title":"N. Engl. J. Med."},{"key":"611_CR46","doi-asserted-by":"publisher","first-page":"487","DOI":"10.1016\/0896-6273(91)90052-2","volume":"6","author":"DJ Selkoe","year":"1991","unstructured":"Selkoe, D. J. The molecular pathology of Alzheimer\u2019s disease. Neuron 6, 487\u2013498 (1991).","journal-title":"Neuron"},{"key":"611_CR47","doi-asserted-by":"publisher","first-page":"184","DOI":"10.1126\/science.1566067","volume":"256","author":"JA Hardy","year":"1992","unstructured":"Hardy, J. A. & Higgins, G. A. Alzheimer\u2019s disease: the amyloid cascade hypothesis. Science 256, 184\u2013185 (1992).","journal-title":"Science"},{"key":"611_CR48","doi-asserted-by":"publisher","first-page":"306","DOI":"10.1038\/s41573-022-00391-w","volume":"21","author":"E Karran","year":"2022","unstructured":"Karran, E. & De Strooper, B. The amyloid hypothesis in Alzheimer disease: new insights from new therapeutics. Nat. Rev. Drug Discov. 21, 306\u2013318 (2022).","journal-title":"Nat. Rev. Drug Discov."},{"key":"611_CR49","doi-asserted-by":"publisher","first-page":"e3001694","DOI":"10.1371\/journal.pbio.3001694","volume":"20","author":"C Haass","year":"2022","unstructured":"Haass, C. & Selkoe, D. If amyloid drives Alzheimer disease, why have anti-amyloid therapies not yet slowed cognitive decline? PLoS Biol. 20, e3001694 (2022).","journal-title":"PLoS Biol."},{"key":"611_CR50","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1038\/22124","volume":"400","author":"D Schenk","year":"1999","unstructured":"Schenk, D. et al. Immunization with amyloid-\u03b2 attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 400, 173\u2013177 (1999).","journal-title":"Nature"},{"key":"611_CR51","doi-asserted-by":"publisher","first-page":"916","DOI":"10.1038\/78682","volume":"6","author":"F Bard","year":"2000","unstructured":"Bard, F. et al. Peripherally administered antibodies against amyloid \u03b2-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat. Med. 6, 916\u2013919 (2000).","journal-title":"Nat. Med."},{"key":"611_CR52","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1172\/JCI200318104","volume":"112","author":"A Monsonego","year":"2003","unstructured":"Monsonego, A. et al. Increased T cell reactivity to amyloid \u03b2 protein in older humans and patients with Alzheimer disease. J. Clin. Invest. 112, 415\u2013422 (2003).","journal-title":"J. Clin. Invest."},{"key":"611_CR53","doi-asserted-by":"publisher","first-page":"1312","DOI":"10.1093\/brain\/awq056","volume":"133","author":"A Serrano-Pozo","year":"2010","unstructured":"Serrano-Pozo, A. et al. Beneficial effect of human anti-amyloid-\u03b2 active immunization on neurite morphology and tau pathology. Brain 133, 1312\u20131327 (2010).","journal-title":"Brain"},{"key":"611_CR54","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 A\u03b2 plaques in Alzheimer\u2019s disease. Nature 537, 50\u201356 (2016).","journal-title":"Nature"},{"key":"611_CR55","doi-asserted-by":"publisher","first-page":"425","DOI":"10.1016\/j.nbd.2009.08.007","volume":"36","author":"A Lord","year":"2009","unstructured":"Lord, A. et al. An amyloid-\u03b2 protofibril-selective antibody prevents amyloid formation in a mouse model of Alzheimer\u2019s disease. Neurobiol. Dis. 36, 425\u2013434 (2009).","journal-title":"Neurobiol. Dis."},{"key":"611_CR56","doi-asserted-by":"publisher","first-page":"2061","DOI":"10.1212\/WNL.0b013e3181c67808","volume":"73","author":"S Salloway","year":"2009","unstructured":"Salloway, S. et al. A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease. Neurology 73, 2061\u20132070 (2009).","journal-title":"Neurology"},{"key":"611_CR57","doi-asserted-by":"crossref","unstructured":"Sperling, R. A. et al. Trial of solanezumab in preclinical Alzheimer\u2019s disease. N. Engl. J. Med. 389, 1096\u20131107 (2023).","DOI":"10.1056\/NEJMoa2305032"},{"key":"611_CR58","first-page":"197","volume":"9","author":"S Budd Haeberlein","year":"2022","unstructured":"Budd Haeberlein, S. et al. Two randomized phase 3 studies of aducanumab in early Alzheimer\u2019s disease. J. Prev. Alzheimers Dis. 9, 197\u2013210 (2022).","journal-title":"J. Prev. Alzheimers Dis."