{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T15:50:37Z","timestamp":1793375437271,"version":"4.5.0"},"reference-count":217,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,11,23]],"date-time":"2021-11-23T00:00:00Z","timestamp":1637625600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.springer.com\/tdm"},{"start":{"date-parts":[[2021,11,23]],"date-time":"2021-11-23T00:00:00Z","timestamp":1637625600000},"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 Neurosci"],"published-print":{"date-parts":[[2022,1]]},"DOI":"10.1038\/s41583-021-00533-w","type":"journal-article","created":{"date-parts":[[2021,11,23]],"date-time":"2021-11-23T04:03:05Z","timestamp":1637640185000},"page":"53-66","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":496,"title":["The probabilistic model of Alzheimer disease: the amyloid hypothesis revised"],"prefix":"10.1038","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7075-7082","authenticated-orcid":false,"given":"Giovanni B.","family":"Frisoni","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1905-8993","authenticated-orcid":false,"given":"Daniele","family":"Altomare","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1036-1075","authenticated-orcid":false,"given":"Dietmar Rudolf","family":"Thal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9208-4472","authenticated-orcid":false,"given":"Federica","family":"Ribaldi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rik","family":"van der Kant","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rik","family":"Ossenkoppele","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1890-4193","authenticated-orcid":false,"given":"Kaj","family":"Blennow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey","family":"Cummings","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2374-9204","authenticated-orcid":false,"given":"Cornelia","family":"van Duijn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5652-8459","authenticated-orcid":false,"given":"Peter M.","family":"Nilsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre-Yves","family":"Dietrich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip","family":"Scheltens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno","family":"Dubois","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,11,23]]},"reference":[{"key":"533_CR1","unstructured":"Prince, M. et al. World Alzheimer Report 2015. The Global Impact of Dementia - An Analysis of Prevalence, Incidence, Cost and Trends. https:\/\/www.alzint.org\/u\/WorldAlzheimerReport2015.pdf (2015)."},{"key":"533_CR2","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.1016\/S0140-6736(10)61349-9","volume":"377","author":"C Ballard","year":"2011","unstructured":"Ballard, C. et al. Alzheimer\u2019s disease. Lancet 377, 1019\u20131031 (2011).","journal-title":"Lancet"},{"key":"533_CR3","doi-asserted-by":"crossref","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":"533_CR4","doi-asserted-by":"crossref","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":"533_CR5","doi-asserted-by":"crossref","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":"533_CR6","first-page":"129","volume":"75","author":"N Sorel","year":"2017","unstructured":"Sorel, N., Cayssials, \u00c9., Brizard, F. & Chomel, J. C. Treatment and molecular monitoring update in chronic myeloid leukemia management. Ann. Biol. Clin. 75, 129\u2013145 (2017).","journal-title":"Ann. Biol. Clin."},{"key":"533_CR7","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1002\/ana.10281","volume":"52","author":"JQ Trojanowski","year":"2002","unstructured":"Trojanowski, J. Q. Tauists, baptists, syners, apostates, and new data. Ann. Neurol. 52, 263\u2013265 (2002).","journal-title":"Ann. Neurol."},{"key":"533_CR8","doi-asserted-by":"crossref","first-page":"S4","DOI":"10.1038\/d41586-018-05719-4","volume":"559","author":"S Makin","year":"2018","unstructured":"Makin, S. The amyloid hypothesis on trial. Nature 559, S4\u2013S7 (2018).","journal-title":"Nature"},{"key":"533_CR9","doi-asserted-by":"crossref","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":"533_CR10","doi-asserted-by":"crossref","first-page":"794","DOI":"10.1038\/nn.4017","volume":"18","author":"K Herrup","year":"2015","unstructured":"Herrup, K. The case for rejecting the amyloid cascade hypothesis. Nat. Neurosci. 18, 794\u2013799 (2015).","journal-title":"Nat. Neurosci."},{"key":"533_CR11","doi-asserted-by":"crossref","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":"533_CR12","first-page":"1","volume":"3","author":"RJ Bateman","year":"2011","unstructured":"Bateman, R. J. et al. Autosomal-dominant Alzheimer\u2019s disease: a review and proposal for the prevention of Alzheimer\u2019s disease. Alzheimer\u2019s Res. Ther. 3, 1 (2011).","journal-title":"Alzheimer\u2019s Res. Ther."},{"key":"533_CR13","doi-asserted-by":"crossref","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 (2012).","journal-title":"Nature"},{"key":"533_CR14","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1038\/nrneurol.2012.263","volume":"9","author":"CC Liu","year":"2013","unstructured":"Liu, C. C., Kanekiyo, T., Xu, H. & Bu, G. Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat. Rev. Neurol. 9, 106\u2013118 (2013).","journal-title":"Nat. Rev. Neurol."},{"key":"533_CR15","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1038\/gim.2015.117","volume":"18","author":"C Van Cauwenberghe","year":"2016","unstructured":"Van Cauwenberghe, C., Van Broeckhoven, C. & Sleegers, K. The genetic landscape of Alzheimer disease: clinical implications and perspectives. Genet. Med. 18, 421\u2013430 (2016).","journal-title":"Genet. Med."},{"key":"533_CR16","first-page":"197","volume":"4","author":"K Sleegers","year":"2001","unstructured":"Sleegers, K. & Van Duijn, C. M. Alzheimer\u2019s disease: genes, pathogenesis and risk prediction. Community Genet. 4, 197\u2013203 (2001).","journal-title":"Community Genet."},{"key":"533_CR17","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1093\/jnen\/nlv028","volume":"75","author":"J Ringman","year":"2016","unstructured":"Ringman, J. et al. Neuropathology of autosomal dominant Alzheimer disease in the National Alzheimer Coordinating Center database. J. Neuropathol. Exp. Neurol. 75, 284\u2013290 (2016).","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"533_CR18","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/S1474-4422(09)70299-6","volume":"9","author":"CR Jack","year":"2010","unstructured":"Jack, C. R. et al. Hypothetical model of dynamic biomarkers of the Alzheimer\u2019s pathological cascade. Lancet Neurol. 9, 119\u2013128 (2010).","journal-title":"Lancet Neurol."},{"key":"533_CR19","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1038\/s41583-019-0240-3","volume":"21","author":"R van der Kant","year":"2020","unstructured":"van der Kant, R., Goldstein, L. S. B. & Ossenkoppele, R. Amyloid-\u03b2-independent regulators of tau pathology in Alzheimer disease. Nat. Rev. Neurosci. 21, 21\u201335 (2020).","journal-title":"Nat. Rev. Neurosci."},{"key":"533_CR20","doi-asserted-by":"crossref","first-page":"1491","DOI":"10.1126\/science.1062097","volume":"293","author":"J G\u00f6tz","year":"2001","unstructured":"G\u00f6tz, J., Chen, F., Van Dorpe, J. & Nitsch, R. M. Formation of neurofibrillary tangles in P301L tau transgenic mice induced by A\u03b242 fibrils. Science 293, 1491\u20131495 (2001).","journal-title":"Science"},{"key":"533_CR21","doi-asserted-by":"crossref","first-page":"1487","DOI":"10.1126\/science.1058189","volume":"293","author":"J Lewis","year":"2001","unstructured":"Lewis, J. et al. Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science 293, 1487\u20131491 (2001).","journal-title":"Science"},{"key":"533_CR22","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1007\/s00401-019-02053-5","volume":"138","author":"LA Gomes","year":"2019","unstructured":"Gomes, L. A. et al. A\u03b2-induced acceleration of Alzheimer-related \u03c4-pathology spreading and its association with prion protein. Acta Neuropathol. 138, 913\u2013941 (2019).","journal-title":"Acta Neuropathol."},{"key":"533_CR23","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1038\/nature13800","volume":"515","author":"SH Choi","year":"2014","unstructured":"Choi, S. H. et al. A three-dimensional human neural cell culture model of Alzheimer\u2019s disease. Nature 515, 274\u2013278 (2014).","journal-title":"Nature"},{"key":"533_CR24","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1016\/j.neuron.2004.07.003","volume":"43","author":"S Oddo","year":"2004","unstructured":"Oddo, S., Billings, L., Kesslak, J. P., Cribbs, D. H. & LaFerla, F. M. A\u03b2 immunotherapy leads to clearance of early, but not late, hyperphosphorylated tau aggregates via the proteasome. Neuron 43, 321\u2013332 (2004).","journal-title":"Neuron"},{"key":"533_CR25","doi-asserted-by":"crossref","first-page":"3230","DOI":"10.1093\/brain\/awz268","volume":"142","author":"CR Jack","year":"2019","unstructured":"Jack, C. R. et al. The bivariate distribution of amyloid-\u03b2 and tau: relationship with established neurocognitive clinical syndromes. Brain 142, 3230\u20133242 (2019).","journal-title":"Brain"},{"key":"533_CR26","doi-asserted-by":"crossref","DOI":"10.1126\/scitranslmed.aau5732","volume":"12","author":"R La Joie","year":"2020","unstructured":"La Joie, R. et al. Prospective longitudinal atrophy in Alzheimer\u2019s disease correlates with the intensity and topography of baseline tau-PET. Sci. Transl. Med. 12, eaau5732 (2020).","journal-title":"Sci. Transl. Med."},{"key":"533_CR27","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/0006-8993(89)91396-6","volume":"477","author":"C Bancher","year":"1989","unstructured":"Bancher, C. et al. Accumulation of abnormally phosphorylated \u03c4 precedes the formation of neurofibrillary tangles in Alzheimer\u2019s disease. Brain Res. 477, 90\u201399 (1989).","journal-title":"Brain Res."