{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T15:02:57Z","timestamp":1793458977780,"version":"4.5.0"},"reference-count":277,"publisher":"Springer Science and Business Media LLC","issue":"8","license":[{"start":{"date-parts":[[2024,6,21]],"date-time":"2024-06-21T00:00:00Z","timestamp":1718928000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"},{"start":{"date-parts":[[2024,6,21]],"date-time":"2024-06-21T00:00:00Z","timestamp":1718928000000},"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 Rev Neurol"],"published-print":{"date-parts":[[2024,8]]},"DOI":"10.1038\/s41582-024-00988-2","type":"journal-article","created":{"date-parts":[[2024,6,21]],"date-time":"2024-06-21T06:06:42Z","timestamp":1718950002000},"page":"457-474","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":214,"title":["Multifaceted roles of APOE in Alzheimer disease"],"prefix":"10.1038","volume":"20","author":[{"given":"Rosemary J.","family":"Jackson","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7959-9401","authenticated-orcid":false,"given":"Bradley T.","family":"Hyman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0899-7530","authenticated-orcid":false,"given":"Alberto","family":"Serrano-Pozo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,6,21]]},"reference":[{"key":"988_CR1","doi-asserted-by":"crossref","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":"988_CR2","doi-asserted-by":"crossref","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":"988_CR3","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":"988_CR4","doi-asserted-by":"crossref","first-page":"763","DOI":"10.3233\/JAD-170184","volume":"59","author":"A Serrano-Pozo","year":"2017","unstructured":"Serrano-Pozo, A., Aldridge, G. M. & Zhang, Q. Four decades of research in Alzheimer\u2019s disease (1975\u20132014): a bibliometric and scientometric analysis. J. Alzheimers Dis. 59, 763\u2013783 (2017).","journal-title":"J. Alzheimers Dis."},{"key":"988_CR5","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":"988_CR6","doi-asserted-by":"crossref","first-page":"1349","DOI":"10.1001\/jama.1997.03550160069041","volume":"278","author":"LA Farrer","year":"1997","unstructured":"Farrer, L. A. et al. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA 278, 1349\u20131356 (1997).","journal-title":"JAMA"},{"key":"988_CR7","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1038\/ng0694-180","volume":"7","author":"EH Corder","year":"1994","unstructured":"Corder, E. H. et al. Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease. Nat. Genet. 7, 180\u2013184 (1994).","journal-title":"Nat. Genet."},{"key":"988_CR8","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":"988_CR9","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":"988_CR10","doi-asserted-by":"crossref","first-page":"1284","DOI":"10.1001\/jamaneurol.2023.3599","volume":"80","author":"ME Belloy","year":"2023","unstructured":"Belloy, M. E. et al. APOE genotype and Alzheimer disease risk across age, sex, and population ancestry. JAMA Neurol. 80, 1284\u20131294 (2023).","journal-title":"JAMA Neurol."},{"key":"988_CR11","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1002\/alz.12205","volume":"17","author":"E Granot-Hershkovitz","year":"2021","unstructured":"Granot-Hershkovitz, E. et al. APOE alleles\u2019 association with cognitive function differs across Hispanic\/Latino groups and genetic ancestry in the study of Latinos \u2014 investigation of neurocognitive aging (HCHS\/SOL). Alzheimers Dement. 17, 466\u2013474 (2021).","journal-title":"Alzheimers Dement."},{"key":"988_CR12","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pgen.1007791","volume":"14","author":"F Rajabli","year":"2018","unstructured":"Rajabli, F. et al. Ancestral origin of ApoE \u03b54 Alzheimer disease risk in Puerto Rican and African American populations. PLoS Genet. 14, e1007791 (2018).","journal-title":"PLoS Genet."},{"key":"988_CR13","doi-asserted-by":"crossref","first-page":"1524","DOI":"10.1016\/j.jalz.2019.07.016","volume":"15","author":"EE Blue","year":"2019","unstructured":"Blue, E. E., Horimoto, A. R. V. R., Mukherjee, S., Wijsman, E. M. & Thornton, T. A. Local ancestry at APOE modifies Alzheimer\u2019s disease risk in Caribbean Hispanics. Alzheimers Dement. 15, 1524\u20131532 (2019).","journal-title":"Alzheimers Dement."},{"key":"988_CR14","doi-asserted-by":"crossref","first-page":"1179","DOI":"10.1002\/alz.12287","volume":"17","author":"AJ Griswold","year":"2021","unstructured":"Griswold, A. J. et al. Increased APOE \u03b54 expression is associated with the difference in Alzheimer\u2019s disease risk from diverse ancestral backgrounds. Alzheimers Dement. 17, 1179\u20131188 (2021).","journal-title":"Alzheimers Dement."},{"key":"988_CR15","doi-asserted-by":"crossref","first-page":"1930","DOI":"10.1002\/alz.12534","volume":"18","author":"K Nuytemans","year":"2022","unstructured":"Nuytemans, K. et al. Identifying differential regulatory control of APOE \u025b4 on African versus European haplotypes as potential therapeutic targets. Alzheimers Dement. 18, 1930\u20131942 (2022).","journal-title":"Alzheimers Dement."},{"key":"988_CR16","doi-asserted-by":"crossref","first-page":"1284","DOI":"10.1038\/s41591-024-02931-w","volume":"30","author":"J Fortea","year":"2024","unstructured":"Fortea, J. et al. APOE4 homozygosity represents a distinct genetic form of Alzheimer\u2019s disease. Nat. Med. 30, 1284\u20131291 (2024).","journal-title":"Nat. Med."},{"key":"988_CR17","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pmed.1002254","volume":"14","author":"J Qian","year":"2017","unstructured":"Qian, J. et al. APOE-related risk of mild cognitive impairment and dementia for prevention trials: an analysis of four cohorts. PLoS Med. 14, e1002254 (2017).","journal-title":"PLoS Med."},{"key":"988_CR18","first-page":"E1","volume":"71","author":"SD Stites","year":"2022","unstructured":"Stites, S. D. et al. Patients asking about APOE gene test results? Here\u2019s what to tell them. J. Fam. Pract. 71, E1\u2013E7 (2022).","journal-title":"J. Fam. Pract."},{"key":"988_CR19","doi-asserted-by":"crossref","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":"988_CR20","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1038\/s41588-022-01024-z","volume":"54","author":"C Bellenguez","year":"2022","unstructured":"Bellenguez, C. et al. New insights into the genetic etiology of Alzheimer\u2019s disease and related dementias. Nat. Genet. 54, 412\u2013436 (2022).","journal-title":"Nat. Genet."},{"key":"988_CR21","volume":"13","author":"AJ Huq","year":"2021","unstructured":"Huq, A. J. et al. Polygenic score modifies risk for Alzheimer\u2019s disease in APOE \u03b54 homozygotes at phenotypic extremes. Alzheimers Dement. 13, e12226 (2021).","journal-title":"Alzheimers Dement."},{"key":"988_CR22","volume":"13","author":"JL Ebenau","year":"2021","unstructured":"Ebenau, J. L. et al. Risk of dementia in APOE \u03b54 carriers is mitigated by a polygenic risk score. Alzheimers Dement. 13, e12229 (2021).","journal-title":"Alzheimers Dement."},{"key":"988_CR23","doi-asserted-by":"crossref","first-page":"e1878","DOI":"10.1212\/WNL.0000000000007323","volume":"92","author":"CM Erickson","year":"2019","unstructured":"Erickson, C. M. et al. KLOTHO heterozygosity attenuates APOE4-related amyloid burden in preclinical AD. Neurology 92, e1878\u2013e1889 (2019).","journal-title":"Neurology"},{"key":"988_CR24","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1001\/jamaneurol.2020.0414","volume":"77","author":"ME Belloy","year":"2020","unstructured":"Belloy, M. E. et al. 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":"988_CR25","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-021-23755-z","volume":"12","author":"J Neitzel","year":"2021","unstructured":"Neitzel, J. et al. KL-VS heterozygosity is associated with lower amyloid-dependent tau accumulation and memory impairment in Alzheimer\u2019s disease. Nat. Commun. 12, 3825 (2021).","journal-title":"Nat. Commun."},{"key":"988_CR26","volume":"17","author":"M Ali","year":"2022","unstructured":"Ali, M. et al. Leveraging large multi-center cohorts of Alzheimer disease endophenotypes to understand the role of klotho heterozygosity on disease risk. PLoS ONE 17, e0267298 (2022).","journal-title":"PLoS ONE"},{"key":"988_CR27","doi-asserted-by":"crossref","first-page":"1612","DOI":"10.1016\/j.jalz.2019.05.011","volume":"15","author":"AJ Huq","year":"2019","unstructured":"Huq, A. J. et al. Genetic resilience to Alzheimer\u2019s disease in APOE \u03b54 homozygotes: a systematic review. Alzheimers Dement. 15, 1612\u20131623 (2019).","journal-title":"Alzheimers Dement."},{"key":"988_CR28","doi-asserted-by":"crossref","first-page":"795","DOI":"10.3233\/JAD181028","volume":"67","author":"A Serrano-Pozo","year":"2019","unstructured":"Serrano-Pozo, A. & Growdon, J. H. Is Alzheimer\u2019s disease risk modifiable? J. Alzheimers Dis. 67, 795\u2013819 (2019).","journal-title":"J. Alzheimers Dis."},{"key":"988_CR29","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1097\/WCO.0000000000001243","volume":"37","author":"M Jaisa-Aad","year":"2024","unstructured":"Jaisa-Aad, M., Mu\u00f1oz-Castro, C. & Serrano-Pozo, A. Update on modifiable risk factors for Alzheimer\u2019s disease and related dementias. Curr. Opin. Neurol. 37, 166\u2013181 (2024).","journal-title":"Curr. Opin. Neurol."},{"key":"988_CR30","doi-asserted-by":"crossref","first-page":"938","DOI":"10.1186\/s12877-022-03652-w","volume":"22","author":"A Kolli","year":"2022","unstructured":"Kolli, A. et al. Interactions between the apolipoprotein E4 gene and modifiable risk factors for cognitive impairment: a nationally representative panel study. BMC Geriatr. 22, 938 (2022).","journal-title":"BMC Geriatr."},{"key":"988_CR31","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-023-40775-z","volume":"14","author":"S Langella","year":"2023","unstructured":"Langella, S. et al. Effect of apolipoprotein genotype and educational attainment on cognitive function in autosomal dominant Alzheimer\u2019s disease. Nat. Commun. 14, 5120 (2023).","journal-title":"Nat. Commun."},{"key":"988_CR32","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1002\/alz.12677","volume":"19","author":"S-Y Park","year":"2023","unstructured":"Park, S.-Y. et al. Modifying effects of race and ethnicity and APOE on the association of physical activity with risk of Alzheimer\u2019s disease and related dementias. Alzheimers Dement. 19, 507\u2013517 (2023).","journal-title":"Alzheimers Dement."},{"key":"988_CR33","volume":"380","author":"J Jia","year":"2023","unstructured":"Jia, J. et al. Association between healthy lifestyle and memory decline in older adults: 10 year, population based, prospective cohort study. Br. Med. J. 380, e072691 (2023).","journal-title":"Br. Med. J."},{"key":"988_CR34","volume":"102","author":"S-Y Park","year":"2024","unstructured":"Park, S.-Y. et al. Racial and ethnic differences in the population-attributable fractions of Alzheimer disease and related dementias. Neurology 102, e208116 (2024).","journal-title":"Neurology"},{"key":"988_CR35","volume":"5","author":"M Lee","year":"2022","unstructured":"Lee, M. et al. Variation in population attributable fraction of dementia associated with potentially modifiable risk factors by race and ethnicity in the US. JAMA Netw. Open 5, e2219672 (2022).","journal-title":"JAMA Netw. Open"},{"key":"988_CR36","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":"988_CR37","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1186\/s13024-023-00684-7","volume":"18","author":"KY He","year":"2023","unstructured":"He, K. Y. et al. Characterization of APOE Christchurch carriers in 455,306 UK Biobank participants. Mol. Neurodegener. 18, 92 (2023).","journal-title":"Mol. Neurodegener."},{"key":"988_CR38","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1172\/JCI113096","volume":"80","author":"MR Wardell","year":"1987","unstructured":"Wardell, M. R., Brennan, S. O., Janus, E. D., Fraser, R. & Carrell, R. W. Apolipoprotein E2-Christchurch (136 Arg\u2013Ser). New variant of human apolipoprotein E in a patient with type III hyperlipoproteinemia. J. Clin. Invest. 80, 483\u2013490 (1987).","journal-title":"J. Clin. Invest."