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Alzheimers Dement. 2023; 19:1598-1695.","DOI":"10.1002\/alz.13016"},{"key":"2","doi-asserted-by":"crossref","unstructured":"2. Jia L, Quan M, Fu Y, <i>et al<\/i>. Dementia in China: Epidemiology, clinical management, and research advances. Lancet Neurol. 2020; 19:81-92.","DOI":"10.1016\/S1474-4422(19)30290-X"},{"key":"3","doi-asserted-by":"crossref","unstructured":"3. Kao YC, Ho PC, Tu YK, Jou IM, Tsai KJ. Lipids and Alzheimer&apos;s disease. Int J Mol Sci. 2020; 21:1505.","DOI":"10.3390\/ijms21041505"},{"key":"4","doi-asserted-by":"crossref","unstructured":"4. Gatz M, Reynolds CA, Fratiglioni L, Johansson B, Mortimer JA, Berg S, Fiske A, Pedersen NL. Role of genes and environments for explaining Alzheimer disease. Arc Gen Psychiatry. 2006; 63:168-174.","DOI":"10.1001\/archpsyc.63.2.168"},{"key":"5","doi-asserted-by":"crossref","unstructured":"5. Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer&apos;s disease in late onset families. Science. 1993; 261:921-923.","DOI":"10.1126\/science.8346443"},{"key":"6","doi-asserted-by":"crossref","unstructured":"6. Scheltens P, De Strooper B, Kivipelto M, Holstege H, Ch\u00e9telat G, Teunissen CE, Cummings J, van der Flier WM. Alzheimer&apos;s disease. Lancet. 2021; 397:1577-1590.","DOI":"10.1016\/S0140-6736(20)32205-4"},{"key":"7","doi-asserted-by":"crossref","unstructured":"7. Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R, Myers RH, Pericak-Vance MA, Risch N, van Duijn CM. 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. 1997; 278:1349-1356.","DOI":"10.1001\/jama.1997.03550160069041"},{"key":"8","doi-asserted-by":"crossref","unstructured":"8. Hu X, Ma YN, Xia Y. Association between abnormal lipid metabolism and Alzheimer&apos;s disease: New research has revealed significant findings on the APOE4 genotype in microglia. Biosci Trends. 2024; 18:195-197.","DOI":"10.5582\/bst.2024.01092"},{"key":"9","doi-asserted-by":"crossref","unstructured":"9. Lin YT, Seo J, Gao F, <i>et al<\/i>. APOE4 causes widespread molecular and cellular alterations associated with Alzheimer&apos;s disease phenotypes in human iPSC-derived brain cell types. Neuron. 2018; 98:1141-1154.e7.","DOI":"10.1016\/j.neuron.2018.05.008"},{"key":"10","doi-asserted-by":"crossref","unstructured":"10. Windham IA, Cohen S. The cell biology of APOE in the brain. Trends Cell Biol. 2024; 34:338-348.","DOI":"10.1016\/j.tcb.2023.09.004"},{"key":"11","doi-asserted-by":"crossref","unstructured":"11. Yang LG, March ZM, Stephenson RA, Narayan PS. Apolipoprotein E in lipid metabolism and neurodegenerative disease. Trends Endocrinol Metab. 2023; 34:430-445.","DOI":"10.1016\/j.tem.2023.05.002"},{"key":"12","doi-asserted-by":"crossref","unstructured":"12. Eyo UB, Wu LJ. Microglia: Lifelong patrolling immune cells of the brain. Prog Neurobiol. 2019; 179:101614.","DOI":"10.1016\/j.pneurobio.2019.04.003"},{"key":"13","doi-asserted-by":"crossref","unstructured":"13. Guo S, Wang H, Yin Y. Microglia polarization from M1 to M2 in Neurodegenerative diseases. Front Aging Neurosci. 