},{"key":"533_CR28","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1007\/s00401-019-02103-y","volume":"139","author":"MJ Koper","year":"2020","unstructured":"Koper, M. J. et al. Necrosome complex detected in granulovacuolar degeneration is associated with neuronal loss in Alzheimer\u2019s disease. Acta Neuropathol. 139, 463\u2013484 (2020).","journal-title":"Acta Neuropathol."},{"key":"533_CR29","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1007\/s00401-019-02046-4","volume":"138","author":"VI Wiersma","year":"2019","unstructured":"Wiersma, V. I. et al. Granulovacuolar degeneration bodies are neuron-selective lysosomal structures induced by intracellular tau pathology. Acta Neuropathol. 138, 943\u2013970 (2019).","journal-title":"Acta Neuropathol."},{"key":"533_CR30","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1038\/s41418-017-0012-4","volume":"25","author":"L Galluzzi","year":"2018","unstructured":"Galluzzi, L. et al. Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death Differ. 25, 486\u2013541 (2018).","journal-title":"Cell Death Differ."},{"key":"533_CR31","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1038\/s41422-019-0164-5","volume":"29","author":"D Tang","year":"2019","unstructured":"Tang, D. et al. The molecular machinery of regulated cell death. Cell Res. 29, 347\u2013364 (2019).","journal-title":"Cell Res."},{"key":"533_CR32","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1002\/ana.24910","volume":"81","author":"BJ Hanseeuw","year":"2017","unstructured":"Hanseeuw, B. J. et al. Fluorodeoxyglucose metabolism associated with tau-amyloid interaction predicts memory decline. Ann. Neurol. 81, 583\u2013596 (2017).","journal-title":"Ann. Neurol."},{"key":"533_CR33","doi-asserted-by":"crossref","first-page":"3286","DOI":"10.1093\/brain\/awx243","volume":"140","author":"A Bejanin","year":"2017","unstructured":"Bejanin, A. et al. Tau pathology and neurodegeneration contribute to cognitive impairment in Alzheimer\u2019s disease. Brain 140, 3286\u20133300 (2017).","journal-title":"Brain"},{"key":"533_CR34","doi-asserted-by":"crossref","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":"533_CR35","unstructured":"US National Library of Medicine. ClinicalTrials.gov https:\/\/clinicaltrials.gov\/ct2\/show\/NCT02477800 (2021)."},{"key":"533_CR36","unstructured":"US National Library of Medicine. ClinicalTrials.gov https:\/\/clinicaltrials.gov\/ct2\/show\/NCT02484547 (2021)."},{"key":"533_CR37","unstructured":"Haeberlein, S. B. et al. EMERGE and ENGAGE topline results: two phase 3 studies to evaluate aducanumab in patients with early Alzheimer\u2019s disease. https:\/\/investors.biogen.com\/static-files\/ddd45672-9c7e-4c99-8a06-3b557697c06f (2019)."},{"key":"533_CR38","unstructured":"ALZFORUM. Gantenerumab https:\/\/www.alzforum.org\/therapeutics\/gantenerumab (2021)."},{"key":"533_CR39","unstructured":"ALZFORUM. AADvac1 https:\/\/www.alzforum.org\/therapeutics\/aadvac1 (2021)."},{"key":"533_CR40","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1016\/S1474-4422(13)70044-9","volume":"12","author":"VL Villemagne","year":"2013","unstructured":"Villemagne, V. L. et al. Amyloid \u03b2 deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer\u2019s disease: a prospective cohort study. Lancet Neurol. 12, 357\u2013367 (2013).","journal-title":"Lancet Neurol."},{"key":"533_CR41","doi-asserted-by":"crossref","first-page":"890","DOI":"10.1212\/WNL.0b013e3182840bbe","volume":"80","author":"CR Jack","year":"2013","unstructured":"Jack, C. R. et al. Brain \u03b2-amyloid load approaches a plateau. Neurology 80, 890\u2013896 (2013).","journal-title":"Neurology"},{"key":"533_CR42","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1186\/s13195-021-00813-8","volume":"13","author":"CJ Swanson","year":"2021","unstructured":"Swanson, C. J. et al. A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer\u2019s disease with lecanemab, an anti-A\u03b2 protofibril antibody. Alzheimers Res. Ther. 13, 80 (2021).","journal-title":"Alzheimers Res. Ther."},{"key":"533_CR43","doi-asserted-by":"crossref","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":"533_CR44","doi-asserted-by":"crossref","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. Transl. Res. Clin. Interv. 5, 272\u2013293 (2019).","journal-title":"Alzheimers Dement. Transl. Res. Clin. Interv."},{"key":"533_CR45","unstructured":"National Institute on Aging. NIA-funded active Alzheimer\u2019s and related dementias clinical trials and studies. https:\/\/www.nia.nih.gov\/research\/ongoing-AD-trials#section2 (2021)."},{"key":"533_CR46","doi-asserted-by":"crossref","first-page":"E1635","DOI":"10.1212\/WNL.0000000000008361","volume":"93","author":"D Altomare","year":"2019","unstructured":"Altomare, D. et al. Applying the ATN scheme in a memory clinic population: the ABIDE project. Neurology 93, E1635\u2013E1646 (2019).","journal-title":"Neurology"},{"key":"533_CR47","doi-asserted-by":"crossref","first-page":"E1567","DOI":"10.1212\/WNL.0000000000007248","volume":"92","author":"A Soldan","year":"2019","unstructured":"Soldan, A. et al. ATN profiles among cognitively normal individuals and longitudinal cognitive outcomes. Neurology 92, E1567\u2013E1579 (2019).","journal-title":"Neurology"},{"key":"533_CR48","doi-asserted-by":"publisher","DOI":"10.1212\/wnl.0000000000009724","author":"JL Ebenau","year":"2020","unstructured":"Ebenau, J. L. et al. ATN classification and clinical progression in subjective cognitive decline. Neurology https:\/\/doi.org\/10.1212\/wnl.0000000000009724 (2020).","journal-title":"Neurology"},{"key":"533_CR49","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1016\/S1474-4422(13)70194-7","volume":"12","author":"SJB Vos","year":"2013","unstructured":"Vos, S. J. B. et al. Preclinical Alzheimer\u2019s disease and its outcome: a longitudinal cohort study. Lancet Neurol. 12, 957\u2013965 (2013).","journal-title":"Lancet Neurol."},{"key":"533_CR50","doi-asserted-by":"crossref","first-page":"fcz046","DOI":"10.1093\/braincomms\/fcz046","volume":"2","author":"A Weigand","year":"2020","unstructured":"Weigand, A. et al. Is tau in the absence of amyloid on the Alzheimer\u2019s continuum?: a study of discordant PET positivity. Brain Commun. 2, fcz046 (2020).","journal-title":"Brain Commun."},{"key":"533_CR51","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1177\/1533317507308779","volume":"22","author":"GD Rabinovici","year":"2008","unstructured":"Rabinovici, G. D. et al. Distinct MRI atrophy patterns in autopsy-proven Alzheimer\u2019s disease and frontotemporal lobar degeneration. Am. J. Alzheimers. Dis. Other Demen. 22, 474\u2013488 (2008).","journal-title":"Am. J. Alzheimers. Dis. Other Demen."},{"key":"533_CR52","doi-asserted-by":"crossref","DOI":"10.1038\/s41598-018-26151-8","volume":"8","author":"U Ekman","year":"2018","unstructured":"Ekman, U., Ferreira, D. & Westman, E. The A\/T\/N biomarker scheme and patterns of brain atrophy assessed in mild cognitive impairment. Sci. Rep. 8, 8431 (2018).","journal-title":"Sci. Rep."},{"key":"533_CR53","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1038\/s41582-019-0210-4","volume":"15","author":"D Adams","year":"2019","unstructured":"Adams, D., Koike, H., Slama, M. & Coelho, T. Hereditary transthyretin amyloidosis: a model of medical progress for a fatal disease. Nat. Rev. Neurol. 15, 387\u2013404 (2019).","journal-title":"Nat. Rev. Neurol."},{"key":"533_CR54","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awaa180","author":"TA Pascoal","year":"2020","unstructured":"Pascoal, T. A. et al. 18F-MK-6240 PET for early and late detection of neurofibrillary tangles. Brain https:\/\/doi.org\/10.1093\/brain\/awaa180 (2020).","journal-title":"Brain"},{"key":"533_CR55","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1001\/jamaneurol.2020.0989","volume":"77","author":"A Leuzy","year":"2020","unstructured":"Leuzy, A. et al. Diagnostic performance of RO948 F 18 tau positron emission tomography in the differentiation of Alzheimer disease from other neurodegenerative disorders. JAMA Neurol. 77, 955\u2013965 (2020).","journal-title":"JAMA Neurol."},{"key":"533_CR56","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1007\/s00401-014-1349-0","volume":"128","author":"JF Crary","year":"2014","unstructured":"Crary, J. F. et al. Primary age-related tauopathy (PART): a common pathology associated with human aging. Acta Neuropathol. 128, 755\u2013766 (2014).","journal-title":"Acta Neuropathol."},{"key":"533_CR57","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1007\/s00401-015-1390-7","volume":"129","author":"C Duyckaerts","year":"2015","unstructured":"Duyckaerts, C. et al. PART is part of Alzheimer disease. Acta Neuropathol. 129, 749\u2013756 (2015).","journal-title":"Acta Neuropathol."},{"key":"533_CR58","doi-asserted-by":"crossref","first-page":"960","DOI":"10.1097\/NEN.0b013e318232a379","volume":"70","author":"H Braak","year":"2011","unstructured":"Braak, H., Thal, D. R., Ghebremedhin, E. & Del Tredici, K. Stages of the pathologic process in Alzheimer disease: age categories from 1 to 100 years. J. Neuropathol. Exp. Neurol. 70, 960\u2013969 (2011).","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"533_CR59","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1007\/s00401-017-1709-7","volume":"134","author":"TL Spires-Jones","year":"2017","unstructured":"Spires-Jones, T. L., Attems, J. & Thal, D. R. Interactions of pathological proteins in neurodegenerative diseases. Acta Neuropathol. 134, 187\u2013205 (2017).","journal-title":"Acta Neuropathol."},{"key":"533_CR60","doi-asserted-by":"crossref","first-page":"13287","DOI":"10.1073\/pnas.94.24.13287","volume":"94","author":"C Sturchler-Pierrat","year":"1997","unstructured":"Sturchler-Pierrat, C. et al. Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. Proc. Natl Acad. Sci. USA 94, 13287\u201313292 (1997).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"533_CR61","doi-asserted-by":"crossref","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":"533_CR62","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1126\/science.274.5284.99","volume":"274","author":"K Hsiao","year":"1996","unstructured":"Hsiao, K. et al. Correlative memory deficits, A\u03b2 elevation, and amyloid plaques in transgenic mice. Science 274, 99\u2013102 (1996).","journal-title":"Science"},{"key":"533_CR63","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1007\/s00401-019-02114-9","volume":"139","author":"GT Corbett","year":"2020","unstructured":"Corbett, G. T. et al. PrP is a central player in toxicity mediated by soluble aggregates of neurodegeneration-causing proteins. Acta Neuropathol. 139, 503\u2013526 (2020).","journal-title":"Acta Neuropathol."},{"key":"533_CR64","doi-asserted-by":"crossref","first-page":"9207","DOI":"10.1523\/JNEUROSCI.0722-17.2017","volume":"37","author":"SV Salazar","year":"2017","unstructured":"Salazar, S. V. et al. Conditional deletion of Prnp rescues behavioral and synaptic deficits after disease onset in transgenic Alzheimer\u2019s disease. J. Neurosci. 37, 9207\u20139221 (2017).","journal-title":"J. Neurosci."},{"key":"533_CR65","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1007\/BF00308809","volume":"82","author":"H Braak","year":"1991","unstructured":"Braak, H. & Braak, E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathologica 82, 239\u2013259 (1991).","journal-title":"Acta Neuropathologica"},{"key":"533_CR66","doi-asserted-by":"crossref","first-page":"1791","DOI":"10.1212\/WNL.58.12.1791","volume":"58","author":"DR Thal","year":"2002","unstructured":"Thal, D. R., R\u00fcb, U., Orantes, M. & Braak, H. Phases of A\u03b2-deposition in the human brain and its relevance for the development of AD. Neurology 58, 1791\u20131800 (2002).","journal-title":"Neurology"},{"key":"533_CR67","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1038\/nature24016","volume":"549","author":"Y Shi","year":"2017","unstructured":"Shi, Y. et al. ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature 549, 523\u2013527 (2017).","journal-title":"Nature"},{"key":"533_CR68","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2020.1741","author":"S Karanth","year":"2020","unstructured":"Karanth, S. et al. Prevalence and clinical phenotype of quadruple misfolded proteins in older adults. JAMA Neurol. https:\/\/doi.org\/10.1001\/jamaneurol.2020.1741 (2020).","journal-title":"JAMA Neurol."},{"key":"533_CR69","doi-asserted-by":"crossref","first-page":"2197","DOI":"10.1212\/01.wnl.0000271090.28148.24","volume":"69","author":"JA Schneider","year":"2007","unstructured":"Schneider, J. A., Arvanitakis, Z., Bang, W. & Bennett, D. A. Mixed brain pathologies account for most dementia cases in community-dwelling older persons. Neurology 69, 2197\u20132204 (2007).","journal-title":"Neurology"},{"key":"533_CR70","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1080\/13543784.2019.1683160","volume":"28","author":"BP Imbimbo","year":"2019","unstructured":"Imbimbo, B. P. & Watling, M. Investigational BACE inhibitors for the treatment of Alzheimer\u2019s disease. Expert Opin. Investig. Drugs 28, 967\u2013975 (2019).","journal-title":"Expert Opin. Investig. Drugs"},{"key":"533_CR71","doi-asserted-by":"crossref","first-page":"966","DOI":"10.1038\/s41375-020-0776-2","volume":"34","author":"A Hochhaus","year":"2020","unstructured":"Hochhaus, A. et al. European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia. Leukemia 34, 966\u2013984 (2020).","journal-title":"Leukemia"},{"key":"533_CR72","unstructured":"US National Library of Medicine. ClinicalTrials.gov https:\/\/clinicaltrials.gov\/ct2\/show\/NCT01760005 (2021)."},{"key":"533_CR73","unstructured":"ALZFORUM. Solanezumab https:\/\/www.alzforum.org\/therapeutics\/solanezumab (2021)."},{"key":"533_CR74","unstructured":"Alzheimer\u2019s Association. DIAN-TU phase 3 clinical trials, topline results\u2013news https:\/\/www.alz.org\/news\/2020\/dian-tu-phase-3-clinical-trials-topline-results (2020)."},{"key":"533_CR75","unstructured":"Eisai Co. Ltd. Eisai and Biogen announce presentation of additional data from the phase II clinical trial of BAN2401 in early Alzheimer\u2019s disease and the 2018 Clinical Trials on Alzheimer\u2019s Disease (CTAD) Conference https:\/\/www.eisai.com\/news\/2018\/news201892.html (2018)."},{"key":"533_CR76","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1016\/S1474-4422(11)70156-9","volume":"10","author":"ME Murray","year":"2011","unstructured":"Murray, M. E. et al. Neuropathologically defined subtypes of Alzheimer\u2019s disease with distinct clinical characteristics: a retrospective study. Lancet Neurol. 10, 785\u2013796 (2011).","journal-title":"Lancet Neurol."},{"key":"533_CR77","doi-asserted-by":"crossref","first-page":"862","DOI":"10.1016\/j.jalz.2016.01.010","volume":"12","author":"JM Schott","year":"2016","unstructured":"Schott, J. M. et al. Genetic risk factors for the posterior cortical atrophy variant of Alzheimer\u2019s disease. Alzheimers Dement. 12, 862\u2013871 (2016).","journal-title":"Alzheimers Dement."},{"key":"533_CR78","doi-asserted-by":"crossref","first-page":"1455","DOI":"10.1212\/WNL.0000000000000335","volume":"82","author":"MM Carrasquillo","year":"2014","unstructured":"Carrasquillo, M. M. et al. Late-onset Alzheimer disease genetic variants in posterior cortical atrophy and posterior AD. Neurology 82, 1455\u20131462 (2014).","journal-title":"Neurology"},{"key":"533_CR79","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1001\/jamaneurol.2018.0395","volume":"75","author":"ZA Miller","year":"2018","unstructured":"Miller, Z. A. et al. Prevalence of mathematical and visuospatial learning disabilities in patients with posterior cortical atrophy. JAMA Neurol. 75, 728\u2013737 (2018).","journal-title":"JAMA Neurol."},{"key":"533_CR80","doi-asserted-by":"crossref","first-page":"3461","DOI":"10.1093\/brain\/awt242","volume":"136","author":"ZA Miller","year":"2013","unstructured":"Miller, Z. A. et al. Handedness and language learning disability differentially distribute in progressive aphasia variants. Brain 136, 3461\u20133473 (2013).","journal-title":"Brain"},{"key":"533_CR81","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1056\/NEJMoa1202753","volume":"367","author":"RJ Bateman","year":"2012","unstructured":"Bateman, R. J. et al. Clinical and biomarker changes in dominantly inherited Alzheimer\u2019s disease. N. Engl. J. Med. 367, 795\u2013804 (2012).","journal-title":"N. Engl. J. Med."},{"key":"533_CR82","doi-asserted-by":"crossref","first-page":"1281","DOI":"10.1016\/j.jalz.2018.04.011","volume":"14","author":"BJ Hanseeuw","year":"2018","unstructured":"Hanseeuw, B. J. et al. PET staging of amyloidosis using striatum. Alzheimers Dement. 14, 1281\u20131292 (2018).","journal-title":"Alzheimers Dement."},{"key":"533_CR83","doi-asserted-by":"crossref","first-page":"1282","DOI":"10.1126\/science.1105681","volume":"307","author":"GB Stokin","year":"2005","unstructured":"Stokin, G. B. et al. Axonopathy and transport deficits early in the pathogenesis of Alzheimer\u2019s diseases. Science 307, 1282\u20131288 (2005).","journal-title":"Science"},{"key":"533_CR84","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1038\/nrn2808","volume":"11","author":"VE Johnson","year":"2010","unstructured":"Johnson, V. E., Stewart, W. & Smith, D. H. Traumatic brain injury and amyloid-\u03b2 pathology: a link to alzheimer\u2019s disease? Nat. Rev. Neurosci. 11, 361\u2013370 (2010).","journal-title":"Nat. Rev. Neurosci."},{"key":"533_CR85","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1016\/j.expneurol.2004.06.011","volume":"190","author":"MD Ikonomovic","year":"2004","unstructured":"Ikonomovic, M. D. et al. Alzheimer\u2019s pathology in human temporal cortex surgically excised after severe brain injury. Exp. Neurol. 190, 192\u2013203 (2004).","journal-title":"Exp. Neurol."},{"key":"533_CR86","doi-asserted-by":"crossref","first-page":"1422","DOI":"10.1016\/0140-6736(91)92724-G","volume":"338","author":"GW Roberts","year":"1991","unstructured":"Roberts, G. W., Gentleman, S. M., Lynch, A. & Graham, D. I. \u03b2A4 amyloid protein deposition in brain after head trauma. Lancet 338, 1422\u20131423 (1991).","journal-title":"Lancet"},{"key":"533_CR87","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1016\/S1474-4422(10)70159-9","volume":"9","author":"MN Rossor","year":"2010","unstructured":"Rossor, M. N., Fox, N. C., Mummery, C. J., Schott, J. M. & Warren, J. D. The diagnosis of young-onset dementia. Lancet Neurol. 9, 793\u2013806 (2010).","journal-title":"Lancet Neurol."},{"key":"533_CR88","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1212\/WNL.0000000000000596","volume":"83","author":"DC Ryman","year":"2014","unstructured":"Ryman, D. C. et al. Symptom onset in autosomal dominant Alzheimer disease: a systematic review and meta-analysis. Neurology 83, 253\u2013260 (2014).","journal-title":"Neurology"},{"key":"533_CR89","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1186\/s13195-020-00765-5","volume":"13","author":"JS Sanchez","year":"2021","unstructured":"Sanchez, J. S. et al. Longitudinal amyloid and tau accumulation in autosomal dominant Alzheimer\u2019s disease: findings from the Colombia-Boston (COLBOS) biomarker study. Alzheimers Res. Ther. 13, 27 (2021).","journal-title":"Alzheimers Res. Ther."},{"key":"533_CR90","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/S1474-4422(18)30028-0","volume":"17","author":"BA Gordon","year":"2018","unstructured":"Gordon, B. A. et al. Spatial patterns of neuroimaging biomarker change in individuals from families with autosomal dominant Alzheimer\u2019s disease: a longitudinal study. Lancet Neurol. 