},{"key":"988_CR39","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/0021-9150(95)06745-0","volume":"122","author":"M Pocovi","year":"1996","unstructured":"Pocovi, M. et al. Incomplete dominance of type III hyperlipoproteinemia is associated with the rare apolipoprotein E2 (Arg136\u2192Ser) variant in multigenerational pedigree studies. Atherosclerosis 122, 33\u201346 (1996).","journal-title":"Atherosclerosis"},{"key":"988_CR40","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1111\/nan.12670","volume":"47","author":"I Hernandez","year":"2021","unstructured":"Hernandez, I. et al. Heterozygous APOE Christchurch in familial Alzheimer\u2019s disease without mutations in other Mendelian genes. Neuropathol. Appl. Neurobiol. 47, 579\u2013582 (2021).","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"988_CR41","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1001\/jama.2023.0268","volume":"329","author":"Y Le Guen","year":"2023","unstructured":"Le Guen, Y. et al. Association of African ancestry-specific APOE missense variant r145c with risk of Alzheimer disease. JAMA 329, 551\u2013560 (2023).","journal-title":"JAMA"},{"key":"988_CR42","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1186\/1750-1326-9-11","volume":"9","author":"CW Medway","year":"2014","unstructured":"Medway, C. W. et al. ApoE variant p.V236E is associated with markedly reduced risk of Alzheimer\u2019s disease. Mol. Neurodegener. 9, 11 (2014).","journal-title":"Mol. Neurodegener."},{"key":"988_CR43","doi-asserted-by":"crossref","first-page":"652","DOI":"10.1001\/jamaneurol.2022.1166","volume":"79","author":"Y Le Guen","year":"2022","unstructured":"Le Guen, Y. et al. Association of rare APOE missense variants V236E and R251G with risk of Alzheimer disease. JAMA Neurol. 79, 652\u2013663 (2022).","journal-title":"JAMA Neurol."},{"key":"988_CR44","doi-asserted-by":"crossref","first-page":"eabc9375","DOI":"10.1126\/scitranslmed.abc9375","volume":"13","author":"C-C Liu","year":"2021","unstructured":"Liu, C.-C. et al. APOE3-Jacksonville (V236E) variant reduces self-aggregation and risk of dementia. Sci. Transl. Med. 13, eabc9375 (2021).","journal-title":"Sci. Transl. Med."},{"key":"988_CR45","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1002\/ana.25123","volume":"83","author":"PA Boyle","year":"2018","unstructured":"Boyle, P. A. et al. Person-specific contribution of neuropathologies to cognitive loss in old age. Ann. Neurol. 83, 74\u201383 (2018).","journal-title":"Ann. Neurol."},{"key":"988_CR46","doi-asserted-by":"crossref","first-page":"1194","DOI":"10.1136\/jnnp.2004.054445","volume":"76","author":"DA Bennett","year":"2005","unstructured":"Bennett, D. A. et al. Amyloid mediates the association of apolipoprotein E e4 allele to cognitive function in older people. J. Neurol. Neurosurg. Psychiatry 76, 1194\u20131199 (2005).","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"988_CR47","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1016\/j.neurobiolaging.2013.08.007","volume":"35","author":"D Mungas","year":"2014","unstructured":"Mungas, D., Tractenberg, R., Schneider, J. A., Crane, P. K. & Bennett, D. A. A 2-process model for neuropathology of Alzheimer\u2019s disease. Neurobiol. Aging 35, 301\u2013308 (2014).","journal-title":"Neurobiol. Aging"},{"key":"988_CR48","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1002\/ana.24369","volume":"77","author":"A Serrano-Pozo","year":"2015","unstructured":"Serrano-Pozo, A., Qian, J., Monsell, S. E., Betensky, R. A. & Hyman, B. T. APOE\u03b52 is associated with milder clinical and pathological Alzheimer disease. Ann. Neurol. 77, 917\u2013929 (2015).","journal-title":"Ann. Neurol."},{"key":"988_CR49","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-020-18198-x","volume":"11","author":"TE Goldberg","year":"2020","unstructured":"Goldberg, T. E., Huey, E. D. & Devanand, D. P. Association of APOE \u03b52 genotype with Alzheimer\u2019s and non-Alzheimer\u2019s neurodegenerative pathologies. Nat. Commun. 11, 4727 (2020).","journal-title":"Nat. Commun."},{"key":"988_CR50","doi-asserted-by":"publisher","unstructured":"Goldberg, T. E., Huey, E. D. & Devanand, D. P. Associations of APOE \u03b52 genotype with cerebrovascular pathology: a postmortem study of 1275 brains. J. Neurol. Neurosurg. Psychiatry https:\/\/doi.org\/10.1136\/jnnp-2020-323746 (2020).","DOI":"10.1136\/jnnp-2020-323746"},{"key":"988_CR51","doi-asserted-by":"crossref","first-page":"2946","DOI":"10.1016\/j.neurobiolaging.2015.08.008","volume":"36","author":"L Yu","year":"2015","unstructured":"Yu, L. et al. APOE and cerebral amyloid angiopathy in community-dwelling older persons. Neurobiol. Aging 36, 2946\u20132953 (2015).","journal-title":"Neurobiol. Aging"},{"key":"988_CR52","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":"988_CR53","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.neurobiolaging.2015.09.011","volume":"37","author":"JM Farfel","year":"2016","unstructured":"Farfel, J. M., Yu, L., De Jager, P. L., Schneider, J. A. & Bennett, D. A. Association of APOE with tau-tangle pathology with and without \u03b2-amyloid. Neurobiol. Aging 37, 19\u201325 (2016).","journal-title":"Neurobiol. Aging"},{"key":"988_CR54","doi-asserted-by":"crossref","first-page":"e2127","DOI":"10.1212\/WNL.0000000000005677","volume":"90","author":"S Oveisgharan","year":"2018","unstructured":"Oveisgharan, S. et al. APOE \u03b52\u03b54 genotype, incident AD and MCI, cognitive decline, and AD pathology in older adults. Neurology 90, e2127\u2013e2134 (2018).","journal-title":"Neurology"},{"key":"988_CR55","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1016\/j.jalz.2018.08.007","volume":"15","author":"M Lamar","year":"2019","unstructured":"Lamar, M. et al. APOE genotypes as a risk factor for age-dependent accumulation of cerebrovascular disease in older adults. Alzheimers Dement. 15, 258\u2013266 (2019).","journal-title":"Alzheimers Dement."},{"key":"988_CR56","doi-asserted-by":"crossref","first-page":"961","DOI":"10.1212\/WNL.50.4.961","volume":"50","author":"SM Greenberg","year":"1998","unstructured":"Greenberg, S. M. et al. Association of apolipoprotein E \u03b52 and vasculopathy in cerebral amyloid angiopathy. Neurology 50, 961\u2013965 (1998).","journal-title":"Neurology"},{"key":"988_CR57","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1097\/00005072-199907000-00005","volume":"58","author":"MO McCarron","year":"1999","unstructured":"McCarron, M. O. et al. The apolipoprotein E \u03b52 allele and the pathological features in cerebral amyloid angiopathy-related hemorrhage. J. Neuropathol. Exp. Neurol. 58, 711\u2013718 (1999).","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"988_CR58","doi-asserted-by":"crossref","first-page":"1182","DOI":"10.1097\/NEN.0000000000000016","volume":"72","author":"A Serrano-Pozo","year":"2013","unstructured":"Serrano-Pozo, A. et al. Examination of the clinicopathologic continuum of Alzheimer disease in the autopsy cohort of the National Alzheimer Coordinating Center. J. Neuropathol. Exp. Neurol. 72, 1182\u20131192 (2013).","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"988_CR59","doi-asserted-by":"crossref","first-page":"953","DOI":"10.1093\/brain\/awaa438","volume":"144","author":"JL Robinson","year":"2021","unstructured":"Robinson, J. L. et al. The development and convergence of co-pathologies in Alzheimer\u2019s disease. Brain 144, 953\u2013962 (2021).","journal-title":"Brain"},{"key":"988_CR60","doi-asserted-by":"crossref","first-page":"1299","DOI":"10.1001\/jamaneurol.2020.1741","volume":"77","author":"S Karanth","year":"2020","unstructured":"Karanth, S. et al. Prevalence and clinical phenotype of quadruple misfolded proteins in older adults. JAMA Neurol. 77, 1299\u20131307 (2020).","journal-title":"JAMA Neurol."},{"key":"988_CR61","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1093\/jnen\/nlac115","volume":"82","author":"JM Walker","year":"2023","unstructured":"Walker, J. M. & Richardson, T. E. Cognitive resistance to and resilience against multiple comorbid neurodegenerative pathologies and the impact of APOE status. J. Neuropathol. Exp. Neurol. 82, 110\u2013119 (2023).","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"988_CR62","doi-asserted-by":"crossref","first-page":"e1182","DOI":"10.1212\/WNL.0000000000006212","volume":"91","author":"DW Dickson","year":"2018","unstructured":"Dickson, D. W. et al. APOE \u03b54 is associated with severity of Lewy body pathology independent of Alzheimer pathology. Neurology 91, e1182\u2013e1195 (2018).","journal-title":"Neurology"},{"key":"988_CR63","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1016\/S1474-4422(18)30251-5","volume":"17","author":"H-S 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":"988_CR64","doi-asserted-by":"crossref","first-page":"1347","DOI":"10.1001\/jamaneurol.2018.3139","volume":"75","author":"AM Wennberg","year":"2018","unstructured":"Wennberg, A. M. et al. Association of apolipoprotein E \u03b54 with transactive response DNA-binding protein 43. JAMA Neurol. 75, 1347\u20131354 (2018).","journal-title":"JAMA Neurol."},{"key":"988_CR65","doi-asserted-by":"crossref","first-page":"2181","DOI":"10.1093\/brain\/awy146","volume":"141","author":"JL Robinson","year":"2018","unstructured":"Robinson, J. L. et al. Neurodegenerative disease concomitant proteinopathies are prevalent, age-related and APOE4-associated. Brain 141, 2181\u20132193 (2018).","journal-title":"Brain"},{"key":"988_CR66","volume":"9","author":"N Zhao","year":"2018","unstructured":"Zhao, N. et al. APOE \u03b52 is associated with increased tau pathology in primary tauopathy. Nat. Commun. 9, 4388 (2018).","journal-title":"Nat. Commun."},{"key":"988_CR67","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.nbd.2019.02.016","volume":"127","author":"MS Sabir","year":"2019","unstructured":"Sabir, M. S. et al. Assessment of APOE in atypical parkinsonism syndromes. Neurobiol. Dis. 127, 142\u2013146 (2019).","journal-title":"Neurobiol. Dis."},{"key":"988_CR68","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1001\/jamaneurol.2022.1634","volume":"79","author":"K Atherton","year":"2022","unstructured":"Atherton, K. et al. Association of APOE genotypes and chronic traumatic encephalopathy. JAMA Neurol. 79, 787\u2013796 (2022).","journal-title":"JAMA Neurol."},{"key":"988_CR69","doi-asserted-by":"crossref","first-page":"eaay3069","DOI":"10.1126\/scitranslmed.aay3069","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":"988_CR70","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1001\/jamaneurol.2013.600","volume":"70","author":"D Tsuang","year":"2013","unstructured":"Tsuang, D. et al. APOE \u03b54 increases risk for dementia in pure synucleinopathies. JAMA Neurol. 70, 223\u2013228 (2013).","journal-title":"JAMA Neurol."},{"key":"988_CR71","doi-asserted-by":"crossref","first-page":"eaay1809","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":"988_CR72","doi-asserted-by":"crossref","first-page":"1757","DOI":"10.1093\/brain\/awab402","volume":"145","author":"K Kaivola","year":"2022","unstructured":"Kaivola, K., Shah, Z. & Chia, R., International LBD Genomics Consortium & Scholz, S. W. Genetic evaluation of dementia with Lewy bodies implicates distinct disease subgroups. Brain 145, 1757\u20131762 (2022).","journal-title":"Brain"},{"key":"988_CR73","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1186\/s40478-023-01626-6","volume":"11","author":"S Talyansky","year":"2023","unstructured":"Talyansky, S., Le Guen, Y., Kasireddy, N., Belloy, M. E. & Greicius, M. D. APOE-\u03b54 and BIN1 increase risk of Alzheimer\u2019s disease pathology but not specifically of Lewy body pathology. Acta Neuropathol. Commun. 11, 149 (2023).","journal-title":"Acta Neuropathol. Commun."},{"key":"988_CR74","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1002\/mds.27297","volume":"33","author":"K Ogaki","year":"2018","unstructured":"Ogaki, K. et al. Multiple system atrophy and apolipoprotein E. Mov. Disord. 33, 647\u2013650 (2018).","journal-title":"Mov. Disord."},{"key":"988_CR75","doi-asserted-by":"crossref","first-page":"830","DOI":"10.1002\/ana.26580","volume":"93","author":"AD Meneses","year":"2023","unstructured":"Meneses, A. D. et al. APOE2 exacerbates TDP-43 related toxicity in the absence of Alzheimer pathology. Ann. Neurol. 93, 830\u2013843 (2023).","journal-title":"Ann. Neurol."