2022; 14:815347.","DOI":"10.3389\/fnagi.2022.815347"},{"key":"14","doi-asserted-by":"crossref","unstructured":"14. Dias D, Portugal CC, Relvas J, Socodato R. From genetics to neuroinflammation: The impact of ApoE4 on microglial function in Alzheimer&apos;s disease. Cells. 2025; 14:243.","DOI":"10.3390\/cells14040243"},{"key":"15","doi-asserted-by":"crossref","unstructured":"15. Chausse B, Kakimoto PA, Kann O. Microglia and lipids: How metabolism controls brain innate immunity. Semin Cell Dev Biol. 2021; 112:137-144.","DOI":"10.1016\/j.semcdb.2020.08.001"},{"key":"16","doi-asserted-by":"crossref","unstructured":"16. Strittmatter WJ, Saunders AM, Schmechel D, Pericak-Vance M, Enghild J, Salvesen GS, Roses AD. Apolipoprotein E: High-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci U S A. 1993; 90:1977-1981.","DOI":"10.1073\/pnas.90.5.1977"},{"key":"17","doi-asserted-by":"crossref","unstructured":"17. McIntosh AM, Bennett C, Dickson D, Anestis SF, Watts DP, Webster TH, Fontenot MB, Bradley BJ. The apolipoprotein E (APOE) gene appears functionally monomorphic in chimpanzees (Pan troglodytes). PloS One. 2012; 7:e47760.","DOI":"10.1371\/journal.pone.0047760"},{"key":"18","doi-asserted-by":"crossref","unstructured":"18. Weisgraber KH, Rall SC, Jr., Mahley RW. Human E apoprotein heterogeneity. Cysteine-arginine interchanges in the amino acid sequence of the apo-E isoforms. J Biol Chem. 1981; 256:9077-9083.","DOI":"10.1016\/S0021-9258(19)52510-8"},{"key":"19","doi-asserted-by":"crossref","unstructured":"19. Hatters DM, Peters-Libeu CA, Weisgraber KH. Apolipoprotein E structure: insights into function. Trends Biochem Sci. 2006; 31:445-454.","DOI":"10.1016\/j.tibs.2006.06.008"},{"key":"20","doi-asserted-by":"crossref","unstructured":"20. Morrow JA, Hatters DM, Lu B, Hochtl P, Oberg KA, Rupp B, Weisgraber KH. Apolipoprotein E4 forms a molten globule. A potential basis for its association with disease. J Biol Chem. 2002; 277:50380-50385.","DOI":"10.1074\/jbc.M204898200"},{"key":"21","doi-asserted-by":"crossref","unstructured":"21. Chetty PS, Mayne L, Lund-Katz S, Englander SW, Phillips MC. Helical structure, stability, and dynamics in human apolipoprotein E3 and E4 by hydrogen exchange and mass spectrometry. Proc Natl Acad Sci U S A. 2017; 114:968-973.","DOI":"10.1073\/pnas.1617523114"},{"key":"22","doi-asserted-by":"crossref","unstructured":"22. Rawat V, Wang S, Sima J, Bar R, Liraz O, Gundimeda U, Parekh T, Chan J, Johansson JO, Tang C, Chui HC, Harrington MG, Michaelson DM, Yassine HN. ApoE4 alters ABCA1 membrane trafficking in astrocytes. J Neurosci. 2019; 39:9611-9622.","DOI":"10.1523\/JNEUROSCI.1400-19.2019"},{"key":"23","doi-asserted-by":"crossref","unstructured":"23. Zannis VI, McPherson J, Goldberger G, Karathanasis SK, Breslow JL. Synthesis, intracellular processing, and signal peptide of human apolipoprotein E. J Biol Chem. 1984; 259:5495-5499.","DOI":"10.1016\/S0021-9258(18)91039-2"},{"key":"24","doi-asserted-by":"crossref","unstructured":"24. Wahrle SE, Jiang H, Parsadanian M, Legleiter J, Han X, Fryer JD, Kowalewski T, Holtzman DM. ABCA1 is required for normal central nervous system ApoE levels and for lipidation of astrocyte-secreted apoE. J Biol Chem. 2004; 279:40987-40993.","DOI":"10.1074\/jbc.M407963200"},{"key":"25","doi-asserted-by":"crossref","unstructured":"25. Fitz NF, Nam KN, Koldamova R, Lefterov I. Therapeutic targeting of nuclear receptors, liver X and retinoid X receptors, for Alzheimer&apos;s disease. Br J Pharmacol. 