},{"key":"611_CR59","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1056\/NEJMoa2212948","volume":"388","author":"CH van Dyck","year":"2023","unstructured":"van Dyck, C. H. et al. Lecanemab in early Alzheimer\u2019s disease. N. Engl. J. Med. 388, 9\u201321 (2023).","journal-title":"N. Engl. J. Med."},{"key":"611_CR60","doi-asserted-by":"crossref","unstructured":"Sims, J. R. et al. Donanemab in early symptomatic Alzheimer Disease: the TRAILBLAZER-ALZ 2 randomized clinical trial. JAMA 330, 512\u2013527 (2023).","DOI":"10.1001\/jama.2023.21109"},{"key":"611_CR61","unstructured":"Johnson, K. et al. Biomarker assessments from Clarity AD: downstream implications of targeting protofibrils and tau as a predictive biomarker. In 16th Clinical Trialson Alzheimer\u2019s Disease (ed. Shobha, D.) S9\u2013S10 (CTAD, 2023)."},{"key":"611_CR62","doi-asserted-by":"publisher","first-page":"1227","DOI":"10.1002\/alz.12748","volume":"19","author":"MS Rafii","year":"2023","unstructured":"Rafii, M. S. et al. The AHEAD 3-45 Study: design of a prevention trial for Alzheimer\u2019s disease. Alzheimers Dement. 19, 1227\u20131233 (2023).","journal-title":"Alzheimers Dement."},{"key":"611_CR63","doi-asserted-by":"publisher","first-page":"4757","DOI":"10.1016\/j.cell.2023.09.023","volume":"186","author":"AL Boxer","year":"2023","unstructured":"Boxer, A. L. & Sperling, R. Accelerating Alzheimer\u2019s therapeutic development: the past and future of clinical trials. Cell 186, 4757\u20134772 (2023).","journal-title":"Cell"},{"key":"611_CR64","first-page":"362","volume":"10","author":"J Cummings","year":"2023","unstructured":"Cummings, J. et al. Lecanemab: appropriate use recommendations. J. Prev. Alzheimers Dis. 10, 362\u2013377 (2023).","journal-title":"J. Prev. Alzheimers Dis."},{"key":"611_CR65","first-page":"29","volume":"7","author":"A Rosenberg","year":"2020","unstructured":"Rosenberg, A., Mangialasche, F., Ngandu, T., Solomon, A. & Kivipelto, M. Multidomain interventions to prevent cognitive impairment, Alzheimer\u2019s disease, and dementia: from FINGER to world-wide FINGERS. J. Prev. Alzheimers Dis. 7, 29\u201336 (2020).","journal-title":"J. Prev. Alzheimers Dis."},{"key":"611_CR66","doi-asserted-by":"publisher","first-page":"212","DOI":"10.1038\/35102591","volume":"414","author":"S Weggen","year":"2001","unstructured":"Weggen, S. et al. A subset of NSAIDs lower amyloidogenic A\u03b242 independently of cyclooxygenase activity. Nature 414, 212\u2013216 (2001).","journal-title":"Nature"},{"key":"611_CR67","doi-asserted-by":"publisher","first-page":"4815","DOI":"10.1038\/emboj.2011.372","volume":"30","author":"Y Ohki","year":"2011","unstructured":"Ohki, Y. et al. Phenylpiperidine-type gamma-secretase modulators target the transmembrane domain 1 of presenilin 1. EMBO J. 30, 4815\u20134824 (2011).","journal-title":"EMBO J."},{"key":"611_CR68","doi-asserted-by":"crossref","unstructured":"Crump, C. J., Johnson, D. S. & Li, Y. M. Development and mechanism of \u03b3-secretase modulators for Alzheimer\u2019s disease. Biochemistry 52, 3197\u20133216 (2013).","DOI":"10.1021\/bi400377p"},{"key":"611_CR69","doi-asserted-by":"publisher","first-page":"702","DOI":"10.1021\/bi401537v","volume":"53","author":"SL Wagner","year":"2014","unstructured":"Wagner, S. L. et al. Soluble \u03b3-secretase modulators selectively inhibit the production of the 42-amino acid amyloid beta peptide variant and augment the production of multiple carboxy-truncated amyloid beta species. Biochemistry 53, 702\u2013713 (2014).","journal-title":"Biochemistry"},{"key":"611_CR70","doi-asserted-by":"crossref","unstructured":"Johnson, D. S., Li, Y.