},{"key":"988_CR76","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1056\/NEJMoa0809437","volume":"361","author":"RJ Caselli","year":"2009","unstructured":"Caselli, R. J. et al. Longitudinal modeling of age-related memory decline and the APOE \u03b54 effect. N. Engl. J. Med. 361, 255\u2013263 (2009).","journal-title":"N. Engl. J. Med."},{"key":"988_CR77","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1002\/ana.24628","volume":"79","author":"M Shinohara","year":"2016","unstructured":"Shinohara, M. et al. APOE2 eases cognitive decline during aging: clinical and preclinical evaluations. Ann. Neurol. 79, 758\u2013774 (2016).","journal-title":"Ann. Neurol."},{"key":"988_CR78","doi-asserted-by":"crossref","first-page":"1015","DOI":"10.1037\/a0031642","volume":"28","author":"L Yu","year":"2013","unstructured":"Yu, L. et al. APOE \u03b54, Alzheimer\u2019s disease pathology, cerebrovascular disease, and cognitive change over the years prior to death. Psychol. Aging 28, 1015\u20131023 (2013).","journal-title":"Psychol. Aging"},{"key":"988_CR79","doi-asserted-by":"crossref","first-page":"2508","DOI":"10.1002\/alz.12885","volume":"19","author":"E Nichols","year":"2023","unstructured":"Nichols, E. et al. AD and non-AD mediators of the pathway between the APOE genotype and cognition. Alzheimers Dement. 19, 2508\u20132519 (2023).","journal-title":"Alzheimers Dement."},{"key":"988_CR80","doi-asserted-by":"crossref","first-page":"e2414","DOI":"10.1212\/WNL.0000000000011883","volume":"96","author":"J Qian","year":"2021","unstructured":"Qian, J., Betensky, R. A., Hyman, B. T. & Serrano-Pozo, A. Association of APOE genotype with heterogeneity of cognitive decline rate in Alzheimer disease. Neurology 96, e2414\u2013e2428 (2021).","journal-title":"Neurology"},{"key":"988_CR81","doi-asserted-by":"crossref","DOI":"10.1212\/NXG.0000000000200055","volume":"9","author":"J Qian","year":"2023","unstructured":"Qian, J., Zhang, Y., Betensky, R. A., Hyman, B. T. & Serrano-Pozo, A. Neuropathology-independent association between APOE genotype and cognitive decline rate in the normal aging-early Alzheimer continuum. Neurol. Genet. 9, e200055 (2023).","journal-title":"Neurol. Genet."},{"key":"988_CR82","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1001\/jamaneurol.2021.1893","volume":"78","author":"A Bejanin","year":"2021","unstructured":"Bejanin, A. et al. Association of apolipoprotein E \u025b4 allele with clinical and multimodal biomarker changes of Alzheimer disease in adults with down syndrome. JAMA Neurol. 78, 937\u2013947 (2021).","journal-title":"JAMA Neurol."},{"key":"988_CR83","doi-asserted-by":"crossref","first-page":"916","DOI":"10.1038\/mp.2015.177","volume":"21","author":"JI V\u00e9lez","year":"2016","unstructured":"V\u00e9lez, J. I. et al. APOE*E2 allele delays age of onset in PSEN1 E280A Alzheimer\u2019s disease. Mol. Psychiatry 21, 916\u2013924 (2016).","journal-title":"Mol. Psychiatry"},{"key":"988_CR84","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1038\/ng.76","volume":"40","author":"CJ Willer","year":"2008","unstructured":"Willer, C. J. et al. Newly identified loci that influence lipid concentrations and risk of coronary artery disease. Nat. Genet. 40, 161\u2013169 (2008).","journal-title":"Nat. Genet."},{"key":"988_CR85","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1038\/ng.75","volume":"40","author":"S Kathiresan","year":"2008","unstructured":"Kathiresan, S. et al. Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans. Nat. Genet. 40, 189\u2013197 (2008).","journal-title":"Nat. Genet."},{"key":"988_CR86","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1161\/CIRCGENETICS.116.001572","volume":"9","author":"P Natarajan","year":"2016","unstructured":"Natarajan, P. et al. Multiethnic exome-wide association study of subclinical atherosclerosis. Circ. Cardiovasc. Genet. 9, 511\u2013520 (2016).","journal-title":"Circ. Cardiovasc. Genet."},{"key":"988_CR87","doi-asserted-by":"crossref","first-page":"12222","DOI":"10.18632\/aging.103405","volume":"12","author":"C-L Kuo","year":"2020","unstructured":"Kuo, C.-L., Pilling, L. C., Atkins, J. L., Kuchel, G. A. & Melzer, D. ApoE \u03b52 and aging-related outcomes in 379,000 UK Biobank participants. Aging 12, 12222\u201312233 (2020).","journal-title":"Aging"},{"key":"988_CR88","doi-asserted-by":"crossref","first-page":"102954","DOI":"10.1016\/j.ebiom.2020.102954","volume":"59","author":"AL Lumsden","year":"2020","unstructured":"Lumsden, A. L., Mulugeta, A., Zhou, A. & Hypp\u00f6nen, E. Apolipoprotein E (APOE) genotype-associated disease risks: a phenome-wide, registry-based, case\u2013control study utilising the UK Biobank. eBioMedicine 59, 102954 (2020).","journal-title":"eBioMedicine"},{"key":"988_CR89","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1016\/S0140-6736(82)90439-1","volume":"2","author":"G Ghiselli","year":"1982","unstructured":"Ghiselli, G., Gregg, R. E., Zech, L. A., Schaefer, E. J. & Brewer, H. B. Phenotype study of apolipoprotein E isoforms in hyperlipoproteinaemic patients. Lancet 2, 405\u2013407 (1982).","journal-title":"Lancet"},{"key":"988_CR90","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-017-00934-5","volume":"8","author":"PK Joshi","year":"2017","unstructured":"Joshi, P. K. et al. Genome-wide meta-analysis associates HLA-DQA1\/DRB1 and LPA and lifestyle factors with human longevity. Nat. Commun. 8, 910 (2017).","journal-title":"Nat. Commun."},{"key":"988_CR91","doi-asserted-by":"crossref","first-page":"2504","DOI":"10.18632\/aging.101334","volume":"9","author":"LC Pilling","year":"2017","unstructured":"Pilling, L. C. et al. Human longevity: 25 genetic loci associated in 389,166 UK biobank participants. Aging 9, 2504\u20132520 (2017).","journal-title":"Aging"},{"key":"988_CR92","volume":"10","author":"J Deelen","year":"2019","unstructured":"Deelen, J. et al. A meta-analysis of genome-wide association studies identifies multiple longevity genes. Nat. Commun. 10, 3669 (2019).","journal-title":"Nat. Commun."},{"key":"988_CR93","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0219668","volume":"14","author":"FJ Wolters","year":"2019","unstructured":"Wolters, F. J. et al. The impact of APOE genotype on survival: results of 38,537 participants from six population-based cohorts (E2-CHARGE). PLoS ONE 14, e0219668 (2019).","journal-title":"PLoS ONE"},{"key":"988_CR94","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.62199","volume":"9","author":"M Shinohara","year":"2020","unstructured":"Shinohara, M. et al. APOE2 is associated with longevity independent of Alzheimer\u2019s disease. eLife 9, e62199 (2020).","journal-title":"eLife"},{"key":"988_CR95","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1016\/j.tem.2023.05.002","volume":"34","author":"LG Yang","year":"2023","unstructured":"Yang, L. G., March, Z. M., Stephenson, R. A. & Narayan, P. S. Apolipoprotein E in lipid metabolism and neurodegenerative disease. Trends Endocrinol. Metab. 34, 430\u2013445 (2023).","journal-title":"Trends Endocrinol. Metab."},{"key":"988_CR96","doi-asserted-by":"crossref","first-page":"4985","DOI":"10.1523\/JNEUROSCI.5476-05.2006","volume":"26","author":"Q Xu","year":"2006","unstructured":"Xu, Q. et al. Profile and regulation of apolipoprotein E (ApoE) expression in the CNS in mice with targeting of green fluorescent protein gene to the ApoE locus. J. Neurosci. 26, 4985\u20134994 (2006).","journal-title":"J. Neurosci."},{"key":"988_CR97","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1038\/s41586-019-1195-2","volume":"570","author":"H Mathys","year":"2019","unstructured":"Mathys, H. et al. Single-cell transcriptomic analysis of Alzheimer\u2019s disease. Nature 570, 332\u2013337 (2019).","journal-title":"Nature"},{"key":"988_CR98","doi-asserted-by":"crossref","first-page":"41197","DOI":"10.1074\/jbc.M407962200","volume":"279","author":"V Hirsch-Reinshagen","year":"2004","unstructured":"Hirsch-Reinshagen, V. et al. Deficiency of ABCA1 impairs apolipoprotein E metabolism in brain. J. Biol. Chem. 279, 41197\u201341207 (2004).","journal-title":"J. Biol. Chem."},{"key":"988_CR99","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/j.neuron.2020.10.008","volume":"109","author":"Y Chen","year":"2021","unstructured":"Chen, Y., Strickland, M. R., Soranno, A. & Holtzman, D. M. Apolipoprotein E: structural insights and links to Alzheimer disease pathogenesis. Neuron 109, 205\u2013221 (2021).","journal-title":"Neuron"},{"key":"988_CR100","doi-asserted-by":"crossref","first-page":"6292","DOI":"10.1073\/pnas.1705080114","volume":"114","author":"C Frieden","year":"2017","unstructured":"Frieden, C., Wang, H. & Ho, C. M. W. A mechanism for lipid binding to apoE and the role of intrinsically disordered regions coupled to domain\u2013domain interactions. Proc. Natl Acad. Sci. USA 114, 6292\u20136297 (2017).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"988_CR101","doi-asserted-by":"crossref","first-page":"1100","DOI":"10.1016\/j.neuron.2023.12.018","volume":"112","author":"MR Strickland","year":"2024","unstructured":"Strickland, M. R. et al. Apolipoprotein E secreted by astrocytes forms antiparallel dimers in discoidal lipoproteins. Neuron 112, 1100\u20131109.e5 (2024).","journal-title":"Neuron"},{"key":"988_CR102","doi-asserted-by":"crossref","first-page":"10881","DOI":"10.1021\/bi1017655","volume":"49","author":"D Nguyen","year":"2010","unstructured":"Nguyen, D. et al. Molecular basis for the differences in lipid and lipoprotein binding properties of human apolipoproteins E3 and E4. Biochemistry 49, 10881\u201310889 (2010).","journal-title":"Biochemistry"},{"key":"988_CR103","doi-asserted-by":"crossref","DOI":"10.1186\/s13024-022-00566-4","volume":"17","author":"R Fern\u00e1ndez-Calle","year":"2022","unstructured":"Fern\u00e1ndez-Calle, R. et al. APOE in the bullseye of neurodegenerative diseases: impact of the APOE genotype in Alzheimer\u2019s disease pathology and brain diseases. Mol. Neurodegener. 17, 62 (2022).","journal-title":"Mol. Neurodegener."},{"key":"988_CR104","doi-asserted-by":"crossref","first-page":"16458","DOI":"10.1523\/JNEUROSCI.3987-12.2012","volume":"32","author":"T Kanekiyo","year":"2012","unstructured":"Kanekiyo, T., Liu, C.-C., Shinohara, M., Li, J. & Bu, G. LRP1 in brain vascular smooth muscle cells mediates local clearance of Alzheimer\u2019s amyloid-\u03b2. J. Neurosci. 32, 16458\u201316465 (2012).","journal-title":"J. Neurosci."},{"key":"988_CR105","doi-asserted-by":"crossref","first-page":"19276","DOI":"10.1523\/JNEUROSCI.3487-13.2013","volume":"33","author":"T Kanekiyo","year":"2013","unstructured":"Kanekiyo, T. et al. Neuronal clearance of amyloid-\u03b2 by endocytic receptor LRP1. J. Neurosci. 33, 19276\u201319283 (2013).","journal-title":"J. Neurosci."},{"key":"988_CR106","doi-asserted-by":"crossref","first-page":"2413","DOI":"10.1016\/j.neuron.2021.05.034","volume":"109","author":"Y Shi","year":"2021","unstructured":"Shi, Y. et al. Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms. Neuron 109, 2413\u20132426.e7 (2021).","journal-title":"Neuron"},{"key":"988_CR107","doi-asserted-by":"crossref","first-page":"15502","DOI":"10.1073\/pnas.1206446109","volume":"109","author":"JM Castellano","year":"2012","unstructured":"Castellano, J. M. et al. Low-density lipoprotein receptor overexpression enhances the rate of brain-to-blood A\u03b2 clearance in a mouse model of \u03b2-amyloidosis. Proc. Natl Acad. Sci. USA 109, 15502\u201315507 (2012).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"988_CR108","doi-asserted-by":"crossref","first-page":"632","DOI":"10.1016\/j.neuron.2009.11.013","volume":"64","author":"J Kim","year":"2009","unstructured":"Kim, J. et al. Overexpression of low-density lipoprotein receptor in the brain markedly inhibits amyloid deposition and increases extracellular A beta clearance. Neuron 64, 632\u2013644 (2009).","journal-title":"Neuron"},{"key":"988_CR109","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1111\/nan.12529","volume":"45","author":"M Tzioras","year":"2019","unstructured":"Tzioras, M., Davies, C., Newman, A., Jackson, R. & Spires-Jones, T. Invited review: APOE at the interface of inflammation, neurodegeneration and pathological protein spread in Alzheimer\u2019s disease. Neuropathol. Appl. Neurobiol. 