2019; 176:3599-3610.","DOI":"10.1111\/bph.14668"},{"key":"26","doi-asserted-by":"crossref","unstructured":"26. Herz J, Bock HH. Lipoprotein receptors in the nervous system. Annu Rev Biochem. 2002; 71:405-434.","DOI":"10.1146\/annurev.biochem.71.110601.135342"},{"key":"27","doi-asserted-by":"crossref","unstructured":"27. Zhao XN, Sun Q, Cao YQ, Ran X, Cao Y. Association between apolipoprotein gene polymorphisms and hyperlipidemia: A meta-analysis. BMC Genom Data. 2021; 22:14.","DOI":"10.1186\/s12863-021-00968-1"},{"key":"28","doi-asserted-by":"crossref","unstructured":"28. Greenberg SM, Rebeck GW, Vonsattel JP, Gomez-Isla T, Hyman BT. Apolipoprotein E epsilon 4 and cerebral hemorrhage associated with amyloid angiopathy. Ann Neurol. 1995; 38:254-259.","DOI":"10.1002\/ana.410380219"},{"key":"29","doi-asserted-by":"crossref","unstructured":"29. Rong X, Chen J, Pan D, Wang Y, Zhang C, Tang Y. Association between Apolipoprotein E genotype and functional outcome in acute ischemic stroke. Aging. 2023; 15:108-118.","DOI":"10.18632\/aging.204460"},{"key":"30","doi-asserted-by":"crossref","unstructured":"30. Teasdale GM, Nicoll JA, Murray G, Fiddes M. Association of apolipoprotein E polymorphism with outcome after head injury. Lancet. 1997; 350:1069-1071.","DOI":"10.1016\/S0140-6736(97)04318-3"},{"key":"31","doi-asserted-by":"crossref","unstructured":"31. Kim R, Park S, Yoo D, Jun JS, Jeon B. Impact of the apolipoprotein E \u03b54 allele on early Parkinson&apos;s disease progression. Parkinsonism Relat Disord. 2021; 83:66-70.","DOI":"10.1016\/j.parkreldis.2021.01.004"},{"key":"32","doi-asserted-by":"crossref","unstructured":"32. Wang YY, Ge YJ, Tan CC, Cao XP, Tan L, Xu W. The proportion of APOE4 carriers among non-demented individuals: A pooled analysis of 389,000 community-dwellers. J Alzheimers Dis. 2021; 81:1331-1339.","DOI":"10.3233\/JAD-201606"},{"key":"33","doi-asserted-by":"crossref","unstructured":"33. Fortea J, Pegueroles J, Alcolea D, Belbin O, Dols-Icardo O, Vaqu\u00e9-Alc\u00e1zar L, Videla L, Gispert JD, Su\u00e1rez-Calvet M, Johnson SC, Sperling R, Bejanin A, Lle\u00f3 A, Montal V. APOE4 homozygosity represents a distinct genetic form of Alzheimer&apos;s disease. Nat Med. 2024; 30:1284-1291.","DOI":"10.1038\/s41591-024-02931-w"},{"key":"34","doi-asserted-by":"crossref","unstructured":"34. Belloy ME, Andrews SJ, Le Guen Y, Cuccaro M, Farrer LA, Napolioni V, Greicius MD. APOE genotype and Alzheimer disease risk across age, sex, and population ancestry. JAMA Neurol. 