-M., Pettersson, M. & St George-Hyslop, P. H. Structural and chemical biology of presenilin complexes. Cold Spring Harb. Perspect. Med. 7, a024067 (2017).","DOI":"10.1101\/cshperspect.a024067"},{"key":"611_CR71","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2021.100393","volume":"296","author":"L Liu","year":"2021","unstructured":"Liu, L., Lauro, B. M., Wolfe, M. S. & Selkoe, D. J. Hydrophilic loop 1 of presenilin-1 and the APP GxxxG transmembrane motif regulate gamma-secretase function in generating Alzheimer-causing Abeta peptides. J. Biol. Chem. 296, 100393 (2021).","journal-title":"J. Biol. Chem."},{"key":"611_CR72","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1016\/j.neuron.2005.06.030","volume":"47","author":"E McGowan","year":"2005","unstructured":"McGowan, E. et al. A\u03b242 is essential for parenchymal and vascular amyloid deposition in mice. Neuron 47, 191\u2013199 (2005).","journal-title":"Neuron"},{"key":"611_CR73","doi-asserted-by":"publisher","first-page":"627","DOI":"10.1523\/JNEUROSCI.4849-06.2007","volume":"27","author":"J Kim","year":"2007","unstructured":"Kim, J. et al. A\u03b240 inhibits amyloid deposition in vivo. J. Neurosci. 27, 627\u2013633 (2007).","journal-title":"J. Neurosci."},{"key":"611_CR74","unstructured":"Sturm, S. RG6289, A new \u03b3-secretase modulator for the treatment of alzheimer\u2019s disease: results from a phase I healthy volunteer study. In 16th Clinical Trials on Alzheimer\u2019s Disease (ed. Shobha, D.) S23-24 (CTAD, 2023)."},{"key":"611_CR75","doi-asserted-by":"crossref","unstructured":"Rynearson, K. D. et al. Preclinical validation of a potent \u03b3-secretase modulator for Alzheimer\u2019s disease prevention. J. Exp. Med. 218, e20202560 (2021).","DOI":"10.1084\/jem.20202560"},{"key":"611_CR76","doi-asserted-by":"crossref","unstructured":"Edwards, A. L. et al. Exploratory tau biomarker results from a multiple ascending-dose study of BIIB080 in Alzheimer disease: a randomized clinical trial. JAMA Neurol. 80, 1344\u20131352 (2023).","DOI":"10.1001\/jamaneurol.2023.3861"},{"key":"611_CR77","doi-asserted-by":"publisher","first-page":"591","DOI":"10.1002\/ana.21340","volume":"63","author":"D Frenkel","year":"2008","unstructured":"Frenkel, D. et al. A nasal proteosome adjuvant activates microglia and prevents amyloid deposition. Ann. Neurol. 63, 591\u2013601 (2008).","journal-title":"Ann. Neurol."},{"key":"611_CR78","unstructured":"He, W. G. D. & Kowal, P. U.S. Census Bureau, International Population Reports P95\/16-1, An Aging World: 2015 (US Government Publishing Office, 2016)."},{"key":"611_CR79","unstructured":"US Census Bureau. 2014 National Population Projections: Downloadable Files (2014)."},{"key":"611_CR80","doi-asserted-by":"publisher","first-page":"1966","DOI":"10.1002\/alz.12362","volume":"17","author":"KB Rajan","year":"2021","unstructured":"Rajan, K. B. et al. Population estimate of people with clinical Alzheimer\u2019s disease and mild cognitive impairment in the United States (2020\u20132060). Alzheimers Dement. 17, 1966\u20131975 (2021).","journal-title":"Alzheimers Dement."},{"key":"611_CR81","doi-asserted-by":"publisher","first-page":"f7051","DOI":"10.1136\/bmj.f7051","volume":"347","author":"K Yaffe","year":"2013","unstructured":"Yaffe, K. et al. Effect of socioeconomic disparities on incidence of dementia among biracial older adults: prospective study. Br. Med. J. 347, f7051 (2013).","journal-title":"Br. Med. J."