45, 327\u2013346 (2019).","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"988_CR110","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/0304-3940(92)90444-C","volume":"135","author":"T Wisniewski","year":"1992","unstructured":"Wisniewski, T. & Frangione, B. Apolipoprotein E: a pathological chaperone protein in patients with cerebral and systemic amyloid. Neurosci. Lett. 135, 235\u2013238 (1992).","journal-title":"Neurosci. Lett."},{"key":"988_CR111","volume":"6","author":"PB Jones","year":"2011","unstructured":"Jones, P. B. et al. Apolipoprotein E: isoform specific differences in tertiary structure and interaction with amyloid-\u03b2 in human Alzheimer brain. PLoS One 6, e14586 (2011).","journal-title":"PLoS One"},{"key":"988_CR112","doi-asserted-by":"crossref","first-page":"1024","DOI":"10.1016\/j.neuron.2017.11.013","volume":"96","author":"C-C Liu","year":"2017","unstructured":"Liu, C.-C. et al. ApoE4 accelerates early seeding of amyloid pathology. Neuron 96, 1024\u20131032.e3 (2017).","journal-title":"Neuron"},{"key":"988_CR113","doi-asserted-by":"crossref","first-page":"15181","DOI":"10.1523\/JNEUROSCI.1542-12.2012","volume":"32","author":"T Hashimoto","year":"2012","unstructured":"Hashimoto, T. et al. Apolipoprotein E, especially apolipoprotein E4, increases the oligomerization of amyloid \u03b2 peptide. J. Neurosci. 32, 15181\u201315192 (2012).","journal-title":"J. Neurosci."},{"key":"988_CR114","doi-asserted-by":"crossref","first-page":"7267","DOI":"10.1074\/jbc.AAC118.003576","volume":"293","author":"Y Hori","year":"2018","unstructured":"Hori, Y., Hashimoto, T., Nomoto, H., Hyman, B. T. & Iwatsubo, T. Role of apolipoprotein E in \u03b2-amyloidogenesis: isoform-specific effects on protofibril to fibril conversion of A\u03b2 in vitro and brain A\u03b2 deposition in vivo. J. Biol. Chem. 293, 7267 (2018).","journal-title":"J. Biol. Chem."},{"key":"988_CR115","doi-asserted-by":"crossref","first-page":"6323","DOI":"10.1021\/bi5008172","volume":"53","author":"K Garai","year":"2014","unstructured":"Garai, K., Verghese, P. B., Baban, B., Holtzman, D. M. & Frieden, C. The binding of apolipoprotein E to oligomers and fibrils of amyloid-\u03b2 alters the kinetics of amyloid aggregation. Biochemistry 53, 6323\u20136331 (2014).","journal-title":"Biochemistry"},{"key":"988_CR116","doi-asserted-by":"crossref","first-page":"13247","DOI":"10.1074\/jbc.RA117.001388","volume":"293","author":"E Kara","year":"2018","unstructured":"Kara, E. et al. A flow cytometry-based in vitro assay reveals that formation of apolipoprotein E (ApoE)-amyloid beta complexes depends on ApoE isoform and cell type. J. Biol. Chem. 293, 13247\u201313256 (2018).","journal-title":"J. Biol. Chem."},{"key":"988_CR117","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1006\/nbdi.2002.0483","volume":"9","author":"AM Fagan","year":"2002","unstructured":"Fagan, A. M. et al. Human and murine ApoE markedly alters A beta metabolism before and after plaque formation in a mouse model of Alzheimer\u2019s disease. Neurobiol. Dis. 9, 305\u2013318 (2002).","journal-title":"Neurobiol. Dis."},{"key":"988_CR118","doi-asserted-by":"crossref","first-page":"15233","DOI":"10.1073\/pnas.96.26.15233","volume":"96","author":"KR Bales","year":"1999","unstructured":"Bales, K. R. et al. Apolipoprotein E is essential for amyloid deposition in the APP(V717F) transgenic mouse model of Alzheimer\u2019s disease. Proc. Natl Acad. Sci. USA 96, 15233\u201315238 (1999).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"988_CR119","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1007\/s004010000263","volume":"100","author":"MC Irizarry","year":"2000","unstructured":"Irizarry, M. C. et al. Apolipoprotein E affects the amount, form, and anatomical distribution of amyloid beta-peptide deposition in homozygous APP(V717F) transgenic mice. Acta Neuropathol. 100, 451\u2013458 (2000).","journal-title":"Acta Neuropathol."},{"key":"988_CR120","doi-asserted-by":"crossref","first-page":"41774","DOI":"10.1074\/jbc.M112.407957","volume":"287","author":"KL Youmans","year":"2012","unstructured":"Youmans, K. L. et al. APOE4-specific changes in A\u03b2 accumulation in a new transgenic mouse model of Alzheimer disease. J. Biol. Chem. 287, 41774\u201341786 (2012).","journal-title":"J. Biol. Chem."},{"key":"988_CR121","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1016\/j.cell.2016.12.044","volume":"168","author":"Y-WA Huang","year":"2017","unstructured":"Huang, Y.-W. A., Zhou, B., Wernig, M. & S\u00fcdhof, T. C. ApoE2, ApoE3, and ApoE4 differentially stimulate APP transcription and A\u03b2 secretion. Cell 168, 427\u2013441.e21 (2017).","journal-title":"Cell"},{"key":"988_CR122","doi-asserted-by":"crossref","DOI":"10.26508\/lsa.201900325","volume":"2","author":"E Hudry","year":"2019","unstructured":"Hudry, E. et al. Opposing roles of apolipoprotein E in aging and neurodegeneration. Life Sci. Alliance 2, e201900325 (2019).","journal-title":"Life Sci. Alliance"},{"key":"988_CR123","doi-asserted-by":"crossref","first-page":"1228","DOI":"10.1001\/jamaneurol.2014.2011","volume":"71","author":"ACY Mak","year":"2014","unstructured":"Mak, A. C. Y. et al. Effects of the absence of apolipoprotein E on lipoproteins, neurocognitive function, and retinal function. JAMA Neurol. 71, 1228 (2014).","journal-title":"JAMA Neurol."},{"key":"988_CR124","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1016\/j.neuron.2017.11.014","volume":"96","author":"T-PV Huynh","year":"2017","unstructured":"Huynh, T.-P. V. et al. Age-dependent effects of apoE reduction using antisense oligonucleotides in a model of \u03b2-amyloidosis. Neuron 96, 1013\u20131023.e4 (2017).","journal-title":"Neuron"},{"key":"988_CR125","doi-asserted-by":"crossref","first-page":"521","DOI":"10.3233\/JAD-190711","volume":"74","author":"T Hou","year":"2020","unstructured":"Hou, T. et al. Apolipoprotein E facilitates amyloid-\u03b2 oligomer-induced tau phosphorylation. J. Alzheimers Dis. 74, 521\u2013534 (2020).","journal-title":"J. Alzheimers Dis."},{"key":"988_CR126","doi-asserted-by":"crossref","first-page":"44795","DOI":"10.1074\/jbc.M408127200","volume":"279","author":"FM Harris","year":"2004","unstructured":"Harris, F. M., Brecht, W. J., Xu, Q., Mahley, R. W. & Huang, Y. Increased tau phosphorylation in apolipoprotein E4 transgenic mice is associated with activation of extracellular signal-regulated kinase: modulation by zinc. J. Biol. Chem. 279, 44795\u201344801 (2004).","journal-title":"J. Biol. Chem."},{"key":"988_CR127","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":"988_CR128","doi-asserted-by":"crossref","first-page":"212ra161","DOI":"10.1126\/scitranslmed.3007000","volume":"5","author":"E Hudry","year":"2013","unstructured":"Hudry, E. et al. Gene transfer of human Apoe isoforms results in differential modulation of amyloid deposition and neurotoxicity in mouse brain. Sci. Transl. Med. 5, 212ra161 (2013).","journal-title":"Sci. Transl. Med."},{"key":"988_CR129","doi-asserted-by":"crossref","first-page":"101594","DOI":"10.1016\/j.smim.2022.101594","volume":"59","author":"S Parhizkar","year":"2022","unstructured":"Parhizkar, S. & Holtzman, D. M. APOE mediated neuroinflammation and neurodegeneration in Alzheimer\u2019s disease. Semin. Immunol. 59, 101594 (2022).","journal-title":"Semin. Immunol."},{"key":"988_CR130","doi-asserted-by":"crossref","first-page":"2546","DOI":"10.1084\/jem.20190980","volume":"216","author":"Y Shi","year":"2019","unstructured":"Shi, Y. et al. Microglia drive APOE-dependent neurodegeneration in a tauopathy mouse model. J. Exp. Med. 216, 2546\u20132561 (2019).","journal-title":"J. Exp. Med."},{"key":"988_CR131","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1007\/s00401-022-02421-8","volume":"143","author":"Y Jin","year":"2022","unstructured":"Jin, Y. et al. APOE4 exacerbates \u03b1-synuclein seeding activity and contributes to neurotoxicity in Alzheimer\u2019s disease with Lewy body pathology. Acta Neuropathol. 143, 641\u2013662 (2022).","journal-title":"Acta Neuropathol."},{"key":"988_CR132","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1016\/j.neulet.2016.02.042","volume":"618","author":"FN Emamzadeh","year":"2016","unstructured":"Emamzadeh, F. N., Aojula, H., McHugh, P. C. & Allsop, D. Effects of different isoforms of apoE on aggregation of the \u03b1-synuclein protein implicated in Parkinson\u2019s disease. Neurosci. Lett. 618, 146\u2013151 (2016).","journal-title":"Neurosci. Lett."},{"key":"988_CR133","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1186\/s40478-023-01623-9","volume":"11","author":"GM Lloyd","year":"2023","unstructured":"Lloyd, G. M. et al. Carboxyl truncation of \u03b1-synuclein occurs early and is influenced by human APOE genotype in transgenic mouse models of \u03b1-synuclein pathogenesis. Acta Neuropathol. Commun. 11, 119 (2023).","journal-title":"Acta Neuropathol. Commun."},{"key":"988_CR134","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1186\/s13024-023-00620-9","volume":"18","author":"M Nemergut","year":"2023","unstructured":"Nemergut, M. et al. Domino-like effect of C112R mutation on ApoE4 aggregation and its reduction by Alzheimer\u2019s disease drug candidate. Mol. Neurodegener. 18, 38 (2023).","journal-title":"Mol. Neurodegener."},{"key":"988_CR135","doi-asserted-by":"crossref","first-page":"10722","DOI":"10.1021\/bi700672v","volume":"46","author":"Y Zhang","year":"2007","unstructured":"Zhang, Y. et al. A monomeric, biologically active, full-length human apolipoprotein E. Biochemistry 46, 10722\u201310732 (2007).","journal-title":"Biochemistry"},{"key":"988_CR136","doi-asserted-by":"crossref","first-page":"2550","DOI":"10.1021\/bi1020106","volume":"50","author":"K Garai","year":"2011","unstructured":"Garai, K., Baban, B. & Frieden, C. Dissociation of apoE oligomers to monomers is required for high affinity binding to phospholipid vesicles. Biochemistry 50, 2550\u20132558 (2011).","journal-title":"Biochemistry"},{"key":"988_CR137","doi-asserted-by":"crossref","first-page":"eabd7522","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":"988_CR138","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1002\/ana.26351","volume":"91","author":"M Gratuze","year":"2022","unstructured":"Gratuze, M. et al. APOE antibody inhibits A\u03b2\u2010associated tau seeding and spreading in a mouse model. Ann. Neurol. 91, 847\u2013852 (2022).","journal-title":"Ann. Neurol."},{"key":"988_CR139","doi-asserted-by":"crossref","first-page":"2144","DOI":"10.1172\/JCI96429","volume":"128","author":"F Liao","year":"2018","unstructured":"Liao, F. et al. Targeting of nonlipidated, aggregated apoE with antibodies inhibits amyloid accumulation. J. Clin. Invest. 128, 2144\u20132155 (2018).","journal-title":"J. Clin. Invest."},{"key":"988_CR140","doi-asserted-by":"crossref","first-page":"14720","DOI":"10.1074\/jbc.M117.784264","volume":"292","author":"E Kara","year":"2017","unstructured":"Kara, E. et al. Isoform- and cell type-specific structure of apolipoprotein E lipoparticles as revealed by a novel Forster resonance energy transfer assay. J. Biol. Chem. 292, 14720\u201314729 (2017).","journal-title":"J. Biol. Chem."},{"key":"988_CR141","doi-asserted-by":"crossref","DOI":"10.1073\/pnas.2215371120","volume":"120","author":"MD Stuchell-Brereton","year":"2023","unstructured":"Stuchell-Brereton, M. D. et al. Apolipoprotein E4 has extensive conformational heterogeneity in lipid-free and lipid-bound forms. Proc. Natl Acad. Sci. USA 120, e2215371120 (2023).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"988_CR142","doi-asserted-by":"crossref","first-page":"2161","DOI":"10.3390\/ijms20092161","volume":"20","author":"GL Suidan","year":"2019","unstructured":"Suidan, G. L. & Ramaswamy, G. Targeting apolipoprotein E for Alzheimer\u2019s disease: an industry perspective. Int. J. Mol. Sci. 20, 2161 (2019).","journal-title":"Int. J. Mol. Sci."},{"key":"988_CR143","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.1016\/j.neuron.2018.05.008","volume":"98","author":"Y-T Lin","year":"2018","unstructured":"Lin, Y.-T. et al. APOE4 causes widespread molecular and cellular alterations associated with Alzheimer\u2019s disease phenotypes in human iPSC-derived brain cell types. Neuron 98, 1141\u20131154.e7 (2018).","journal-title":"Neuron"},{"key":"988_CR144","doi-asserted-by":"crossref","first-page":"2213","DOI":"10.1016\/j.cell.2022.05.017","volume":"185","author":"J Tcw","year":"2022","unstructured":"Tcw, J. et al. Cholesterol and matrisome pathways dysregulated in astrocytes and microglia. Cell 185, 2213\u20132233.e25 (2022).","journal-title":"Cell"},{"key":"988_CR145","doi-asserted-by":"crossref","first-page":"5476","DOI":"10.1111\/ejn.15685","volume":"56","author":"OG Steele","year":"2022","unstructured":"Steele, O. G. et al. A multi\u2010hit hypothesis for an APOE4\u2010dependent pathophysiological state. Eur. J. Neurosci. 