2023; 80:1284-1294.","DOI":"10.1001\/jamaneurol.2023.3599"},{"key":"35","unstructured":"35. Payami H, Zareparsi S, Montee KR, Sexton GJ, Kaye JA, Bird TD, Yu CE, Wijsman EM, Heston LL, Litt M, Schellenberg GD. Gender difference in apolipoprotein E-associated risk for familial Alzheimer disease: a possible clue to the higher incidence of Alzheimer disease in women. Am J Hum Genet. 1996; 58:803-811."},{"key":"36","doi-asserted-by":"crossref","unstructured":"36. Dubal DB, Yokoyama JS. Longevity gene KLOTHO and Alzheimer disease-A better fate for individuals who carry APOE \u03b54. JAMA Neurol. 2020; 77:798-800.","DOI":"10.1001\/jamaneurol.2020.0112"},{"key":"37","doi-asserted-by":"crossref","unstructured":"37. Le Guen Y, Belloy ME, Grenier-Boley B, <i>et al<\/i>. Association of rare APOE missense variants V236E and R251G with risk of Alzheimer disease. JAMA Neurol. 2022; 79:652-663.","DOI":"10.1001\/jamaneurol.2022.1166"},{"key":"38","doi-asserted-by":"crossref","unstructured":"38. Belloy ME, Napolioni V, Han SS, Le Guen Y, Greicius MD. Association of Klotho-VS heterozygosity with risk of Alzheimer disease in individuals who carry APOE4. JAMA Neurol. 2020; 77:849-862.","DOI":"10.1001\/jamaneurol.2020.0414"},{"key":"39","doi-asserted-by":"crossref","unstructured":"39. Huq AJ, Fransquet P, Laws SM, Ryan J, Sebra R, Masters CL, Winship IM, James PA, Lacaze P. Genetic resilience to Alzheimer&apos;s disease in APOE \u03b54 homozygotes: A systematic review. Alzheimers Dement. 2019; 15:1612- 1623.","DOI":"10.1016\/j.jalz.2019.05.011"},{"key":"40","doi-asserted-by":"crossref","unstructured":"40. Haan MN, Shemanski L, Jagust WJ, Manolio TA, Kuller L. The role of APOE epsilon4 in modulating effects of other risk factors for cognitive decline in elderly persons. JAMA. 1999; 282:40-46.","DOI":"10.1001\/jama.282.1.40"},{"key":"41","doi-asserted-by":"crossref","unstructured":"41. Kanekiyo T, Xu H, Bu G. ApoE and A\u03b2 in Alzheimer&apos;s disease: Accidental encounters or partners? Neuron. 2014; 81:740-754.","DOI":"10.1016\/j.neuron.2014.01.045"},{"key":"42","doi-asserted-by":"crossref","unstructured":"42. Kaji S, Berghoff SA, Spieth L, <i>et al<\/i>. Apolipoprotein E aggregation in microglia initiates Alzheimer&apos;s disease pathology by seeding \u03b2-amyloidosis. Immunity. 2024; 57:2651-2668.e12.","DOI":"10.1016\/j.immuni.2024.09.014"},{"key":"43","doi-asserted-by":"crossref","unstructured":"43. Chen Y, Strickland MR, Soranno A, Holtzman DM. Apolipoprotein E: Structural insights and links to Alzheimer disease pathogenesis. Neuron. 2021; 109:205-221.","DOI":"10.1016\/j.neuron.2020.10.008"},{"key":"44","doi-asserted-by":"crossref","unstructured":"44. Balig\u00e1cs N, Albertini G, Borrie SC, Serneels L, Pridans C, Balusu S, De Strooper B. Homeostatic microglia initially seed and activated microglia later reshape amyloid plaques in Alzheimer&apos;s disease. Nat Commun. 2024; 15:10634.","DOI":"10.1038\/s41467-024-54779-w"},{"key":"45","doi-asserted-by":"crossref","unstructured":"45. Bell RD, Winkler EA, Singh I, Sagare AP, Deane R, Wu Z, Holtzman DM, Betsholtz C, Armulik A, Sallstrom J, Berk BC, Zlokovic BV. Apolipoprotein E controls cerebrovascular integrity <i>via<\/i> cyclophilin A. Nature. 