},{"key":"611_CR82","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1159\/000109998","volume":"29","author":"BL Plassman","year":"2007","unstructured":"Plassman, B. L. et al. Prevalence of dementia in the United States: the aging, demographics, and memory study. Neuroepidemiology 29, 125\u2013132 (2007).","journal-title":"Neuroepidemiology"},{"key":"611_CR83","unstructured":"Alzheimer\u2019s Association. Alzheimer\u2019s Disease Facts and Figures 2024 (Alzheimer\u2019s Association, 2024)."},{"key":"611_CR84","unstructured":"CDC WONDER Online Database: About Underlying Cause of Death, 1999\u20132020 (US Centers for Disease Control, accessed 9 December 2022)."},{"key":"611_CR85","doi-asserted-by":"publisher","first-page":"1444","DOI":"10.1001\/jama.2018.0158","volume":"319","author":"US Burden of Disease Collaborators Collaborators","year":"2018","unstructured":"US Burden of Disease Collaborators Collaborators et al. The state of US health, 1990\u20132016: burden of diseases, injuries, and risk factors among US states. JAMA 319, 1444\u20131472 (2018).","journal-title":"JAMA"},{"key":"611_CR86","doi-asserted-by":"publisher","first-page":"488","DOI":"10.1111\/j.1468-1331.2008.02503.x","volume":"16","author":"HR Brunnstrom","year":"2009","unstructured":"Brunnstrom, H. R. & Englund, E. M. Cause of death in patients with dementia disorders. Eur. J. Neurol. 16, 488\u2013492 (2009).","journal-title":"Eur. J. Neurol."},{"key":"611_CR87","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1097\/WAD.0b013e31819fe7d1","volume":"24","author":"HM Arrighi","year":"2010","unstructured":"Arrighi, H. M., Neumann, P. J., Lieberburg, I. M. & Townsend, R. J. Lethality of Alzheimer disease and its impact on nursing home placement. Alzheimer Dis. Assoc. Disord. 24, 90\u201395 (2010).","journal-title":"Alzheimer Dis. Assoc. Disord."},{"key":"611_CR88","unstructured":"Tejada-Vera, B. Mortality from Alzheimer\u2019s disease in the United States: data for 2000 and 2010. NCHS Data Brief 1\u20138 (2013)."},{"key":"611_CR89","doi-asserted-by":"publisher","first-page":"1456","DOI":"10.1212\/WNL.0b013e3182553be6","volume":"78","author":"EM Schrijvers","year":"2012","unstructured":"Schrijvers, E. M. et al. Is dementia incidence declining?: trends in dementia incidence since 1990 in the Rotterdam Study. Neurology 78, 1456\u20131463 (2012).","journal-title":"Neurology"},{"key":"611_CR90","unstructured":"Alzheimer\u2019s Association. Changing the Trajectory of Alzheimer\u2019s Disease: How a Treatment by 2025 Saves Lives and Dollars (Alzheimer\u2019s Association, 2015)."},{"key":"611_CR91","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1515\/fhep-2014-0013","volume":"18","author":"J Zissimopoulos","year":"2014","unstructured":"Zissimopoulos, J., Crimmins, E. & St Clair, P. The value of delaying Alzheimer\u2019s disease onset. Forum Health Econ. Policy 18, 25\u201339 (2014).","journal-title":"Forum Health Econ. Policy"},{"key":"611_CR92","unstructured":"Alzheimer\u2019s Association. 2024 Alzheimer\u2019s Disease Facts and Figures (Alzheimer\u2019s Association, 2024)."},{"key":"611_CR93","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1016\/j.jalz.2009.01.026","volume":"5","author":"KS Hall","year":"2009","unstructured":"Hall, K. S. et al. Prevalence rates for dementia and Alzheimer\u2019s disease in African Americans: 1992 versus 2001. Alzheimers Dement. 5, 227\u2013233 (2009).","journal-title":"Alzheimers Dement."},{"key":"611_CR94","doi-asserted-by":"publisher","first-page":"2472","DOI":"10.1111\/jgs.13833","volume":"63","author":"AB Dufour","year":"2015","unstructured":"Dufour, A. B., Shaffer, M. L., D\u2019Agata, E. M., Habtemariam, D. & Mitchell, S. L. Survival after suspected urinary tract infection in individuals with advanced dementia. J. Am. Geriatr. Soc. 63, 2472\u20132477 (2015).","journal-title":"J. Am. Geriatr. Soc."