56, 5476\u20135515 (2022).","journal-title":"Eur. J. Neurosci."},{"key":"988_CR146","doi-asserted-by":"crossref","first-page":"182","DOI":"10.3390\/cells8020182","volume":"8","author":"BC Farmer","year":"2019","unstructured":"Farmer, B. C., Kluemper, J. & Johnson, L. A. Apolipoprotein E4 alters astrocyte fatty acid metabolism and lipid droplet formation. Cells 8, 182 (2019).","journal-title":"Cells"},{"key":"988_CR147","doi-asserted-by":"crossref","DOI":"10.1038\/s41419-020-02776-4","volume":"11","author":"E Schmukler","year":"2020","unstructured":"Schmukler, E. et al. Altered mitochondrial dynamics and function in APOE4-expressing astrocytes. Cell Death Dis. 11, 578 (2020).","journal-title":"Cell Death Dis."},{"key":"988_CR148","doi-asserted-by":"crossref","DOI":"10.1186\/s13024-022-00516-0","volume":"17","author":"TE Mahan","year":"2022","unstructured":"Mahan, T. E. et al. Selective reduction of astrocyte apoE3 and apoE4 strongly reduces A\u03b2 accumulation and plaque-related pathology in a mouse model of amyloidosis. Mol. Neurodegener. 17, 13 (2022).","journal-title":"Mol. Neurodegener."},{"key":"988_CR149","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2021.03.024","author":"C Wang","year":"2021","unstructured":"Wang, C. et al. Selective removal of astrocytic APOE4 strongly protects against tau-mediated neurodegeneration and decreases synaptic phagocytosis by microglia. Neuron https:\/\/doi.org\/10.1016\/j.neuron.2021.03.024 (2021).","journal-title":"Neuron"},{"key":"988_CR150","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1016\/j.immuni.2017.08.008","volume":"47","author":"S Krasemann","year":"2017","unstructured":"Krasemann, S. et al. The TREM2-APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases. Immunity 47, 566\u2013581.e9 (2017).","journal-title":"Immunity"},{"key":"988_CR151","doi-asserted-by":"crossref","first-page":"1276","DOI":"10.1016\/j.cell.2017.05.018","volume":"169","author":"H Keren-Shaul","year":"2017","unstructured":"Keren-Shaul, H. et al. A unique microglia type associated with restricting development of Alzheimer\u2019s disease. Cell 169, 1276\u20131290.e17 (2017).","journal-title":"Cell"},{"key":"988_CR152","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1038\/s43587-021-00123-6","volume":"1","author":"A Serrano-Pozo","year":"2021","unstructured":"Serrano-Pozo, A. et al. Effect of APOE alleles on the glial transcriptome in normal aging and Alzheimer\u2019s disease. Nat. Aging 1, 919\u2013931 (2021).","journal-title":"Nat. Aging"},{"key":"988_CR153","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1002\/alz.13387","volume":"20","author":"S Das","year":"2023","unstructured":"Das, S. et al. Distinct transcriptomic responses to A\u03b2 plaques, neurofibrillary tangles, and APOE in Alzheimer\u2019s disease. Alzheimers Dement. 20, 74\u201390 (2023).","journal-title":"Alzheimers Dement."},{"key":"988_CR154","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1186\/s40478-019-0729-z","volume":"7","author":"TL Stephen","year":"2019","unstructured":"Stephen, T. L. et al. APOE genotype and sex affect microglial interactions with plaques in Alzheimer\u2019s disease mice. Acta Neuropathol. Commun. 7, 82 (2019).","journal-title":"Acta Neuropathol. Commun."},{"key":"988_CR155","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1084\/jem.20151948","volume":"213","author":"Y Wang","year":"2016","unstructured":"Wang, Y. et al. TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques. J. Exp. Med. 213, 667\u2013675 (2016).","journal-title":"J. Exp. Med."},{"key":"988_CR156","doi-asserted-by":"crossref","first-page":"1478","DOI":"10.1002\/glia.23974","volume":"69","author":"MF Lanfranco","year":"2021","unstructured":"Lanfranco, M. F., Sepulveda, J., Kopetsky, G. & Rebeck, G. W. Expression and secretion of apoE isoforms in astrocytes and microglia during inflammation. Glia 69, 1478\u20131493 (2021).","journal-title":"Glia"},{"key":"988_CR157","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1002\/glia.24105","volume":"70","author":"CM Henningfield","year":"2022","unstructured":"Henningfield, C. M., Arreola, M. A., Soni, N., Spangenberg, E. E. & Green, K. N. Microglia-specific ApoE knock-out does not alter Alzheimer\u2019s disease plaque pathogenesis or gene expression. Glia 70, 287\u2013302 (2022).","journal-title":"Glia"},{"key":"988_CR158","doi-asserted-by":"crossref","first-page":"1839","DOI":"10.1038\/s41590-023-01627-6","volume":"24","author":"Z Yin","year":"2023","unstructured":"Yin, Z. et al. APOE4 impairs the microglial response in Alzheimer\u2019s disease by inducing TGF\u03b2-mediated checkpoints. Nat. Immunol. 24, 1839\u20131853 (2023).","journal-title":"Nat. Immunol."},{"key":"988_CR159","doi-asserted-by":"crossref","first-page":"563","DOI":"10.2353\/ajpath.2010.090973","volume":"177","author":"M Buttini","year":"2010","unstructured":"Buttini, M. et al. Cellular source of apolipoprotein E4 determines neuronal susceptibility to excitotoxic injury in transgenic mice. Am. J. Pathol. 177, 563\u2013569 (2010).","journal-title":"Am. J. Pathol."},{"key":"988_CR160","doi-asserted-by":"crossref","first-page":"734001","DOI":"10.3389\/fnins.2021.734001","volume":"15","author":"SC Konings","year":"2021","unstructured":"Konings, S. C., Torres-Garcia, L., Martinsson, I. & Gouras, G. K. Astrocytic and neuronal apolipoprotein E isoforms differentially affect neuronal excitability. Front. Neurosci. 15, 734001 (2021).","journal-title":"Front. Neurosci."},{"key":"988_CR161","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1038\/s43587-023-00368-3","volume":"3","author":"N Koutsodendris","year":"2023","unstructured":"Koutsodendris, N. et al. Neuronal APOE4 removal protects against tau-mediated gliosis, neurodegeneration and myelin deficits. Nat. Aging 3, 275\u2013296 (2023).","journal-title":"Nat. Aging"},{"key":"988_CR162","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1093\/jnen\/nlac054","volume":"81","author":"GW-Y Cheng","year":"2022","unstructured":"Cheng, G. W.-Y. et al. Apolipoprotein E \u03b54 mediates myelin breakdown by targeting oligodendrocytes in sporadic Alzheimer disease. J. Neuropathol. Exp. Neurol. 81, 717\u2013730 (2022).","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"988_CR163","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1038\/s41586-022-05439-w","volume":"611","author":"JW Blanchard","year":"2022","unstructured":"Blanchard, J. W. et al. APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes. Nature 611, 769\u2013779 (2022).","journal-title":"Nature"},{"key":"988_CR164","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1111\/jnc.15748","volume":"165","author":"KK-S Mok","year":"2023","unstructured":"Mok, K. K.-S. et al. Apolipoprotein E \u03b54 disrupts oligodendrocyte differentiation by interfering with astrocyte-derived lipid transport. J. Neurochem. 165, 55\u201375 (2023).","journal-title":"J. Neurochem."},{"key":"988_CR165","doi-asserted-by":"crossref","first-page":"18694","DOI":"10.1073\/pnas.0508254102","volume":"102","author":"S Chang","year":"2005","unstructured":"Chang, S. et al. Lipid- and receptor-binding regions of apolipoprotein E4 fragments act in concert to cause mitochondrial dysfunction and neurotoxicity. Proc. Natl Acad. Sci. USA 102, 18694\u201318699 (2005).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"988_CR166","doi-asserted-by":"crossref","first-page":"5215","DOI":"10.1074\/jbc.M110.151084","volume":"286","author":"H-K Chen","year":"2011","unstructured":"Chen, H.-K. et al. Apolipoprotein E4 domain interaction mediates detrimental effects on mitochondria and is a potential therapeutic target for Alzheimer disease. J. Biol. Chem. 286, 5215\u20135221 (2011).","journal-title":"J. Biol. Chem."},{"key":"988_CR167","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1016\/j.jalz.2017.07.754","volume":"14","author":"PA Parcon","year":"2018","unstructured":"Parcon, P. A. et al. Apolipoprotein E4 inhibits autophagy gene products through direct, specific binding to CLEAR motifs. Alzheimers Dement. 14, 230\u2013242 (2018).","journal-title":"Alzheimers Dement."},{"key":"988_CR168","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1038\/s41380-022-01631-6","volume":"28","author":"A Mary","year":"2023","unstructured":"Mary, A., Eysert, F., Checler, F. & Chami, M. Mitophagy in Alzheimer\u2019s disease: molecular defects and therapeutic approaches. Mol. Psychiatry 28, 202\u2013216 (2023).","journal-title":"Mol. Psychiatry"},{"key":"988_CR169","doi-asserted-by":"crossref","first-page":"113183","DOI":"10.1016\/j.celrep.2023.113183","volume":"42","author":"H Lee","year":"2023","unstructured":"Lee, H. et al. ApoE4-dependent lysosomal cholesterol accumulation impairs mitochondrial homeostasis and oxidative phosphorylation in human astrocytes. Cell Rep. 42, 113183 (2023).","journal-title":"Cell Rep."},{"key":"988_CR170","first-page":"e2404","volume":"94","author":"J Yin","year":"2020","unstructured":"Yin, J. et al. Effect of ApoE isoforms on mitochondria in Alzheimer disease. Neurology 94, e2404\u2013e2411 (2020).","journal-title":"Neurology"},{"key":"988_CR171","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-020-16074-2","volume":"11","author":"M Calvo-Rodriguez","year":"2020","unstructured":"Calvo-Rodriguez, M. et al. Increased mitochondrial calcium levels associated with neuronal death in a mouse model of Alzheimer\u2019s disease. Nat. Commun. 11, 2146 (2020).","journal-title":"Nat. Commun."},{"key":"988_CR172","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1186\/s13024-024-00702-2","volume":"19","author":"M Calvo-Rodriguez","year":"2024","unstructured":"Calvo-Rodriguez, M. et al. Real-time imaging of mitochondrial redox reveals increased mitochondrial oxidative stress associated with amyloid \u03b2 aggregates in vivo in a mouse model of Alzheimer\u2019s disease. Mol. Neurodegener. 19, 6 (2024).","journal-title":"Mol. Neurodegener."},{"key":"988_CR173","doi-asserted-by":"crossref","first-page":"991","DOI":"10.3233\/JAD-181184","volume":"68","author":"AL Orr","year":"2019","unstructured":"Orr, A. L. et al. Neuronal apolipoprotein E4 expression results in proteome-wide alterations and compromises bioenergetic capacity by disrupting mitochondrial function. J. Alzheimers Dis. 68, 991\u20131011 (2019).","journal-title":"J. Alzheimers Dis."},{"key":"988_CR174","doi-asserted-by":"crossref","DOI":"10.1038\/s41598-020-61142-8","volume":"10","author":"E Area-Gomez","year":"2020","unstructured":"Area-Gomez, E. et al. APOE4 is associated with differential regional vulnerability to bioenergetic deficits in aged APOE mice. Sci. Rep. 10, 4277 (2020).","journal-title":"Sci. Rep."},{"key":"988_CR175","doi-asserted-by":"crossref","first-page":"104742","DOI":"10.1016\/j.nbd.2020.104742","volume":"136","author":"HC Williams","year":"2020","unstructured":"Williams, H. C. et al. APOE alters glucose flux through central carbon pathways in astrocytes. Neurobiol. Dis. 136, 104742 (2020).","journal-title":"Neurobiol. Dis."},{"key":"988_CR176","doi-asserted-by":"crossref","first-page":"112196","DOI":"10.1016\/j.celrep.2023.112196","volume":"42","author":"S Lee","year":"2023","unstructured":"Lee, S. et al. APOE modulates microglial immunometabolism in response to age, amyloid pathology, and inflammatory challenge. Cell Rep. 42, 112196 (2023).","journal-title":"Cell Rep."},{"key":"988_CR177","doi-asserted-by":"crossref","first-page":"108572","DOI":"10.1016\/j.celrep.2020.108572","volume":"34","author":"G Qi","year":"2021","unstructured":"Qi, G. et al. ApoE4 impairs neuron\u2013astrocyte coupling of fatty acid metabolism. Cell Rep. 34, 108572 (2021).","journal-title":"Cell Rep."