2012; 485:512-516.","DOI":"10.1038\/nature11087"},{"key":"46","doi-asserted-by":"crossref","unstructured":"46. Jackson RJ, Meltzer JC, Nguyen H, Commins C, Bennett RE, Hudry E, Hyman BT. APOE4 derived from astrocytes leads to blood-brain barrier impairment. Brain. 2022; 145:3582-3593.","DOI":"10.1093\/brain\/awab478"},{"key":"47","doi-asserted-by":"crossref","unstructured":"47. Schmukler E, Solomon S, Simonovitch S, Goldshmit Y, Wolfson E, Michaelson DM, Pinkas-Kramarski R. Altered mitochondrial dynamics and function in APOE4-expressing astrocytes. Cell Death Dis. 2020; 11:578.","DOI":"10.1038\/s41419-020-02776-4"},{"key":"48","doi-asserted-by":"crossref","unstructured":"48. Farmer BC, Kluemper J, Johnson LA. Apolipoprotein E4 alters astrocyte fatty acid metabolism and lipid droplet formation. Cells. 2019; 8:182.","DOI":"10.3390\/cells8020182"},{"key":"49","doi-asserted-by":"crossref","unstructured":"49. Parhizkar S, Holtzman DM. APOE mediated neuroinflammation and neurodegeneration in Alzheimer&apos;s disease. Semin Immunol. 2022; 59:101594.","DOI":"10.1016\/j.smim.2022.101594"},{"key":"50","doi-asserted-by":"crossref","unstructured":"50. Sienski G, Narayan P, Bonner JM, <i>et al<\/i>. APOE4 disrupts intracellular lipid homeostasis in human iPSC-derived glia. Sci Transl Med. 2021; 13:eaaz4564.","DOI":"10.1126\/scitranslmed.aaz4564"},{"key":"51","doi-asserted-by":"crossref","unstructured":"51. Litvinchuk A, Suh JH, Guo JL, <i>et al<\/i>. Amelioration of Tau and ApoE4-linked glial lipid accumulation and neurodegeneration with an LXR agonist. Neuron. 2024; 112:384-403.e8.","DOI":"10.1016\/j.neuron.2023.10.023"},{"key":"52","doi-asserted-by":"crossref","unstructured":"52. Lee H, Cho S, Kim MJ, <i>et al<\/i>. ApoE4-dependent lysosomal cholesterol accumulation impairs mitochondrial homeostasis and oxidative phosphorylation in human astrocytes. Cell Rep. 2023; 42:113183.","DOI":"10.1016\/j.celrep.2023.113183"},{"key":"53","doi-asserted-by":"crossref","unstructured":"53. Blanchard JW, Akay LA, Davila-Velderrain J, <i>et al<\/i>. APOE4 impairs myelination <i>via<\/i> cholesterol dysregulation in oligodendrocytes. Nature. 2022; 611:769-779.","DOI":"10.1038\/s41586-022-05439-w"},{"key":"54","doi-asserted-by":"crossref","unstructured":"54. Xia Y, Wang ZH, Zhang J, Liu X, Yu SP, Ye KX, Wang JZ, Ye K, Wang XC. C\/EBP\u03b2 is a key transcription factor for APOE and preferentially mediates ApoE4 expression in Alzheimer&apos;s disease. Mol Psychiatry. 2021; 26:6002-6022.","DOI":"10.1038\/s41380-020-00956-4"},{"key":"55","unstructured":"55. Wynne ME, Ogunbona O, Lane AR, <i>et al.<\/i> APOE expression and secretion are modulated by mitochondrial dysfunction. ELife. 2023; 12:e85779."},{"key":"56","doi-asserted-by":"crossref","unstructured":"56. de Leeuw SM, Kirschner AWT, Lindner K, Rust R, Budny V, Wolski WE, Gavin AC, Nitsch RM, Tackenberg C. APOE2, E3, and E4 differentially modulate cellular homeostasis, cholesterol metabolism, and inflammatory response in isogenic iPSC-derived astrocytes. Stem Cell Reports. 