17, 241\u2013250 (2018).","journal-title":"Lancet Neurol."},{"key":"533_CR91","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1093\/brain\/awz019","volume":"142","author":"BA Gordon","year":"2019","unstructured":"Gordon, B. A. et al. Tau PET in autosomal dominant Alzheimer\u2019s disease: relationship with cognition, dementia and other biomarkers. Brain 142, 1063\u20131076 (2019).","journal-title":"Brain"},{"key":"533_CR92","doi-asserted-by":"crossref","first-page":"1425","DOI":"10.1212\/WNL.0b013e3182a841c6","volume":"81","author":"DM Cash","year":"2013","unstructured":"Cash, D. M. et al. The pattern of atrophy in familial Alzheimer disease: volumetric MRI results from the DIAN study. Neurology 81, 1425\u20131433 (2013).","journal-title":"Neurology"},{"key":"533_CR93","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1186\/s40478-020-0891-3","volume":"8","author":"GM Lloyd","year":"2020","unstructured":"Lloyd, G. M. et al. Prominent amyloid plaque pathology and cerebral amyloid angiopathy in APP V717I (London) carrier - phenotypic variability in autosomal dominant Alzheimer\u2019s disease. Acta Neuropathol. Commun. 8, 31 (2020).","journal-title":"Acta Neuropathol. Commun."},{"key":"533_CR94","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1007\/s00702-018-1850-z","volume":"125","author":"S Sutovsky","year":"2018","unstructured":"Sutovsky, S. et al. Neuropathology and biochemistry of early onset familial Alzheimer\u2019s disease caused by presenilin-1 missense mutation Thr116Asn. J. Neural Transm. 125, 965\u2013976 (2018).","journal-title":"J. Neural Transm."},{"key":"533_CR95","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1093\/jnen\/nlz039","volume":"78","author":"DD Gondim","year":"2019","unstructured":"Gondim, D. D. et al. Diffuse Lewy body disease and Alzheimer disease: neuropathologic phenotype associated with the PSEN1 p.A396T mutation. J. Neuropathol. Exp. Neurol. 78, 585\u2013594 (2019).","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"533_CR96","doi-asserted-by":"crossref","first-page":"1365","DOI":"10.1016\/S0002-9440(10)65722-7","volume":"153","author":"CF Lippa","year":"1998","unstructured":"Lippa, C. F. et al. Lewy bodies contain altered \u03b1-synuclein in brains of many familial Alzheimer\u2019s disease patients with mutations in presenilin and amyloid precursor protein genes. Am. J. Pathol. 153, 1365\u20131370 (1998).","journal-title":"Am. J. Pathol."},{"key":"533_CR97","first-page":"1257","volume":"148","author":"D Mann","year":"1996","unstructured":"Mann, D. et al. Predominant deposition of amyloid-beta 42(43) in plaques in cases of Alzheimer\u2019s disease and hereditary cerebral hemorrhage associated with mutations in the amyloid precursor protein gene. Am. J. Pathol. 148, 1257\u20131266 (1996).","journal-title":"Am. J. Pathol."},{"key":"533_CR98","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1002\/ana.410400205","volume":"40","author":"DMA Mann","year":"1996","unstructured":"Mann, D. M. A. et al. Amyloid \u03b2 protein (A\u03b2) deposition in chromosome 14-linked Alzheimer\u2019s disease: predominance of A\u03b2(42(43)). Ann. Neurol. 40, 149\u2013156 (1996).","journal-title":"Ann. Neurol."},{"key":"533_CR99","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1111\/nan.12445","volume":"44","author":"R Taipa","year":"2018","unstructured":"Taipa, R. et al. Inflammatory pathology markers (activated microglia and reactive astrocytes) in early and late onset Alzheimer disease: a post mortem study. Neuropathol. Appl. Neurobiol. 44, 298\u2013313 (2018).","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"533_CR100","doi-asserted-by":"crossref","first-page":"1326","DOI":"10.1016\/S1474-4422(16)30193-4","volume":"15","author":"NS Ryan","year":"2016","unstructured":"Ryan, N. S. et al. Clinical phenotype and genetic associations in autosomal dominant familial Alzheimer\u2019s disease: a case series. Lancet Neurol. 15, 1326\u20131335 (2016).","journal-title":"Lancet Neurol."},{"key":"533_CR101","doi-asserted-by":"crossref","first-page":"1680","DOI":"10.1038\/s41591-019-0611-3","volume":"25","author":"JF Arboleda-Velasquez","year":"2019","unstructured":"Arboleda-Velasquez, J. F. et al. Resistance to autosomal dominant Alzheimer\u2019s disease in an APOE3 Christchurch homozygote: a case report. Nat. Med. 25, 1680\u20131683 (2019).","journal-title":"Nat. Med."},{"key":"533_CR102","doi-asserted-by":"crossref","first-page":"117143","DOI":"10.1016\/j.jns.2020.117143","volume":"418","author":"CE Yu","year":"2020","unstructured":"Yu, C. E., Chen, S., Jayadev, S. & Bird, T. Lack of APOE Christchurch variant in five age of onset outliers with PSEN1, PSEN2 Alzheimer\u2019s disease and MAPT frontotemporal dementia. J. Neurol. Sci. 418, 117143 (2020).","journal-title":"J. Neurol. Sci."},{"key":"533_CR103","doi-asserted-by":"crossref","first-page":"1427","DOI":"10.1016\/j.jalz.2018.06.3059","volume":"14","author":"S M\u00fcller","year":"2018","unstructured":"M\u00fcller, S. et al. Relationship between physical activity, cognition, and Alzheimer pathology in autosomal dominant Alzheimer\u2019s disease. Alzheimers Dement. 14, 1427\u20131437 (2018).","journal-title":"Alzheimers Dement."},{"key":"533_CR104","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1038\/s41582-019-0228-7","volume":"15","author":"Y Yamazaki","year":"2019","unstructured":"Yamazaki, Y., Zhao, N., Caulfield, T. R., Liu, C. C. & Bu, G. Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies. Nat. Rev. Neurol. 15, 501\u2013518 (2019).","journal-title":"Nat. Rev. Neurol."},{"key":"533_CR105","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1016\/j.jalz.2018.02.009","volume":"14","author":"N Mattsson","year":"2018","unstructured":"Mattsson, N. et al. Prevalence of the apolipoprotein E \u03b54 allele in amyloid \u03b2 positive subjects across the spectrum of Alzheimer\u2019s disease. Alzheimers Dement. 14, 913\u2013924 (2018).","journal-title":"Alzheimers Dement."},{"key":"533_CR106","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1212\/WNL.46.3.673","volume":"46","author":"RH Myers","year":"1996","unstructured":"Myers, R. H. et al. Apolipoprotein E \u03b54 association with dementia in a population-based study: The Framingham Study. Neurology 46, 673\u2013677 (1996).","journal-title":"Neurology"},{"key":"533_CR107","doi-asserted-by":"crossref","first-page":"964","DOI":"10.1001\/archneur.55.7.964","volume":"55","author":"AJC Slooter","year":"1998","unstructured":"Slooter, A. J. C. et al. Risk estimates of dementia by apolipoprotein E genotypes from a population-based incidence study: The Rotterdam Study. Arch. Neurol. 55, 964\u2013968 (1998).","journal-title":"Arch. Neurol."},{"key":"533_CR108","doi-asserted-by":"crossref","first-page":"820","DOI":"10.1016\/j.neuron.2019.01.056","volume":"101","author":"ME Belloy","year":"2019","unstructured":"Belloy, M. E., Napolioni, V. & Greicius, M. D. A quarter century of APOE and Alzheimer\u2019s disease: progress to date and the path forward. Neuron 101, 820\u2013838 (2019).","journal-title":"Neuron"},{"key":"533_CR109","doi-asserted-by":"crossref","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":"533_CR110","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1146\/annurev.med.47.1.387","volume":"47","author":"AD Roses","year":"1996","unstructured":"Roses, A. D. Apolipoprotein E alleles as risk factors in Alzheimer\u2019s disease. Annu. Rev. Med. 47, 387\u2013400 (1996).","journal-title":"Annu. Rev. Med."},{"key":"533_CR111","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1038\/s41588-018-0311-9","volume":"51","author":"IE Jansen","year":"2019","unstructured":"Jansen, I. E. et al. Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer\u2019s disease risk. Nat. Genet. 51, 404\u2013413 (2019).","journal-title":"Nat. Genet."},{"key":"533_CR112","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1038\/ng0594-74","volume":"7","author":"CM Van Duijn","year":"1994","unstructured":"Van Duijn, C. M. et al. Apolipoprotein E4 allele in a population\u2013based study of early\u2013onset Alzheimer\u2019s disease. Nat. Genet. 7, 74\u201378 (1994).","journal-title":"Nat. Genet."},{"key":"533_CR113","doi-asserted-by":"crossref","first-page":"e1538","DOI":"10.1212\/WNL.0000000000010256","volume":"95","author":"LE Collij","year":"2020","unstructured":"Collij, L. E. et al. Multitracer model for staging cortical amyloid deposition using PET imaging. Neurology 95, e1538\u2013e1553 (2020).","journal-title":"Neurology"},{"key":"533_CR114","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1212\/WNL.0b013e31827f0889","volume":"80","author":"R Ossenkoppele","year":"2013","unstructured":"Ossenkoppele, R. et al. Differential effect of APOE genotype on amyloid load and glucose metabolism in AD dementia. Neurology 80, 359\u2013365 (2013).","journal-title":"Neurology"},{"key":"533_CR115","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1136\/jnnp-2013-305858","volume":"85","author":"M Lehmann","year":"2014","unstructured":"Lehmann, M. et al. Greater medial temporal hypometabolism and lower cortical amyloid burden in ApoE4-positive AD patients. J. Neurol. Neurosurg. Psychiatry 85, 266\u2013273 (2014).","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"533_CR116","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.neurobiolaging.2020.06.001","volume":"95","author":"SC Burnham","year":"2020","unstructured":"Burnham, S. C. et al. Impact of APOE-\u03b54 carriage on the onset and rates of neocortical A\u03b2-amyloid deposition. Neurobiol. Aging 95, 46\u201355 (2020).","journal-title":"Neurobiol. Aging"},{"key":"533_CR117","doi-asserted-by":"crossref","first-page":"783","DOI":"10.3233\/JAD-181282","volume":"69","author":"JB Toledo","year":"2019","unstructured":"Toledo, J. B. et al. APOE effect on amyloid-\u03b2 PET spatial distribution, deposition rate, and cut-points. J. Alzheimers Dis. 69, 783\u2013793 (2019).","journal-title":"J. Alzheimers Dis."