},{"key":"988_CR178","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1038\/s41586-024-07185-7","volume":"628","author":"MS Haney","year":"2024","unstructured":"Haney, M. S. et al. APOE4\/4 is linked to damaging lipid droplets in Alzheimer\u2019s disease microglia. Nature 628, 154\u2013161 (2024).","journal-title":"Nature"},{"key":"988_CR179","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1016\/j.bbalip.2010.05.004","volume":"1801","author":"P Foley","year":"2010","unstructured":"Foley, P. Lipids in Alzheimer\u2019s disease: a century-old story. Biochim. Biophys. Acta 1801, 750\u2013753 (2010).","journal-title":"Biochim. Biophys. Acta"},{"key":"988_CR180","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.85779","volume":"12","author":"ME Wynne","year":"2023","unstructured":"Wynne, M. E. et al. APOE expression and secretion are modulated by mitochondrial dysfunction. eLife 12, e85779 (2023).","journal-title":"eLife"},{"key":"988_CR181","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1186\/s13024-019-0337-1","volume":"14","author":"T-PV Huynh","year":"2019","unstructured":"Huynh, T.-P. V. et al. Lack of hepatic apoE does not influence early A\u03b2 deposition: observations from a new APOE knock-in model. Mol. Neurodegener. 14, 37 (2019).","journal-title":"Mol. Neurodegener."},{"key":"988_CR182","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1172\/JCI115288","volume":"88","author":"MF Linton","year":"1991","unstructured":"Linton, M. F. et al. Phenotypes of apolipoprotein B and apolipoprotein E after liver transplantation. J. Clin. Invest. 88, 270\u2013281 (1991).","journal-title":"J. Clin. Invest."},{"key":"988_CR183","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1038\/nature11087","volume":"485","author":"RD Bell","year":"2012","unstructured":"Bell, R. D. et al. Apolipoprotein E controls cerebrovascular integrity via cyclophilin A. Nature 485, 512\u2013516 (2012).","journal-title":"Nature"},{"key":"988_CR184","doi-asserted-by":"crossref","first-page":"3582","DOI":"10.1093\/brain\/awab478","volume":"145","author":"RJ Jackson","year":"2022","unstructured":"Jackson, R. J. et al. APOE4 derived from astrocytes leads to blood\u2013brain barrier impairment. Brain 145, 3582\u20133593 (2022).","journal-title":"Brain"},{"key":"988_CR185","doi-asserted-by":"crossref","first-page":"71","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, 71\u201376 (2020).","journal-title":"Nature"},{"key":"988_CR186","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1186\/s13024-023-00610-x","volume":"18","author":"M Xiong","year":"2023","unstructured":"Xiong, M. et al. Astrocytic APOE4 removal confers cerebrovascular protection despite increased cerebral amyloid angiopathy. Mol. Neurodegener. 18, 17 (2023).","journal-title":"Mol. Neurodegener."},{"key":"988_CR187","doi-asserted-by":"crossref","first-page":"1826","DOI":"10.1177\/0271678X231172842","volume":"43","author":"O Bonnar","year":"2023","unstructured":"Bonnar, O. et al. APOE4 expression confers a mild, persistent reduction in neurovascular function in the visual cortex and hippocampus of awake mice. J. Cereb. Blood Flow Metab. 43, 1826\u20131841 (2023).","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"988_CR188","volume":"9","author":"K Koizumi","year":"2018","unstructured":"Koizumi, K. et al. Apo\u03b54 disrupts neurovascular regulation and undermines white matter integrity and cognitive function. Nat. Commun. 9, 3816 (2018).","journal-title":"Nat. Commun."},{"key":"988_CR189","doi-asserted-by":"crossref","first-page":"6846721","DOI":"10.1155\/2016\/6846721","volume":"2016","author":"M Wiesmann","year":"2016","unstructured":"Wiesmann, M. et al. A dietary treatment improves cerebral blood flow and brain connectivity in aging apoE4 mice. Neural Plast. 2016, 6846721 (2016).","journal-title":"Neural Plast."},{"key":"988_CR190","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":"988_CR191","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1002\/ana.26864","volume":"95","author":"JM Vance","year":"2024","unstructured":"Vance, J. M. et al. Report of the APOE4 National Institute on Aging\/Alzheimer Disease Sequencing Project Consortium Working Group: reducing APOE4 in carriers is a therapeutic goal for Alzheimer\u2019s disease. Ann. Neurol. 95, 625\u2013634 (2024).","journal-title":"Ann. Neurol."},{"key":"988_CR192","doi-asserted-by":"crossref","first-page":"2155","DOI":"10.1093\/brain\/aws127","volume":"135","author":"RM Koffie","year":"2012","unstructured":"Koffie, R. M. et al. Apolipoprotein E4 effects in Alzheimer\u2019s disease are mediated by synaptotoxic oligomeric amyloid-\u03b2. Brain 135, 2155\u20132168 (2012).","journal-title":"Brain"},{"key":"988_CR193","doi-asserted-by":"crossref","first-page":"1750","DOI":"10.1016\/j.ajpath.2013.01.034","volume":"182","author":"MA Kuszczyk","year":"2013","unstructured":"Kuszczyk, M. A. et al. Blocking the interaction between apolipoprotein E and A\u03b2 reduces intraneuronal accumulation of A\u03b2 and inhibits synaptic degeneration. Am. J. Pathol. 182, 1750\u20131768 (2013).","journal-title":"Am. J. Pathol."},{"key":"988_CR194","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1111\/jnc.12484","volume":"128","author":"S Liu","year":"2014","unstructured":"Liu, S. et al. Blocking the apolipoprotein E\/amyloid \u03b2 interaction in triple transgenic mice ameliorates Alzheimer\u2019s disease related amyloid \u03b2 and tau pathology. J. Neurochem. 128, 577\u2013591 (2014).","journal-title":"J. Neurochem."},{"key":"988_CR195","doi-asserted-by":"crossref","first-page":"2535","DOI":"10.4049\/jimmunol.1002847","volume":"186","author":"DJ Christensen","year":"2011","unstructured":"Christensen, D. J. et al. Apolipoprotein E and peptide mimetics modulate inflammation by binding the SET protein and activating protein phosphatase 2A. J. Immunol. 186, 2535\u20132542 (2011).","journal-title":"J. Immunol."},{"key":"988_CR196","doi-asserted-by":"crossref","first-page":"146685","DOI":"10.1016\/j.brainres.2020.146685","volume":"1733","author":"K Krishnamurthy","year":"2020","unstructured":"Krishnamurthy, K. et al. ApoE mimetic improves pathology and memory in a model of Alzheimer\u2019s disease. Brain Res. 1733, 146685 (2020).","journal-title":"Brain Res."},{"key":"988_CR197","doi-asserted-by":"crossref","first-page":"2104","DOI":"10.1038\/s41593-023-01480-8","volume":"26","author":"MR Nelson","year":"2023","unstructured":"Nelson, M. R. et al. The APOE-R136S mutation protects against APOE4-driven Tau pathology, neurodegeneration and neuroinflammation. Nat. Neurosci. 26, 2104\u20132121 (2023).","journal-title":"Nat. Neurosci."},{"key":"988_CR198","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1016\/j.cell.2023.11.029","volume":"187","author":"Y Chen","year":"2023","unstructured":"Chen, Y. et al. APOE3ch alters microglial response and suppresses A\u03b2-induced tau seeding and spread. Cell 187, 428\u2013445.e20 (2023).","journal-title":"Cell"},{"key":"988_CR199","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1002\/alz.13436","volume":"20","author":"C Marino","year":"2023","unstructured":"Marino, C. et al. APOE Christchurch-mimetic therapeutic antibody reduces APOE-mediated toxicity and tau phosphorylation. Alzheimers Dement. 20, 819\u2013836 (2023).","journal-title":"Alzheimers Dement."},{"key":"988_CR200","doi-asserted-by":"crossref","first-page":"1723","DOI":"10.1056\/NEJMoa1702752","volume":"377","author":"RS Finkel","year":"2017","unstructured":"Finkel, R. S. et al. Nusinersen versus sham control in infantile-onset spinal muscular atrophy. N. Engl. J. Med. 377, 1723\u20131732 (2017).","journal-title":"N. Engl. J. Med."},{"key":"988_CR201","doi-asserted-by":"crossref","first-page":"1713","DOI":"10.1056\/NEJMoa1706198","volume":"377","author":"JR Mendell","year":"2017","unstructured":"Mendell, J. R. et al. Single-dose gene-replacement therapy for spinal muscular atrophy. N. Engl. J. Med. 377, 1713\u20131722 (2017).","journal-title":"N. Engl. J. Med."},{"key":"988_CR202","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.neurobiolaging.2016.04.020","volume":"44","author":"L Zhao","year":"2016","unstructured":"Zhao, L. et al. Intracerebral adeno-associated virus gene delivery of apolipoprotein E2 markedly reduces brain amyloid pathology in Alzheimer\u2019s disease mouse models. Neurobiol. Aging 44, 159\u2013172 (2016).","journal-title":"Neurobiol. Aging"},{"key":"988_CR203","doi-asserted-by":"crossref","first-page":"1373","DOI":"10.1016\/j.ymthe.2024.03.024","volume":"32","author":"RJ Jackson","year":"2024","unstructured":"Jackson, R. J. et al. APOE2 gene therapy reduces amyloid deposition and improves markers of neuroinflammation and neurodegeneration in a mouse model of Alzheimer disease. Mol. Ther. 32, 1373\u20131386 (2024).","journal-title":"Mol. Ther."},{"key":"988_CR204","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1089\/humc.2017.231","volume":"29","author":"JB Rosenberg","year":"2018","unstructured":"Rosenberg, J. B. et al. AAVrh.10-mediated APOE2 central nervous system gene therapy for APOE4-associated Alzheimer\u2019s disease. Hum. Gene Ther. Clin. Dev. 29, 24\u201347 (2018).","journal-title":"Hum. Gene Ther. Clin. Dev."},{"key":"988_CR205","doi-asserted-by":"crossref","first-page":"811","DOI":"10.3389\/fimmu.2019.00811","volume":"10","author":"S Ben Mkaddem","year":"2019","unstructured":"Ben Mkaddem, S., Benhamou, M. & Monteiro, R. C. Understanding Fc receptor involvement in inflammatory diseases: from mechanisms to new therapeutic tools. Front. Immunol. 10, 811 (2019).","journal-title":"Front. Immunol."},{"key":"988_CR206","doi-asserted-by":"crossref","first-page":"952","DOI":"10.1002\/ana.26043","volume":"89","author":"A Litvinchuk","year":"2021","unstructured":"Litvinchuk, A. et al. Apolipoprotein E4 reduction with antisense oligonucleotides decreases neurodegeneration in a tauopathy model. Ann. Neurol. 89, 952\u2013966 (2021).","journal-title":"Ann. Neurol."},{"key":"988_CR207","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1073\/pnas.98.2.507","volume":"98","author":"BA Laffitte","year":"2001","unstructured":"Laffitte, B. A. et al. LXRs control lipid-inducible expression of the apolipoprotein E gene in macrophages and adipocytes. Proc. Natl Acad. Sci. USA 98, 507\u2013512 (2001).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"988_CR208","doi-asserted-by":"crossref","first-page":"7293","DOI":"10.1523\/JNEUROSCI.5198-13.2014","volume":"34","author":"A Boehm-Cagan","year":"2014","unstructured":"Boehm-Cagan, A. & Michaelson, D. M. Reversal of apoE4-driven brain pathology and behavioral deficits by bexarotene. J. Neurosci. 34, 7293\u20137301 (2014).","journal-title":"J. Neurosci."},{"key":"988_CR209","doi-asserted-by":"crossref","first-page":"1503","DOI":"10.1126\/science.1217697","volume":"335","author":"PE Cramer","year":"2012","unstructured":"Cramer, P. E. et al. ApoE-directed therapeutics rapidly clear \u03b2-amyloid and reverse deficits in AD mouse models. Science 335, 1503\u20131506 (2012).","journal-title":"Science"},{"key":"988_CR210","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.trci.2016.06.001","volume":"2","author":"K Ghosal","year":"2016","unstructured":"Ghosal, K. et al. A randomized controlled study to evaluate the effect of bexarotene on amyloid-\u03b2 and apolipoprotein E metabolism in healthy subjects. Alzheimers Dement. (N. Y.) 2, 110\u2013120 (2016).","journal-title":"Alzheimers Dement. (N. Y.)"},{"key":"988_CR211","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/s13195-016-0173-2","volume":"8","author":"JL Cummings","year":"2016","unstructured":"Cummings, J. L. et al. Double-blind, placebo-controlled, proof-of-concept trial of bexarotene Xin moderate Alzheimer\u2019s disease. Alzheimers Res. Ther. 8, 4 (2016).","journal-title":"Alzheimers Res. Ther."},{"key":"988_CR212","doi-asserted-by":"crossref","first-page":"1219","DOI":"10.3233\/JAD-160467","volume":"54","author":"A Boehm-Cagan","year":"2016","unstructured":"Boehm-Cagan, A. et al. ABCA1 agonist reverses the ApoE4-driven cognitive and brain pathologies. J. Alzheimers Dis. 54, 1219\u20131233 (2016).","journal-title":"J. Alzheimers Dis."},{"key":"988_CR213","doi-asserted-by":"crossref","first-page":"17217","DOI":"10.1074\/jbc.M110.217380","volume":"286","author":"J Brodbeck","year":"2011","unstructured":"Brodbeck, J. et al. Structure-dependent impairment of intracellular apolipoprotein E4 trafficking and its detrimental effects are rescued by small-molecule structure correctors. J. Biol. Chem. 286, 17217\u201317226 (2011).","journal-title":"J. Biol. Chem."