},{"key":"611_CR95","doi-asserted-by":"publisher","first-page":"757","DOI":"10.1086\/313996","volume":"31","author":"LE Nicolle","year":"2000","unstructured":"Nicolle, L. E. Urinary tract infection in long-term-care facility residents. Clin. Infect. Dis. 31, 757\u2013761 (2000).","journal-title":"Clin. Infect. Dis."},{"key":"611_CR96","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1016\/j.jalz.2012.11.002","volume":"9","author":"PJ Lin","year":"2013","unstructured":"Lin, P. J., Fillit, H. M., Cohen, J. T. & Neumann, P. J. Potentially avoidable hospitalizations among Medicare beneficiaries with Alzheimer\u2019s disease and related disorders. Alzheimers Dement. 9, 30\u201338 (2013).","journal-title":"Alzheimers Dement."},{"key":"611_CR97","doi-asserted-by":"publisher","first-page":"S188","DOI":"10.37765\/ajmc.2022.89236","volume":"28","author":"AP Skaria","year":"2022","unstructured":"Skaria, A. P. The economic and societal burden of Alzheimer disease: managed care considerations. Am. J. Manag. Care 28, S188\u2013S196 (2022).","journal-title":"Am. J. Manag. Care"},{"key":"611_CR98","doi-asserted-by":"publisher","first-page":"M267","DOI":"10.1093\/gerona\/54.5.M267","volume":"54","author":"SM Albert","year":"1999","unstructured":"Albert, S. M. et al. Hospitalization and Alzheimer\u2019s disease: results from a community-based study. J. Gerontol. A Biol. Sci. Med Sci. 54, M267\u2013M271 (1999).","journal-title":"J. Gerontol. A Biol. Sci. Med Sci."},{"key":"611_CR99","first-page":"528","volume":"34","author":"H Fillit","year":"2002","unstructured":"Fillit, H., Hill, J. W. & Futterman, R. Health care utilization and costs of Alzheimer\u2019s disease: the role of co-morbid conditions, disease stage, and pharmacotherapy. Fam. Med. 34, 528\u2013535 (2002).","journal-title":"Fam. Med."},{"key":"611_CR100","doi-asserted-by":"publisher","first-page":"1001","DOI":"10.1016\/j.molcel.2018.11.028","volume":"73","author":"S Fanning","year":"2019","unstructured":"Fanning, S. et al. Lipidomic analysis of \u03b1-synuclein neurotoxicity identifies stearoyl CoA desaturase as a target for parkinson treatment. Mol. Cell. 73, 1001\u20131014(2019).","journal-title":"Mol. Cell."},{"key":"611_CR101","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1002\/ana.25920","volume":"89","author":"S Nuber","year":"2021","unstructured":"Nuber, S. et al. A stearoyl-coenzyme a dDesaturase inhibitor prevents multiple Parkinson disease phenotypes in \u03b1-synuclein mice. Ann. Neurol. 89, 74\u201390 (2021).","journal-title":"Ann. Neurol."}],"container-title":["Nature Aging"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s43587-024-00611-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s43587-024-00611-5","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s43587-024-00611-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,3]],"date-time":"2024-05-03T13:38:07Z","timestamp":1714743487000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s43587-024-00611-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,4,19]]},"references-count":101,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2024,4]]}},"alternative-id":["611"],"URL":"https:\/\/doi.org\/10.1038\/s43587-024-00611-5","relation":{},"ISSN":["2662-8465"],"issn-type":[{"value":"2662-8465","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,4,19]]},"assertion":[{"value":"21 July 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 March 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 April 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"D.J.S. is a director of and consultant to Prothena Biosciences and an ad hoc consultant to Eisai.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}