},{"key":"533_CR118","doi-asserted-by":"crossref","first-page":"9649","DOI":"10.1073\/pnas.90.20.9649","volume":"90","author":"DE Schmechel","year":"1993","unstructured":"Schmechel, D. E. et al. Increased amyloid \u03b2-peptide deposition in cerebral cortex as a consequence of apolipoprotein E genotype in late-onset Alzheimer disease. Proc. Natl Acad. Sci. USA 90, 9649\u20139653 (1993).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"533_CR119","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1111\/j.1749-6632.2000.tb06360.x","volume":"903","author":"JM Olichney","year":"2000","unstructured":"Olichney, J. M. et al. Relationship between severe amyloid angiopathy, apolipoprotein E genotype, and vascular lesions in Alzheimer\u2019s disease. Ann. N. Y. Acad. Sci. 903, 138\u2013143 (2000).","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"533_CR120","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1093\/jnen\/61.3.282","volume":"61","author":"DR Thal","year":"2002","unstructured":"Thal, D. R. et al. Two types of sporadic cerebral amyloid angiopathy. J. Neuropathol. Exp. Neurol. 61, 282\u2013293 (2002).","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"533_CR121","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1007\/s00401-008-0366-2","volume":"115","author":"DR Thal","year":"2008","unstructured":"Thal, D. R., Griffin, W. S. T., de Vos, R. A. I. & Ghebremedhin, E. Cerebral amyloid angiopathy and its relationship to Alzheimer\u2019s disease. Acta Neuropathologica 115, 599\u2013609 (2008).","journal-title":"Acta Neuropathologica"},{"key":"533_CR122","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1007\/s00401-010-0707-9","volume":"120","author":"DR Thal","year":"2010","unstructured":"Thal, D. R. et al. Capillary cerebral amyloid angiopathy identifies a distinct APOE \u03b54-associated subtype of sporadic Alzheimer\u2019s disease. Acta Neuropathol. 120, 169\u2013183 (2010).","journal-title":"Acta Neuropathol."},{"key":"533_CR123","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1038\/s41582-019-0281-2","volume":"16","author":"SM Greenberg","year":"2020","unstructured":"Greenberg, S. M. et al. Cerebral amyloid angiopathy and Alzheimer disease \u2014 one peptide, two pathways. Nat. Rev. Neurol. 16, 30\u201342 (2020).","journal-title":"Nat. Rev. Neurol."},{"key":"533_CR124","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.1001\/jama.2018.12917","volume":"320","author":"R Ossenkoppele","year":"2018","unstructured":"Ossenkoppele, R. et al. Discriminative accuracy of [18F]flortaucipir positron emission tomography for Alzheimer disease vs other neurodegenerative disorders. JAMA 320, 1151\u20131162 (2018).","journal-title":"JAMA"},{"key":"533_CR125","doi-asserted-by":"crossref","first-page":"720","DOI":"10.1093\/brain\/awl377","volume":"130","author":"GB Frisoni","year":"2007","unstructured":"Frisoni, G. B. et al. The topography of grey matter involvement in early and late onset Alzheimer\u2019s disease. Brain 130, 720\u2013730 (2007).","journal-title":"Brain"},{"key":"533_CR126","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1186\/s13195-018-0403-x","volume":"10","author":"N Mattsson","year":"2018","unstructured":"Mattsson, N. et al. Greater tau load and reduced cortical thickness in APOE \u03b54-negative Alzheimer\u2019s disease: a cohort study. Alzheimers Res. Ther. 10, 77 (2018).","journal-title":"Alzheimers Res. Ther."},{"key":"533_CR127","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1186\/s13195-020-00712-4","volume":"12","author":"S Emrani","year":"2020","unstructured":"Emrani, S., Arain, H. A., DeMarshall, C. & Nuriel, T. APOE4 is associated with cognitive and pathological heterogeneity in patients with Alzheimer\u2019s disease: a systematic review. Alzheimers Res. Ther. 12, 141 (2020).","journal-title":"Alzheimers Res. Ther."},{"key":"533_CR128","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1001\/jamaneurol.2019.4421","volume":"77","author":"J Therriault","year":"2020","unstructured":"Therriault, J. et al. Association of apolipoprotein E \u03b54 with medial temporal tau independent of amyloid-\u03b2. JAMA Neurol. 77, 470\u2013479 (2020).","journal-title":"JAMA Neurol."},{"key":"533_CR129","doi-asserted-by":"crossref","first-page":"1825","DOI":"10.1212\/WNL.53.8.1825","volume":"53","author":"C Geroldi","year":"1999","unstructured":"Geroldi, C. et al. APOE-\u03b54 is associated with less frontal and more medial temporal lobe atrophy in AD. Neurology 53, 1825\u20131832 (1999).","journal-title":"Neurology"},{"key":"533_CR130","doi-asserted-by":"crossref","first-page":"1503","DOI":"10.1093\/brain\/awz099","volume":"142","author":"PT Nelson","year":"2019","unstructured":"Nelson, P. T. et al. Limbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report. Brain 142, 1503\u20131527 (2019).","journal-title":"Brain"},{"key":"533_CR131","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1186\/s40478-018-0624-z","volume":"6","author":"D Twohig","year":"2018","unstructured":"Twohig, D. et al. The relevance of cerebrospinal fluid \u03b1-synuclein levels to sporadic and familial Alzheimer\u2019s disease. Acta Neuropathol. Commun. 6, 130 (2018).","journal-title":"Acta Neuropathol. Commun."},{"key":"533_CR132","doi-asserted-by":"crossref","first-page":"e607","DOI":"10.1212\/WNL.0000000000008666","volume":"94","author":"S Weintraub","year":"2020","unstructured":"Weintraub, S. et al. APOE is a correlate of phenotypic heterogeneity in Alzheimer disease in a national cohort. Neurology 94, e607\u2013e612 (2020).","journal-title":"Neurology"},{"key":"533_CR133","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-019-14279-8","volume":"11","author":"EM Reiman","year":"2020","unstructured":"Reiman, E. M. et al. Exceptionally low likelihood of Alzheimer\u2019s dementia in APOE2 homozygotes from a 5,000-person neuropathological study. Nat. Commun. 11, 667 (2020).","journal-title":"Nat. Commun."},{"key":"533_CR134","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1038\/mp.2011.52","volume":"16","author":"E Genin","year":"2011","unstructured":"Genin, E. et al. APOE and Alzheimer disease: a major gene with semi-dominant inheritance. Mol. Psychiatry 16, 903\u2013907 (2011).","journal-title":"Mol. Psychiatry"},{"key":"533_CR135","first-page":"10","volume":"17","author":"C Bellenguez","year":"2020","unstructured":"Bellenguez, C. et al. New insights on the genetic etiology of Alzheimer\u2019s and related dementia. medRxiv 17, 10 (2020).","journal-title":"medRxiv"},{"key":"533_CR136","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1016\/S1474-4422(18)30053-X","volume":"17","author":"SJ van der Lee","year":"2018","unstructured":"van der Lee, S. J. et al. The effect of APOE and other common genetic variants on the onset of Alzheimer\u2019s disease and dementia: a community-based cohort study. Lancet Neurol. 17, 434\u2013444 (2018).","journal-title":"Lancet Neurol."},{"key":"533_CR137","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pmed.1002258","volume":"14","author":"RS Desikan","year":"2017","unstructured":"Desikan, R. S. et al. Genetic assessment of age-associated Alzheimer disease risk: development and validation of a polygenic hazard score. PLoS Med. 14, e1002258 (2017).","journal-title":"PLoS Med."},{"key":"533_CR138","doi-asserted-by":"crossref","first-page":"921","DOI":"10.3233\/JAD-150749","volume":"53","author":"V Chouraki","year":"2016","unstructured":"Chouraki, V. et al. Evaluation of a genetic risk score to improve risk prediction for Alzheimer\u2019s disease. J. Alzheimers Dis. 53, 921\u2013932 (2016).","journal-title":"J. Alzheimers Dis."},{"key":"533_CR139","doi-asserted-by":"crossref","first-page":"1229","DOI":"10.1007\/s10654-018-0451-3","volume":"33","author":"H Holstege","year":"2018","unstructured":"Holstege, H. et al. The 100-plus Study of cognitively healthy centenarians: rationale, design and cohort description. Eur. J. Epidemiol. 33, 1229\u20131249 (2018).","journal-title":"Eur. J. Epidemiol."},{"key":"533_CR140","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1161\/HYPERTENSIONAHA.119.12655","volume":"74","author":"S Laurent","year":"2019","unstructured":"Laurent, S., Boutouyrie, P., Cunha, P. G., Lacolley, P. & Nilsson, P. M. Concept of extremes in vascular aging: from early vascular aging to supernormal vascular aging. Hypertension 74, 218\u2013228 (2019).","journal-title":"Hypertension"},{"key":"533_CR141","doi-asserted-by":"crossref","first-page":"1616","DOI":"10.1161\/HYPERTENSIONAHA.120.14971","volume":"76","author":"RM Bruno","year":"2020","unstructured":"Bruno, R. M. et al. Early and supernormal vascular aging. Hypertension 76, 1616\u20131624 (2020).","journal-title":"Hypertension"},{"key":"533_CR142","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1007\/978-981-13-1117-8_4","volume":"1086","author":"Y-N Ding","year":"2018","unstructured":"Ding, Y.-N., Tang, X., Chen, H.-Z. & Liu, D.-P. Epigenetic regulation of vascular aging and age-related vascular diseases. Adv. Exp. Med. Biol. 1086, 55\u201375 (2018).","journal-title":"Adv. Exp. Med. Biol."},{"key":"533_CR143","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.3233\/JAD-180507","volume":"65","author":"C Dang","year":"2018","unstructured":"Dang, C. et al. Relationship between amyloid-\u03b2 positivity and progression to mild cognitive impairment or dementia over 8 years in cognitively normal older adults. J. Alzheimers Dis. 65, 1313\u20131325 (2018).","journal-title":"J. Alzheimers Dis."},{"key":"533_CR144","doi-asserted-by":"crossref","first-page":"1349","DOI":"10.1001\/jama.1997.03550160069041","volume":"278","author":"L Farrer","year":"1997","unstructured":"Farrer, L. et al. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. JAMA 278, 1349\u20131356 (1997).","journal-title":"JAMA"},{"key":"533_CR145","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pmed.1003289","volume":"17","author":"H Saddiki","year":"2020","unstructured":"Saddiki, H. et al. Age and the association between apolipoprotein E genotype and Alzheimer disease: a cerebrospinal fluid biomarker\u2013based case\u2013control study. PLoS Med. 17, e1003289 (2020).","journal-title":"PLoS Med."},{"key":"533_CR146","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1093\/ageing\/afy155","volume":"48","author":"SM Nelis","year":"2019","unstructured":"Nelis, S. M. et al. The impact of co-morbidity on the quality of life of people with dementia: findings from the IDEAL study. Age Ageing 48, 361\u2013367 (2019).","journal-title":"Age Ageing"},{"key":"533_CR147","doi-asserted-by":"crossref","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 \u03b2-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc. Natl. Acad. Sci. U. S. A. 90, 1977\u20131981 (1993).","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"533_CR148","doi-asserted-by":"crossref","first-page":"1221","DOI":"10.1016\/j.neurobiolaging.2006.05.029","volume":"28","author":"DR Thal","year":"2007","unstructured":"Thal, D. R. et al. Occurrence and co-localization of amyloid \u03b2-protein and apolipoprotein E in perivascular drainage channels of wild-type and APP-transgenic mice. Neurobiol. Aging 28, 1221\u20131230 (2007).","journal-title":"Neurobiol. Aging"},{"key":"533_CR149","doi-asserted-by":"crossref","first-page":"4002","DOI":"10.1172\/JCI36663","volume":"118","author":"R Deane","year":"2008","unstructured":"Deane, R. et al. apoE isoform-specific disruption of amyloid \u03b2 peptide clearance from mouse brain. J. Clin. Invest. 118, 4002\u20134013 (2008).","journal-title":"J. Clin. Invest."},{"key":"533_CR150","doi-asserted-by":"publisher","DOI":"10.1002\/alz.12333","author":"V Damotte","year":"2021","unstructured":"Damotte, V. et al. Plasma amyloid \u03b2 levels are driven by genetic variants near APOE, BACE1, APP, PSEN2: a genome-wide association study in over 12,000 non-demented participants. Alzheimers Dement. https:\/\/doi.org\/10.1002\/alz.12333 (2021).","journal-title":"Alzheimers Dement."},{"key":"533_CR151","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1038\/s41591-018-0004-z","volume":"24","author":"C Wang","year":"2018","unstructured":"Wang, C. et al. Gain of toxic apolipoprotein E4 effects in human iPSC-derived neurons is ameliorated by a small-molecule structure corrector article. Nat. Med. 24, 647\u2013657 (2018).","journal-title":"Nat. Med."},{"key":"533_CR152","volume":"12","author":"AA Davis","year":"2020","unstructured":"Davis, A. A. et al. APOE genotype regulates pathology and disease progression in synucleinopathy. Sci. Transl. Med. 12, eaay3069 (2020).","journal-title":"Sci. Transl. Med."},{"key":"533_CR153","doi-asserted-by":"crossref","DOI":"10.1126\/scitranslmed.aay1809","volume":"12","author":"N Zhao","year":"2020","unstructured":"Zhao, N. et al. APOE4 exacerbates \u03b1-synuclein pathology and related toxicity independent of amyloid. Sci. Transl. Med. 12, eaay1809 (2020).","journal-title":"Sci. Transl. Med."},{"key":"533_CR154","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1016\/S1474-4422(18)30251-5","volume":"17","author":"HS Yang","year":"2018","unstructured":"Yang, H. S. et al. Evaluation of TDP-43 proteinopathy and hippocampal sclerosis in relation to APOE \u03b54 haplotype status: a community-based cohort study. Lancet Neurol. 17, 773\u2013781 (2018).","journal-title":"Lancet Neurol."},{"key":"533_CR155","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41586-020-2247-3","volume":"581","author":"A Montagne","year":"2020","unstructured":"Montagne, A. et al. APOE4 leads to blood\u2013brain barrier dysfunction predicting cognitive decline. Nature 581, 1\u20136 (2020).","journal-title":"Nature"},{"key":"533_CR156","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41591-020-0886-4","volume":"26","author":"JW Blanchard","year":"2020","unstructured":"Blanchard, J. W. et al. Reconstruction of the human blood\u2013brain barrier in vitro reveals a pathogenic mechanism of APOE4 in pericytes. Nat. Med. 26, 1\u201312 (2020).","journal-title":"Nat. Med."},{"key":"533_CR157","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1007\/s00401-018-1834-y","volume":"135","author":"M Hecht","year":"2018","unstructured":"Hecht, M., Kr\u00e4mer, L. M., von Arnim, C. A. F., Otto, M. & Thal, D. R. Capillary cerebral amyloid angiopathy in Alzheimer\u2019s disease: association with allocortical\/hippocampal microinfarcts and cognitive decline. Acta Neuropathol. 135, 681\u2013694 (2018).","journal-title":"Acta Neuropathol."},{"key":"533_CR158","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1001\/jamaneurol.2013.4544","volume":"71","author":"DC Dean","year":"2014","unstructured":"Dean, D. C. et al. Brain differences in infants at differential genetic risk for late-onset Alzheimer disease: a cross-sectional imaging study. JAMA Neurol. 71, 11\u201322 (2014).","journal-title":"JAMA Neurol."},{"key":"533_CR159","doi-asserted-by":"crossref","first-page":"752","DOI":"10.1056\/NEJM199603213341202","volume":"334","author":"EM Reiman","year":"1996","unstructured":"Reiman, E. M. et al. Preclinical evidence of Alzheimer\u2019s disease in persons homozygous for the \u03b54 allele for apolipoprotein E. N. Engl. J. Med. 334, 752\u2013758 (1996).","journal-title":"N. Engl. J. Med."},{"key":"533_CR160","volume":"10","author":"SL Evans","year":"2020","unstructured":"Evans, S. L. et al. Mid age APOE \u03b54 carriers show memory-related functional differences and disrupted structure-function relationships in hippocampal regions. Sci. Rep. 10, 3110 (2020).","journal-title":"Sci. Rep."},{"key":"533_CR161","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1073\/pnas.2635903100","volume":"101","author":"EM Reiman","year":"2004","unstructured":"Reiman, E. M. et al. Functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer\u2019s dementia. Proc. Natl Acad. Sci. USA 101, 284\u2013289 (2004).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"533_CR162","doi-asserted-by":"crossref","first-page":"447","DOI":"10.2174\/156720512800492549","volume":"9","author":"M Reale,","year":"2012","unstructured":"Reale,, M. et al. Relationship between inflammatory mediators, A\u03b2 levels and ApoE genotype in Alzheimer disease. Curr. Alzheimer Res. 9, 447\u2013457 (2012).","journal-title":"Curr. Alzheimer Res."},{"key":"533_CR163","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1111\/j.1749-6632.2010.05726.x","volume":"1207","author":"PB Gorelick","year":"2010","unstructured":"Gorelick, P. B. Role of inflammation in cognitive impairment: results of observational epidemiological studies and clinical trials. Ann. N. Y. Acad. Sci. 1207, 155\u2013162 (2010).","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"533_CR164","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1016\/j.jalz.2019.03.007","volume":"15","author":"AR Morgan","year":"2019","unstructured":"Morgan, A. R. et al. Inflammatory biomarkers in Alzheimer\u2019s disease plasma. Alzheimers Dement. 15, 776\u2013787 (2019).","journal-title":"Alzheimers Dement."},{"key":"533_CR165","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.neurobiolaging.2016.08.019","volume":"49","author":"A Cattaneo","year":"2017","unstructured":"Cattaneo, A. et al. Association of brain amyloidosis with pro-inflammatory gut bacterial taxa and peripheral inflammation markers in cognitively impaired elderly. Neurobiol. Aging 49, 60\u201368 (2017).","journal-title":"Neurobiol. Aging"},{"key":"533_CR166","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1016\/S1474-4422(15)70016-5","volume":"14","author":"MT Heneka","year":"2015","unstructured":"Heneka, M. T. et al. Neuroinflammation in Alzheimer\u2019s disease. Lancet Neurol. 14, 388\u2013405 (2015).","journal-title":"Lancet Neurol."},{"key":"533_CR167","doi-asserted-by":"crossref","DOI":"10.1038\/s41598-020-59869-5","volume":"10","author":"JS Friedberg","year":"2020","unstructured":"Friedberg, J. S. et al. Associations between brain inflammatory profiles and human neuropathology are altered based on apolipoprotein E \u03b54 genotype. Sci. Rep. 10, 29624 (2020).","journal-title":"Sci. Rep."},{"key":"533_CR168","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1097\/00005072-199703000-00007","volume":"56","author":"J Sheng","year":"1997","unstructured":"Sheng, J., Mrak, R. & Griffin, W. Glial-neuronal interactions in Alzheimer disease: progressive association of IL-1alpha+ microglia and S100beta+ astrocytes with neurofibrillary tangle stages. J. Neuropathol. Exp. Neurol. 56, 285\u2013290 (1997).","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"533_CR169","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1097\/00005072-199503000-00014","volume":"54","author":"WST Griffin","year":"1995","unstructured":"Griffin, W. S. T., Sheng, J. G., Roberts, G. W. & Mrak, R. E. Interleukin-1 expression in different plaque types in Alzheimer\u2019s disease significance in plaque evolution. J. Neuropathol. Exp. Neurol. 