},{"key":"988_CR214","doi-asserted-by":"crossref","first-page":"5253","DOI":"10.1074\/jbc.M111.276162","volume":"287","author":"HK Chen","year":"2012","unstructured":"Chen, H. K. et al. Small molecule structure correctors abolish detrimental effects of apolipoprotein E4 in cultured neurons. J. Biol. Chem. 287, 5253\u20135266 (2012).","journal-title":"J. Biol. Chem."},{"key":"988_CR215","doi-asserted-by":"crossref","first-page":"8997","DOI":"10.1021\/jm3008618","volume":"55","author":"RW Mahley","year":"2012","unstructured":"Mahley, R. W. & Huang, Y. Small-molecule structure correctors target abnormal protein structure and function: the structure corrector rescue of apolipoprotein E4-associated neuropathology. J. Med. Chem. 55, 8997\u20139008 (2012).","journal-title":"J. Med. Chem."},{"key":"988_CR216","doi-asserted-by":"crossref","first-page":"4120","DOI":"10.1021\/acs.jmedchem.9b00178","volume":"62","author":"AM Petros","year":"2019","unstructured":"Petros, A. M. et al. Fragment-based discovery of an apolipoprotein E4 (apoE4) stabilizer. J. Med. Chem. 62, 4120\u20134130 (2019).","journal-title":"J. Med. Chem."},{"key":"988_CR217","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. Nat. Med. 24, 647\u2013657 (2018).","journal-title":"Nat. Med."},{"key":"988_CR218","doi-asserted-by":"crossref","first-page":"630502","DOI":"10.3389\/fnins.2021.630502","volume":"15","author":"MA Husain","year":"2021","unstructured":"Husain, M. A., Laurent, B. & Plourde, M. APOE and Alzheimer\u2019s disease: from lipid transport to physiopathology and therapeutics. Front. Neurosci. 15, 630502 (2021).","journal-title":"Front. Neurosci."},{"key":"988_CR219","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1186\/s13024-022-00574-4","volume":"17","author":"A-C Raulin","year":"2022","unstructured":"Raulin, A.-C. et al. ApoE in Alzheimer\u2019s disease: pathophysiology and therapeutic strategies. Mol. Neurodegener. 17, 72 (2022).","journal-title":"Mol. Neurodegener."},{"key":"988_CR220","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1093\/glycob\/cwz084","volume":"30","author":"SA Flowers","year":"2020","unstructured":"Flowers, S. A., Grant, O. C., Woods, R. J. & Rebeck, G. W. O-glycosylation on cerebrospinal fluid and plasma apolipoprotein E differs in the lipid-binding domain. Glycobiology 30, 74\u201385 (2020).","journal-title":"Glycobiology"},{"key":"988_CR221","doi-asserted-by":"crossref","first-page":"40987","DOI":"10.1074\/jbc.M407963200","volume":"279","author":"SE Wahrle","year":"2004","unstructured":"Wahrle, S. E. et al. ABCA1 is required for normal central nervous system ApoE levels and for lipidation of astrocyte-secreted apoE. J. Biol. Chem. 279, 40987\u201340993 (2004).","journal-title":"J. Biol. Chem."},{"key":"988_CR222","doi-asserted-by":"crossref","first-page":"eaaz4564","DOI":"10.1126\/scitranslmed.aaz4564","volume":"13","author":"G Sienski","year":"2021","unstructured":"Sienski, G. et al. APOE4 disrupts intracellular lipid homeostasis in human iPSC-derived glia. Sci. Transl. Med. 13, eaaz4564 (2021).","journal-title":"Sci. Transl. Med."},{"key":"988_CR223","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1016\/j.neuron.2016.06.015","volume":"91","author":"FL Yeh","year":"2016","unstructured":"Yeh, F. L., Wang, Y., Tom, I., Gonzalez, L. C. & Sheng, M. TREM2 binds to apolipoproteins, including APOE and CLU\/APOJ, and thereby facilitates uptake of amyloid-beta by microglia. Neuron 91, 328\u2013340 (2016).","journal-title":"Neuron"},{"key":"988_CR224","doi-asserted-by":"crossref","first-page":"100715","DOI":"10.1016\/j.jbc.2021.100715","volume":"296","author":"JM Cooper","year":"2021","unstructured":"Cooper, J. M. et al. Regulation of tau internalization, degradation, and seeding by LRP1 reveals multiple pathways for tau catabolism. J. Biol. Chem. 296, 100715 (2021).","journal-title":"J. Biol. Chem."},{"key":"988_CR225","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1038\/s41586-020-2156-5","volume":"580","author":"JN Rauch","year":"2020","unstructured":"Rauch, J. N. et al. LRP1 is a master regulator of tau uptake and spread. Nature 580, 381\u2013385 (2020).","journal-title":"Nature"},{"key":"988_CR226","first-page":"E3138","volume":"110","author":"BB Holmes","year":"2013","unstructured":"Holmes, B. B. et al. Heparan sulfate proteoglycans mediate internalization and propagation of specific proteopathic seeds. Proc. Natl Acad. Sci. USA 110, E3138\u2013E3147 (2013).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"988_CR227","doi-asserted-by":"crossref","first-page":"6820","DOI":"10.1073\/pnas.0900345106","volume":"106","author":"EM Reiman","year":"2009","unstructured":"Reiman, E. M. et al. Fibrillar amyloid-beta burden in cognitively normal people at 3 levels of genetic risk for Alzheimer\u2019s disease. Proc. Natl Acad. Sci. USA 106, 6820\u20136825 (2009).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"988_CR228","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1001\/jamaneurol.2020.0387","volume":"77","author":"RA Sperling","year":"2020","unstructured":"Sperling, R. A. et al. Association of factors with elevated amyloid burden in clinically normal older individuals. JAMA Neurol. 77, 735\u2013745 (2020).","journal-title":"JAMA Neurol."},{"key":"988_CR229","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1001\/jamaneurol.2021.5216","volume":"79","author":"WJ Jansen","year":"2022","unstructured":"Jansen, W. J. et al. Prevalence estimates of amyloid abnormality across the Alzheimer disease clinical spectrum. JAMA Neurol. 79, 228\u2013243 (2022).","journal-title":"JAMA Neurol."},{"key":"988_CR230","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1001\/jamaneurol.2020.3780","volume":"78","author":"PS Insel","year":"2021","unstructured":"Insel, P. S., Hansson, O. & Mattsson-Carlgren, N. Association between apolipoprotein E \u03b52 vs \u03b54, age, and \u03b2-amyloid in adults without cognitive impairment. JAMA Neurol. 78, 229\u2013235 (2021).","journal-title":"JAMA Neurol."},{"key":"988_CR231","doi-asserted-by":"crossref","DOI":"10.1001\/jamanetworkopen.2019.13909","volume":"2","author":"VK Ramanan","year":"2019","unstructured":"Ramanan, V. K. et al. Association of apolipoprotein E \u025b4, educational level, and sex with tau deposition and tau-mediated metabolic dysfunction in older adults. JAMA Netw. Open 2, e1913909 (2019).","journal-title":"JAMA Netw. Open"},{"key":"988_CR232","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13024-022-00590-4","volume":"18","author":"CB Young","year":"2023","unstructured":"Young, C. B. et al. APOE effects on regional tau in preclinical Alzheimer\u2019s disease. Mol. Neurodegener. 18, 1 (2023).","journal-title":"Mol. Neurodegener."},{"key":"988_CR233","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":"988_CR234","doi-asserted-by":"crossref","first-page":"1295","DOI":"10.1001\/jamaneurol.2023.4038","volume":"80","author":"A Steward","year":"2023","unstructured":"Steward, A. et al. ApoE4 and connectivity-mediated spreading of tau pathology at lower amyloid levels. JAMA Neurol. 80, 1295\u20131306 (2023).","journal-title":"JAMA Neurol."},{"key":"988_CR235","doi-asserted-by":"crossref","first-page":"1210","DOI":"10.1038\/s43587-023-00490-2","volume":"3","author":"JP Ferrari-Souza","year":"2023","unstructured":"Ferrari-Souza, J. P. et al. APOE\u03b54 potentiates amyloid \u03b2 effects on longitudinal tau pathology. Nat. Aging 3, 1210\u20131218 (2023).","journal-title":"Nat. Aging"},{"key":"988_CR236","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1002\/ana.21843","volume":"67","author":"JC Morris","year":"2010","unstructured":"Morris, J. C. et al. APOE predicts amyloid-beta but not tau Alzheimer pathology in cognitively normal aging. Ann. Neurol. 67, 122\u2013131 (2010).","journal-title":"Ann. Neurol."},{"key":"988_CR237","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1212\/WNL.0b013e318224afa3","volume":"77","author":"SS Maxwell","year":"2011","unstructured":"Maxwell, S. S. et al. Genetic associations with brain microbleeds: systematic review and meta-analyses. Neurology 77, 158\u2013167 (2011).","journal-title":"Neurology"},{"key":"988_CR238","first-page":"e3331","volume":"95","author":"MJ Knol","year":"2020","unstructured":"Knol, M. J. et al. Association of common genetic variants with brain microbleeds: a genome-wide association study. Neurology 95, e3331\u2013e3343 (2020).","journal-title":"Neurology"},{"key":"988_CR239","first-page":"e358","volume":"93","author":"A Charidimou","year":"2019","unstructured":"Charidimou, A. et al. APOE and cortical superficial siderosis in CAA: meta-analysis and potential mechanisms. Neurology 93, e358\u2013e371 (2019).","journal-title":"Neurology"},{"key":"988_CR240","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1001\/jamaneurol.2015.4078","volume":"73","author":"E Auriel","year":"2016","unstructured":"Auriel, E. et al. Validation of clinicoradiological criteria for the diagnosis of cerebral amyloid angiopathy-related inflammation. JAMA Neurol. 73, 197\u2013202 (2016).","journal-title":"JAMA Neurol."},{"key":"988_CR241","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1161\/STROKEAHA.122.040671","volume":"54","author":"A Theodorou","year":"2023","unstructured":"Theodorou, A. et al. Clinical, neuroimaging, and genetic markers in cerebral amyloid angiopathy-related inflammation: a systematic review and meta-analysis. Stroke 54, 178\u2013188 (2023).","journal-title":"Stroke"},{"key":"988_CR242","doi-asserted-by":"crossref","first-page":"3334","DOI":"10.1073\/pnas.061509598","volume":"98","author":"EM Reiman","year":"2001","unstructured":"Reiman, E. M. et al. Declining brain activity in cognitively normal apolipoprotein E \u03b54 heterozygotes: a foundation for using positron emission tomography to efficiently test treatments to prevent Alzheimer\u2019s disease. Proc. Natl Acad. Sci. USA 98, 3334\u20133339 (2001).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"988_CR243","doi-asserted-by":"crossref","first-page":"8299","DOI":"10.1073\/pnas.0500579102","volume":"102","author":"EM Reiman","year":"2005","unstructured":"Reiman, E. M. et al. Correlations between apolipoprotein E \u03b54 gene dose and brain-imaging measurements of regional hypometabolism. Proc. Natl Acad. Sci. USA 102, 8299\u20138302 (2005).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"988_CR244","first-page":"462","volume":"67","author":"JBS Langbaum","year":"2010","unstructured":"Langbaum, J. B. S. et al. Hypometabolism in Alzheimer-affected brain regions in cognitively healthy Latino individuals carrying the apolipoprotein E \u03b54 allele. Arch. Neurol. 67, 462\u2013468 (2010).","journal-title":"Arch. Neurol."},{"key":"988_CR245","doi-asserted-by":"crossref","first-page":"2096","DOI":"10.1016\/j.neurobiolaging.2014.03.006","volume":"35","author":"DS Knopman","year":"2014","unstructured":"Knopman, D. S. et al. 18F-fluorodeoxyglucose positron emission tomography, aging, and apolipoprotein E genotype in cognitively normal persons. Neurobiol. Aging 35, 2096\u20132106 (2014).","journal-title":"Neurobiol. Aging"},{"key":"988_CR246","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1186\/s13195-023-01221-w","volume":"15","author":"M Malek-Ahmadi","year":"2023","unstructured":"Malek-Ahmadi, M. et al. Plasma NfL is associated with the APOE \u03b54 allele, brain imaging measurements of neurodegeneration, and lower recall memory scores in cognitively unimpaired late-middle-aged and older adults. Alzheimers Res. Ther. 15, 74 (2023).","journal-title":"Alzheimers Res. Ther."},{"key":"988_CR247","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1093\/brain\/awab294","volume":"145","author":"A Strom","year":"2022","unstructured":"Strom, A. et al. Cortical hypometabolism reflects local atrophy and tau pathology in symptomatic Alzheimer\u2019s disease. Brain 145, 713\u2013728 (2022).","journal-title":"Brain"},{"key":"988_CR248","doi-asserted-by":"crossref","first-page":"1383","DOI":"10.1002\/alz.12487","volume":"18","author":"G Salvad\u00f3","year":"2022","unstructured":"Salvad\u00f3, G. et al. The protective gene dose effect of the APOE \u03b52 allele on gray matter volume in cognitively unimpaired individuals. Alzheimers Dement. 18, 1383\u20131395 (2022).","journal-title":"Alzheimers Dement."