54, 276\u2013281 (1995).","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"533_CR170","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1016\/S0197-4580(00)00124-X","volume":"21","author":"H Akiyama","year":"2000","unstructured":"Akiyama, H. et al. Inflammation and Alzheimer\u2019s disease. Neurobiol. Aging 21, 383\u2013421 (2000).","journal-title":"Neurobiol. Aging"},{"key":"533_CR171","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)32205-4","author":"P Scheltens","year":"2021","unstructured":"Scheltens, P. et al. Alzheimer\u2019s disease. Lancet https:\/\/doi.org\/10.1016\/S0140-6736(20)32205-4 (2021).","journal-title":"Lancet"},{"key":"533_CR172","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1001\/archpsyc.63.2.168","volume":"63","author":"M Gatz","year":"2006","unstructured":"Gatz, M. et al. Role of genes and environments for explaining Alzheimer disease. Arch. Gen. Psychiatry 63, 168\u2013174 (2006).","journal-title":"Arch. Gen. Psychiatry"},{"key":"533_CR173","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1016\/S0140-6736(20)30367-6","volume":"396","author":"G Livingston","year":"2020","unstructured":"Livingston, G. et al. Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. Lancet 396, 413\u2013446 (2020).","journal-title":"Lancet"},{"key":"533_CR174","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1038\/s41593-020-0599-5","volume":"23","author":"R Sims","year":"2020","unstructured":"Sims, R., Hill, M. & Williams, J. The multiplex model of the genetics of Alzheimer\u2019s disease. Nat. Neurosci. 23, 311\u2013322 (2020).","journal-title":"Nat. Neurosci."},{"key":"533_CR175","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":"533_CR176","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1038\/s41593-020-0650-6","volume":"23","author":"BJ Andreone","year":"2020","unstructured":"Andreone, B. J. et al. Alzheimer\u2019s-associated PLC\u03b32 is a signaling node required for both TREM2 function and the inflammatory response in human microglia. Nat. Neurosci. 23, 927\u2013938 (2020).","journal-title":"Nat. Neurosci."},{"key":"533_CR177","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1016\/j.neuron.2019.12.007","volume":"105","author":"AA Nugent","year":"2020","unstructured":"Nugent, A. A. et al. TREM2 regulates microglial cholesterol metabolism upon chronic phagocytic challenge. Neuron 105, 837\u2013854.e9 (2020).","journal-title":"Neuron"},{"key":"533_CR178","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1007\/s00401-019-01994-1","volume":"138","author":"A De Roeck","year":"2019","unstructured":"De Roeck, A., Van Broeckhoven, C. & Sleegers, K. The role of ABCA7 in Alzheimer\u2019s disease: evidence from genomics, transcriptomics and methylomics. Acta Neuropathol. 138, 201\u2013220 (2019).","journal-title":"Acta Neuropathol."},{"key":"533_CR179","doi-asserted-by":"crossref","first-page":"1373","DOI":"10.1038\/ng.3916","volume":"49","author":"R Sims","year":"2017","unstructured":"Sims, R. et al. Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer\u2019s disease. Nat. Genet. 49, 1373\u20131384 (2017).","journal-title":"Nat. Genet."},{"key":"533_CR180","doi-asserted-by":"crossref","first-page":"762","DOI":"10.1016\/j.bbalip.2010.05.009","volume":"1801","author":"MA Wollmer","year":"2010","unstructured":"Wollmer, M. A. Cholesterol-related genes in Alzheimer\u2019s disease. Biochim. Biophys. Acta 1801, 762\u2013773 (2010).","journal-title":"Biochim. Biophys. Acta"},{"key":"533_CR181","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1016\/S1474-4422(16)00127-7","volume":"15","author":"E Cuyvers","year":"2016","unstructured":"Cuyvers, E. & Sleegers, K. Genetic variations underlying Alzheimer\u2019s disease: Evidence from genome-wide association studies and beyond. Lancet Neurol. 15, 857\u2013868 (2016).","journal-title":"Lancet Neurol."},{"key":"533_CR182","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1038\/s41588-019-0358-2","volume":"51","author":"BW Kunkle","year":"2019","unstructured":"Kunkle, B. W. et al. Genetic meta-analysis of diagnosed Alzheimer\u2019s disease identifies new risk loci and implicates A\u03b2, tau, immunity and lipid processing. Nat. Genet. 51, 414\u2013430 (2019).","journal-title":"Nat. Genet."},{"key":"533_CR183","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1007\/s00401-019-02026-8","volume":"138","author":"SJ van der Lee","year":"2019","unstructured":"van der Lee, S. J. et al. A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer\u2019s disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity. Acta Neuropathol. 138, 237\u2013250 (2019).","journal-title":"Acta Neuropathol."},{"key":"533_CR184","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1186\/s13195-019-0469-0","volume":"11","author":"L Magno","year":"2019","unstructured":"Magno, L. et al. Alzheimer\u2019s disease phospholipase C-gamma-2 (PLCG2) protective variant is a functional hypermorph. Alzheimers Res. Ther. 11, 16 (2019).","journal-title":"Alzheimers Res. Ther."},{"key":"533_CR185","volume":"6","author":"SS Jiao","year":"2016","unstructured":"Jiao, S. S. et al. Brain-derived neurotrophic factor protects against tau-related neurodegeneration of Alzheimer\u2019s disease. Transl. Psychiatry 6, e907 (2016).","journal-title":"Transl. Psychiatry"},{"key":"533_CR186","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1001\/jamaneurol.2020.0414","volume":"77","author":"ME Belloy","year":"2020","unstructured":"Belloy, M. E., Napolioni, V., Han, S. S., Le Guen, Y. & Greicius, M. D. Association of Klotho-VS heterozygosity with risk of Alzheimer disease in individuals who carry APOE4. JAMA Neurol. 77, 849\u2013862 (2020).","journal-title":"JAMA Neurol."},{"key":"533_CR187","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1186\/alzrt247","volume":"6","author":"J-I Satoh","year":"2014","unstructured":"Satoh, J.-I. et al. TMEM106B expression is reduced in Alzheimer\u2019s disease brains. Alzheimers. Res. Ther. 6, 17 (2014).","journal-title":"Alzheimers. Res. Ther."},{"key":"533_CR188","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1016\/j.jalz.2013.12.022","volume":"10","author":"TJ Hohman","year":"2014","unstructured":"Hohman, T. J., Koran, M. E. I. & Thornton-Wells, T. A. Genetic modification of the relationship between phosphorylated tau and neurodegeneration. Alzheimers Dement. 10, 637\u2013645.e1 (2014).","journal-title":"Alzheimers Dement."},{"key":"533_CR189","doi-asserted-by":"crossref","first-page":"1364","DOI":"10.1038\/s41591-019-0547-7","volume":"25","author":"S Licher","year":"2019","unstructured":"Licher, S. et al. Genetic predisposition, modifiable-risk-factor profile and long-term dementia risk in the general population. Nat. Med. 25, 1364\u20131369 (2019).","journal-title":"Nat. Med."},{"key":"533_CR190","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1001\/jama.2019.9879","volume":"322","author":"I Lourida","year":"2019","unstructured":"Lourida, I. et al. Association of lifestyle and genetic risk with incidence of dementia. JAMA 322, 430\u2013437 (2019).","journal-title":"JAMA"},{"key":"533_CR191","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1001\/jamaneurol.2017.4365","volume":"75","author":"A Solomon","year":"2018","unstructured":"Solomon, A. et al. Effect of the apolipoprotein E genotype on cognitive change during a multidomain lifestyle intervention a subgroup analysis of a randomized clinical trial. JAMA Neurol. 75, 462\u2013470 (2018).","journal-title":"JAMA Neurol."},{"key":"533_CR192","doi-asserted-by":"crossref","first-page":"954","DOI":"10.1111\/jam.14264","volume":"127","author":"M Bostanciklio\u011flu","year":"2019","unstructured":"Bostanciklio\u011flu, M. The role of gut microbiota in pathogenesis of Alzheimer\u2019s disease. J. Appl. Microbiol. 127, 954\u2013967 (2019).","journal-title":"J. Appl. Microbiol."},{"key":"533_CR193","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1097\/WCO.0000000000000496","volume":"30","author":"M Marizzoni","year":"2017","unstructured":"Marizzoni, M., Provasi, S., Cattaneo, A. & Frisoni, G. B. Microbiota and neurodegenerative diseases. Curr. Opin. Neurol. 30, 630\u2013638 (2017).","journal-title":"Curr. Opin. Neurol."},{"key":"533_CR194","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/S1474-4422(19)30356-4","volume":"19","author":"JF Cryan","year":"2020","unstructured":"Cryan, J. F., O\u2019Riordan, K. J., Sandhu, K., Peterson, V. & Dinan, T. G. The gut microbiome in neurological disorders. Lancet Neurol. 19, 179\u2013194 (2020).","journal-title":"Lancet Neurol."},{"key":"533_CR195","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1212\/WNL.0000000000005303","volume":"90","author":"EM Arenaza-Urquijo","year":"2018","unstructured":"Arenaza-Urquijo, E. M. & Vemuri, P. Resistance vs resilience to Alzheimer disease. Neurology 90, 695\u2013703 (2018).","journal-title":"Neurology"},{"key":"533_CR196","doi-asserted-by":"crossref","first-page":"2561","DOI":"10.1093\/brain\/awaa209","volume":"143","author":"L Dumitrescu","year":"2020","unstructured":"Dumitrescu, L. et al. Genetic variants and functional pathways associated with resilience to Alzheimer\u2019s disease. Brain 143, 2561\u20132575 (2020).","journal-title":"Brain"},{"key":"533_CR197","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1111\/acel.12480","volume":"15","author":"VN Gladyshev","year":"2016","unstructured":"Gladyshev, V. N. Aging: progressive decline in fitness due to the rising deleteriome adjusted by genetic, environmental, and stochastic processes. Aging Cell 15, 594\u2013602 (2016).","journal-title":"Aging Cell"},{"key":"533_CR198","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1038\/s41586-018-0457-8","volume":"561","author":"L Partridge","year":"2018","unstructured":"Partridge, L., Deelen, J. & Slagboom, P. E. Facing up to the global challenges of ageing. Nature 561, 45\u201356 (2018).","journal-title":"Nature"},{"key":"533_CR199","doi-asserted-by":"crossref","first-page":"808","DOI":"10.1038\/nature01135","volume":"419","author":"LA Herndon","year":"2002","unstructured":"Herndon, L. A. et al. Stochastic and genetic factors influence tissue-specific decline in ageing C. Elegans. Nature 419, 808\u2013814 (2002).","journal-title":"Nature"},{"key":"533_CR200","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1111\/j.1558-5646.1957.tb02911.x","volume":"11","author":"GC Williams","year":"1957","unstructured":"Williams, G. C. Pleiotropy, natural selection, and the evolution of senescence. Evolution 11, 398\u2013411 (1957).","journal-title":"Evolution"},{"key":"533_CR201","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1002\/ana.24135","volume":"75","author":"A Altmann","year":"2014","unstructured":"Altmann, A., Tian, L., Henderson, V. W. & Greicius, M. D. Sex modifies the APOE-related risk of developing Alzheimer disease. Ann. Neurol. 75, 563\u2013573 (2014).","journal-title":"Ann. Neurol."},{"key":"533_CR202","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1016\/j.neurobiolaging.2018.04.004","volume":"70","author":"DW Fisher","year":"2018","unstructured":"Fisher, D. W., Bennett, D. A. & Dong, H. Sexual dimorphism in predisposition to Alzheimer\u2019s disease. Neurobiol. Aging 70, 308\u2013324 (2018).","journal-title":"Neurobiol. Aging"},{"key":"533_CR203","doi-asserted-by":"crossref","first-page":"1362","DOI":"10.1111\/ene.13987","volume":"26","author":"S Shen","year":"2019","unstructured":"Shen, S., Zhou, W., Chen, X. & Zhang, J. Sex differences in the association of APOE \u03b54 genotype with longitudinal hippocampal atrophy in cognitively normal older people. Eur. J. Neurol. 26, 1362\u20131369 (2019).","journal-title":"Eur. J. Neurol."},{"key":"533_CR204","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1001\/jamaneurol.2018.4249","volume":"76","author":"JC Morris","year":"2019","unstructured":"Morris, J. C. et al. Assessment of racial disparities in biomarkers for Alzheimer disease. JAMA Neurol. 76, 264\u2013273 (2019).","journal-title":"JAMA Neurol."},{"key":"533_CR205","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1186\/s13024-020-0358-9","volume":"15","author":"T Williams","year":"2020","unstructured":"Williams, T., Borchelt, D. R. & Chakrabarty, P. Therapeutic approaches targeting Apolipoprotein e function in Alzheimer\u2019s disease. Mol. Neurodegener. 15, 8 (2020).","journal-title":"Mol. Neurodegener."},{"key":"533_CR206","doi-asserted-by":"crossref","DOI":"10.1126\/scitranslmed.abd7522","volume":"13","author":"M Xiong","year":"2021","unstructured":"Xiong, M. et al. APOE immunotherapy reduces cerebral amyloid angiopathy and amyloid plaques while improving cerebrovascular function. Sci. Transl. Med. 13, eabd7522 (2021).","journal-title":"Sci. Transl. Med."},{"key":"533_CR207","doi-asserted-by":"crossref","first-page":"1161","DOI":"10.1001\/jamainternmed.2019.2629","volume":"179","author":"KM Langa","year":"2019","unstructured":"Langa, K. M. & Burke, J. F. Preclinical Alzheimer disease - early diagnosis or overdiagnosis? JAMA Intern. Med. 179, 1161\u20131162 (2019).","journal-title":"JAMA Intern. Med."},{"key":"533_CR208","doi-asserted-by":"crossref","first-page":"1180","DOI":"10.1212\/WNL.0b013e318289714a","volume":"80","author":"GA Jicha","year":"2013","unstructured":"Jicha, G. A. & Rentz, D. M. Cognitive and brain reserve and the diagnosis and treatment of preclinical Alzheimer disease. Neurology 80, 1180\u20131181 (2013).","journal-title":"Neurology"},{"key":"533_CR209","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1016\/S1474-4422(19)30323-0","volume":"18","author":"GB Frisoni","year":"2019","unstructured":"Frisoni, G. B. et al. Re-aligning scientific and lay narratives of Alzheimer\u2019s disease. Lancet Neurol. 18, 918\u2013919 (2019).","journal-title":"Lancet Neurol."},{"key":"533_CR210","doi-asserted-by":"publisher","DOI":"10.1002\/alz.12132","author":"GB Frisoni","year":"2020","unstructured":"Frisoni, G. B. et al. Precision prevention of Alzheimer\u2019s and other dementias: anticipating future needs in the control of risk factors and implementation of disease-modifying therapies. Alzheimers Dement. https:\/\/doi.org\/10.1002\/alz.12132 (2020).","journal-title":"Alzheimers Dement."},{"key":"533_CR211","doi-asserted-by":"crossref","first-page":"73","DOI":"10.2147\/CIA.S159148","volume":"14","author":"JP Tavana","year":"2019","unstructured":"Tavana, J. P. et al. RAB10: an Alzheimer\u2019s disease resilience locus and potential drug target. Clin. Interv. Aging 14, 73\u201379 (2019).","journal-title":"Clin. Interv. Aging"},{"key":"533_CR212","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1016\/j.nbd.2018.10.009","volume":"121","author":"I Barroeta-Espar","year":"2019","unstructured":"Barroeta-Espar, I. et al. Distinct cytokine profiles in human brains resilient to Alzheimer\u2019s pathology. Neurobiol. Dis. 121, 327\u2013337 (2019).","journal-title":"Neurobiol. Dis."},{"key":"533_CR213","volume":"6","author":"J Cummings","year":"2020","unstructured":"Cummings, J., Lee, G., Ritter, A., Sabbagh, M. & Zhong, K. Alzheimer\u2019s disease drug development pipeline: 2020. Alzheimers Dement. Transl. Res. Clin. Interv. 6, e12050 (2020).","journal-title":"Alzheimers Dement. Transl. Res. Clin. Interv."},{"key":"533_CR214","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/S1474-4422(18)30039-5","volume":"17","author":"C Ballard","year":"2018","unstructured":"Ballard, C. et al. Evaluation of the safety, tolerability, and efficacy of pimavanserin versus placebo in patients with Alzheimer\u2019s disease psychosis: a phase 2, randomised, placebo-controlled, double-blind study. Lancet Neurol. 17, 213\u2013222 (2018).","journal-title":"Lancet Neurol."},{"key":"533_CR215","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1111\/j.1582-4934.2008.00225.x","volume":"12","author":"K Iqbal","year":"2008","unstructured":"Iqbal, K. & Grundke-Iqbal, I. Alzheimer neurofibrillary degeneration: significance, etiopathogenesis, therapeutics and prevention. J. Cell. Mol. Med. 12, 38\u201355 (2008).","journal-title":"J. Cell. Mol. Med."},{"key":"533_CR216","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.jalz.2018.08.005","volume":"15","author":"DP Veitch","year":"2019","unstructured":"Veitch, D. P. et al. Understanding disease progression and improving Alzheimer\u2019s disease clinical trials: recent highlights from the Alzheimer\u2019s Disease Neuroimaging Initiative. Alzheimers Dement. 15, 106\u2013152 (2019).","journal-title":"Alzheimers Dement."},{"key":"533_CR217","doi-asserted-by":"crossref","first-page":"101716","DOI":"10.1016\/j.pneurobio.2019.101716","volume":"184","author":"PJ Derry","year":"2020","unstructured":"Derry, P. J. et al. Revisiting the intersection of amyloid, pathologically modified tau and iron in Alzheimer\u2019s disease from a ferroptosis perspective. Prog. Neurobiol. 184, 101716 (2020).","journal-title":"Prog. Neurobiol."}],"container-title":["Nature Reviews Neuroscience"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41583-021-00533-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41583-021-00533-w","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41583-021-00533-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,12,16]],"date-time":"2021-12-16T09:28:42Z","timestamp":1639646922000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41583-021-00533-w"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,23]]},"references-count":217,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2022,1]]}},"alternative-id":["533"],"URL":"https:\/\/doi.org\/10.1038\/s41583-021-00533-w","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.741216194.793590634","asserted-by":"object"}]},"ISSN":["1471-003X","1471-0048"],"issn-type":[{"value":"1471-003X","type":"print"},{"value":"1471-0048","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,23]]},"assertion":[{"value":"4 October 2021","order":1,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 November 2021","order":2,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"G.B.F. has received grants from Avid Radiopharmaceuticals, Biogen, GE International, Guerbert, IXICO, Merz Pharma, Nestl\u00e9, Novartis, Eisai, Piramal, Roche, Siemens, Teva Pharmaceutical Industries and Vifor Pharma. He has received personal fees from AstraZeneca, Avid Radiopharmaceuticals, Biogen, Roche, Diadem, Neurodiem, Elan Pharmaceuticals, GE International, Lundbeck, Pfizer and TauRx Therapeutics. D.R.T. has received speaker honoraria from Novartis Pharma Basel (Switzerland) and Biogen (USA), has received travel reimbursement from GE Healthcare (UK), and UCB (Belgium) and has collaborated with GE Healthcare (UK), Novartis Pharma Basel (Switzerland), Probiodrug (Germany) and Janssen Pharmaceuticals (Belgium). K.B. has served as a consultant, on advisory boards or on data monitoring committees for Abcam, Axon, Biogen, Shimadzu, Julius Clinical, Lilly, MagQu, Novartis, Roche Diagnostics and Siemens Healthineers, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB, which is part of the GU Ventures incubator programme. J.C. has acted as a consultant for Acadia, Actinogen, Alkahest, Alzheon, Annovis, Avanir, Axsome, Biogen, Cassava, Cerecin, Cerevel, Cortexyme, Cytox, EIP Pharma, Eisai, Foresight, GemVax, Genentech, Green Valley, Grifols, Karuna, Merck, Novo Nordisk, Otsuka, Resverlogix, Roche, Samumed, Samus, Signant Health, Suven and United Neuroscience. J.C. also has stock options in ADAMAS, AnnovisBio, MedAvante and BiOasis, and owns the copyright of the Neuropsychiatric Inventory. P.S. has received consultancy fees (paid to Amsterdam UMC) from AC Immune, Brainstorm Cell, EIP, ImmunoBrain Checkpoint, Genentech, Novartis, and Novo Noridisk. He is a principal investigator on studies with AC Immune, FUJIFILM Toyama, UCB, and Vivoryon. He is a part-time employee of Life Sciences Partners Amsterdam. B.D. has received research funding (paid to the institution) from Merck-Avenir Foundation and Roche and consultancy fees from Biogen, Neurodiem, Green Valley, Cytox and Brainstorm. He is a principal investigator on clinical trials with Eisai, Genentech, Novartis, Biogen and Roche. D.A., F.R., R.v.d.K., R.O., C.v.D., P.M.N. and P.-Y.D. declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}