},{"key":"988_CR249","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.neurobiolaging.2021.02.008","volume":"102","author":"OH Butt","year":"2021","unstructured":"Butt, O. H. et al. Cognitively normal APOE \u03b54 carriers have specific elevation of CSF SNAP-25. Neurobiol. Aging 102, 64\u201372 (2021).","journal-title":"Neurobiol. Aging"},{"key":"988_CR250","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.1016\/j.jalz.2016.05.003","volume":"12","author":"X Sun","year":"2016","unstructured":"Sun, X. et al. APOE \u03b54 carriers may undergo synaptic damage conferring risk of Alzheimer\u2019s disease. Alzheimers Dement. 12, 1159\u20131166 (2016).","journal-title":"Alzheimers Dement."},{"key":"988_CR251","doi-asserted-by":"crossref","first-page":"eade1474","DOI":"10.1126\/sciadv.ade1474","volume":"9","author":"JP Ferrari-Souza","year":"2023","unstructured":"Ferrari-Souza, J. P. et al. APOE\u03b54 associates with microglial activation independently of A\u03b2 plaques and tau tangles. Sci. Adv. 9, eade1474 (2023).","journal-title":"Sci. Adv."},{"key":"988_CR252","doi-asserted-by":"crossref","first-page":"1471","DOI":"10.1001\/jamaneurol.2021.3671","volume":"78","author":"AL Benedet","year":"2021","unstructured":"Benedet, A. L. et al. Differences between plasma and cerebrospinal fluid glial fibrillary acidic protein levels across the Alzheimer disease continuum. JAMA Neurol. 78, 1471\u20131483 (2021).","journal-title":"JAMA Neurol."},{"key":"988_CR253","doi-asserted-by":"crossref","first-page":"fcac135","DOI":"10.1093\/braincomms\/fcac135","volume":"4","author":"N Spotorno","year":"2022","unstructured":"Spotorno, N. et al. Astrocytic function is associated with both amyloid-\u03b2 and tau pathology in non-demented APOE \u03b54 carriers. Brain Commun. 4, fcac135 (2022).","journal-title":"Brain Commun."},{"key":"988_CR254","doi-asserted-by":"crossref","first-page":"101983","DOI":"10.1016\/j.nicl.2019.101983","volume":"24","author":"G Operto","year":"2019","unstructured":"Operto, G. et al. Interactive effect of age and APOE-\u03b54 allele load on white matter myelin content in cognitively normal middle-aged subjects. NeuroImage Clin. 24, 101983 (2019).","journal-title":"NeuroImage Clin."},{"key":"988_CR255","doi-asserted-by":"crossref","first-page":"118988","DOI":"10.1016\/j.neuroimage.2022.118988","volume":"251","author":"C Triebswetter","year":"2022","unstructured":"Triebswetter, C. et al. Differential associations between apolipoprotein E alleles and cerebral myelin content in normative aging. NeuroImage 251, 118988 (2022).","journal-title":"NeuroImage"},{"key":"988_CR256","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1016\/j.neurobiolaging.2016.11.017","volume":"51","author":"S Janelidze","year":"2017","unstructured":"Janelidze, S. et al. Increased blood\u2013brain barrier permeability is associated with dementia and diabetes but not amyloid pathology or APOE genotype. Neurobiol. Aging 51, 104\u2013112 (2017).","journal-title":"Neurobiol. Aging"},{"key":"988_CR257","doi-asserted-by":"crossref","first-page":"e30","DOI":"10.1212\/WNL.0000000000207358","volume":"101","author":"C Cicognola","year":"2023","unstructured":"Cicognola, C. et al. Associations of CSF PDGFR\u03b2 with aging, blood\u2013brain barrier damage, neuroinflammation, and Alzheimer disease pathologic changes. Neurology 101, e30\u2013e39 (2023).","journal-title":"Neurology"},{"key":"988_CR258","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1016\/S0197-4580(99)00081-0","volume":"20","author":"RW Mahley","year":"1999","unstructured":"Mahley, R. W. & Rall, S. C. Is \u03b54 the ancestral human apoE allele? Neurobiol. Aging 20, 429\u2013430 (1999).","journal-title":"Neurobiol. Aging"},{"key":"988_CR259","first-page":"1001","volume":"71","author":"S Seixas","year":"1999","unstructured":"Seixas, S., Trovoada, M. J. & Rocha, J. Haplotype analysis of the apolipoprotein E and apolipoprotein C1 loci in Portugal and S\u00e3o Tom\u00e9 e Pr\u00edncipe (Gulf of Guinea): linkage disequilibrium evidence that APOE*4 is the ancestral APOE allele. Hum. Biol. 71, 1001\u20131008 (1999).","journal-title":"Hum. Biol."},{"key":"988_CR260","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1086\/303070","volume":"67","author":"SM Fullerton","year":"2000","unstructured":"Fullerton, S. M. et al. Apolipoprotein E variation at the sequence haplotype level: implications for the origin and maintenance of a major human polymorphism. Am. J. Hum. Genet. 67, 881\u2013900 (2000).","journal-title":"Am. J. Hum. Genet."},{"key":"988_CR261","doi-asserted-by":"crossref","first-page":"907","DOI":"10.3233\/JAD-221218","volume":"93","author":"CJ Smith","year":"2023","unstructured":"Smith, C. J. & Ashford, J. W. Apolipoprotein \u025b4-associated protection against pediatric enteric infections is a survival advantage in pre-industrial populations. J. Alzheimers Dis. 93, 907\u2013918 (2023).","journal-title":"J. Alzheimers Dis."},{"key":"988_CR262","doi-asserted-by":"crossref","first-page":"eade9797","DOI":"10.1126\/sciadv.ade9797","volume":"9","author":"BC Trumble","year":"2023","unstructured":"Trumble, B. C. et al. Apolipoprotein-\u03b54 is associated with higher fecundity in a natural fertility population. Sci. Adv. 9, eade9797 (2023).","journal-title":"Sci. Adv."},{"key":"988_CR263","doi-asserted-by":"crossref","first-page":"1048","DOI":"10.1038\/s41591-020-0879-3","volume":"26","author":"BN Ostendorf","year":"2020","unstructured":"Ostendorf, B. N. et al. Common germline variants of the human APOE gene modulate melanoma progression and survival. Nat. Med. 26, 1048\u20131053 (2020).","journal-title":"Nat. Med."},{"key":"988_CR264","doi-asserted-by":"crossref","DOI":"10.1038\/s41598-020-66114-6","volume":"10","author":"N Zokaei","year":"2020","unstructured":"Zokaei, N. et al. Short-term memory advantage for brief durations in human APOE \u03b54 carriers. Sci. Rep. 10, 9503 (2020).","journal-title":"Sci. Rep."},{"key":"988_CR265","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/j.bbr.2017.07.015","volume":"334","author":"C Lancaster","year":"2017","unstructured":"Lancaster, C., Forster, S., Tabet, N. & Rusted, J. Putting attention in the spotlight: the influence of APOE genotype on visual search in mid adulthood. Behav. Brain Res. 334, 97\u2013104 (2017).","journal-title":"Behav. Brain Res."},{"key":"988_CR266","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1016\/j.neurobiolaging.2016.08.015","volume":"48","author":"C Lancaster","year":"2016","unstructured":"Lancaster, C., Tabet, N. & Rusted, J. The APOE paradox: do attentional control differences in mid-adulthood reflect risk of late-life cognitive decline. Neurobiol. Aging 48, 114\u2013121 (2016).","journal-title":"Neurobiol. Aging"},{"key":"988_CR267","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1017\/S1355617716000990","volume":"23","author":"C Lancaster","year":"2017","unstructured":"Lancaster, C., Tabet, N. & Rusted, J. The elusive nature of APOE \u03b54 in mid-adulthood: understanding the cognitive profile. J. Int. Neuropsychol. Soc. 23, 239\u2013253 (2017).","journal-title":"J. Int. Neuropsychol. Soc."},{"key":"988_CR268","doi-asserted-by":"crossref","first-page":"1002","DOI":"10.1038\/s43587-021-00117-4","volume":"1","author":"K Lu","year":"2021","unstructured":"Lu, K. et al. Dissociable effects of APOE-\u03b54 and \u03b2-amyloid pathology on visual working memory. Nat. Aging 1, 1002\u20131009 (2021).","journal-title":"Nat. Aging"},{"key":"988_CR269","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1016\/j.neuroimage.2018.10.046","volume":"185","author":"N Zink","year":"2019","unstructured":"Zink, N., Bensmann, W., Arning, L., Beste, C. & Stock, A.-K. Apolipoprotein \u03b54 is associated with better cognitive control allocation in healthy young adults. NeuroImage 185, 274\u2013285 (2019).","journal-title":"NeuroImage"},{"key":"988_CR270","doi-asserted-by":"crossref","first-page":"17972","DOI":"10.1074\/jbc.272.29.17972","volume":"272","author":"PM Sullivan","year":"1997","unstructured":"Sullivan, P. M. et al. Targeted replacement of the mouse apolipoprotein E gene with the common human APOE3 allele enhances diet-induced hypercholesterolemia and atherosclerosis. J. Biol. Chem. 272, 17972\u201317980 (1997).","journal-title":"J. Biol. Chem."},{"key":"988_CR271","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1172\/JCI2673","volume":"102","author":"PM Sullivan","year":"1998","unstructured":"Sullivan, P. M., Mezdour, H., Quarfordt, S. H. & Maeda, N. Type III hyperlipoproteinemia and spontaneous atherosclerosis in mice resulting from gene replacement of mouse Apoe with human Apoe*2. J. Clin. Invest. 102, 130\u2013135 (1998).","journal-title":"J. Clin. Invest."},{"key":"988_CR272","doi-asserted-by":"crossref","first-page":"11587","DOI":"10.1073\/pnas.201279298","volume":"98","author":"RL Raffai","year":"2001","unstructured":"Raffai, R. L., Dong, L. M., Farese, R. V. & Weisgraber, K. H. Introduction of human apolipoprotein E4 \u2018domain interaction\u2019 into mouse apolipoprotein E. Proc. Natl Acad. Sci. USA 98, 11587\u201311591 (2001).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"988_CR273","doi-asserted-by":"crossref","first-page":"838436","DOI":"10.3389\/fnagi.2022.838436","volume":"14","author":"KE Foley","year":"2022","unstructured":"Foley, K. E. et al. The APOE \u03b53\/\u03b54 genotype drives distinct gene signatures in the cortex of young mice. Front. Aging Neurosci. 14, 838436 (2022).","journal-title":"Front. Aging Neurosci."},{"key":"988_CR274","doi-asserted-by":"crossref","first-page":"4471","DOI":"10.1073\/pnas.89.10.4471","volume":"89","author":"JA Piedrahita","year":"1992","unstructured":"Piedrahita, J. A., Zhang, S. H., Hagaman, J. R., Oliver, P. M. & Maeda, N. Generation of mice carrying a mutant apolipoprotein E gene inactivated by gene targeting in embryonic stem cells. Proc. Natl Acad. Sci. USA 89, 4471\u20134475 (1992).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"988_CR275","doi-asserted-by":"crossref","first-page":"10914","DOI":"10.1073\/pnas.95.18.10914","volume":"95","author":"J Raber","year":"1998","unstructured":"Raber, J. et al. Isoform-specific effects of human apolipoprotein E on brain function revealed in ApoE knockout mice: increased susceptibility of females. Proc. Natl Acad. Sci. USA 95, 10914\u201310919 (1998).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"988_CR276","doi-asserted-by":"crossref","first-page":"3261","DOI":"10.1523\/JNEUROSCI.18-09-03261.1998","volume":"18","author":"Y Sun","year":"1998","unstructured":"Sun, Y. et al. Glial fibrillary acidic protein-apolipoprotein E (apoE) transgenic mice: astrocyte-specific expression and differing biological effects of astrocyte-secreted apoE3 and apoE4 lipoproteins. J. Neurosci. 18, 3261\u20133272 (1998).","journal-title":"J. Neurosci."},{"key":"988_CR277","doi-asserted-by":"crossref","DOI":"10.1002\/alz.060213","volume":"18","author":"LR Golden","year":"2022","unstructured":"Golden, L. R. & Johnson, L. A. APOE allele switching in a novel transgenic mouse model as a therapeutic approach for Alzheimer\u2019s disease. Alzheimers Dement. 18, e060213 (2022).","journal-title":"Alzheimers Dement."}],"container-title":["Nature Reviews Neurology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41582-024-00988-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41582-024-00988-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41582-024-00988-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,7,31]],"date-time":"2024-07-31T09:12:21Z","timestamp":1722417141000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41582-024-00988-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,6,21]]},"references-count":277,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2024,8]]}},"alternative-id":["988"],"URL":"https:\/\/doi.org\/10.1038\/s41582-024-00988-2","relation":{},"ISSN":["1759-4758","1759-4766"],"issn-type":[{"value":"1759-4758","type":"print"},{"value":"1759-4766","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,6,21]]},"assertion":[{"value":"24 May 2024","order":1,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 June 2024","order":2,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"R.J.J. declares no competing interest. B.T.H. serves on the SAB of Latus and of Dewpoint and has a family member who is employed by Novartis. A.S.-P. has signed a material transfer agreement with Ionis Pharmaceuticals, Inc.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}