2022; 17:110-126.","DOI":"10.1016\/j.stemcr.2021.11.007"},{"key":"57","doi-asserted-by":"crossref","unstructured":"57. Chung WS, Verghese PB, Chakraborty C, Joung J, Hyman BT, Ulrich JD, Holtzman DM, Barres BA. Novel allele-dependent role for APOE in controlling the rate of synapse pruning by astrocytes. Proc Natl Acad Sci U S A. 2016; 113:10186-10191.","DOI":"10.1073\/pnas.1609896113"},{"key":"58","doi-asserted-by":"crossref","unstructured":"58. Tcw J, Qian L, Pipalia NH, <i>et al<\/i>. Cholesterol and matrisome pathways dysregulated in astrocytes and microglia. Cell. 2022; 185:2213-2233.e25.","DOI":"10.1016\/j.cell.2022.05.017"},{"key":"59","doi-asserted-by":"crossref","unstructured":"59. Staurenghi E, Leoni V, Lo Iacono M, Sottero B, Testa G, Giannelli S, Leonarduzzi G, Gamba P. ApoE3 <i>vs.<\/i> ApoE4 astrocytes: A detailed analysis provides new insights into differences in cholesterol homeostasis. Antioxidants (Basel). 2022; 11:2168.","DOI":"10.3390\/antiox11112168"},{"key":"60","doi-asserted-by":"crossref","unstructured":"60. Zhao J, Davis MD, Martens YA, Shinohara M, Graff-Radford NR, Younkin SG, Wszolek ZK, Kanekiyo T, Bu G. APOE \u03b54\/\u03b54 diminishes neurotrophic function of human iPSC-derived astrocytes. Hum Mol Genet. 2017; 26:2690-2700.","DOI":"10.1093\/hmg\/ddx155"},{"key":"61","doi-asserted-by":"crossref","unstructured":"61. Qi G, Mi Y, Shi X, Gu H, Brinton RD, Yin F. ApoE4 impairs neuron-astrocyte coupling of fatty acid metabolism. Cell Rep. 2021; 34:108572.","DOI":"10.1016\/j.celrep.2020.108572"},{"key":"62","doi-asserted-by":"crossref","unstructured":"62. Windham IA, Powers AE, Ragusa JV, Wallace ED, Zanellati MC, Williams VH, Wagner CH, White KK, Cohen S. APOE traffics to astrocyte lipid droplets and modulates triglyceride saturation and droplet size. J Cell Biol. 2024; 223:e202305003.","DOI":"10.1083\/jcb.202305003"},{"key":"63","doi-asserted-by":"crossref","unstructured":"63. Li X, Zhang J, Li D, He C, He K, Xue T, Wan L, Zhang C, Liu Q. Astrocytic ApoE reprograms neuronal cholesterol metabolism and histone-acetylation-mediated memory. Neuron. 2021; 109:957-970.e8.","DOI":"10.1016\/j.neuron.2021.01.005"},{"key":"64","doi-asserted-by":"crossref","unstructured":"64. Saroja SR, Gorbachev K, Julia T, Goate AM, Pereira AC. Astrocyte-secreted glypican-4 drives APOE4-dependent tau hyperphosphorylation. Proc Natl Acad Sci U S A. 2022; 119:e2108870119.","DOI":"10.1073\/pnas.2108870119"},{"key":"65","doi-asserted-by":"crossref","unstructured":"65. Zalocusky KA, Najm R, Taubes AL, <i>et al<\/i>. Neuronal ApoE upregulates MHC-I expression to drive selective neurodegeneration in Alzheimer&apos;s disease. Nat Neurosci. 2021; 24:786-798.","DOI":"10.1038\/s41593-021-00851-3"},{"key":"66","doi-asserted-by":"crossref","unstructured":"66. Koutsodendris N, Blumenfeld J, Agrawal A, Traglia M, Grone B, Zilberter M, Yip O, Rao A, Nelson MR, Hao Y, Thomas R, Yoon SY, Arriola P, Huang Y. Neuronal APOE4 removal protects against tau-mediated gliosis, neurodegeneration and myelin deficits. Nat Aging. 2023; 3:275-296.","DOI":"10.1038\/s43587-023-00368-3"},{"key":"67","doi-asserted-by":"crossref","unstructured":"67. Guo JL, Braun D, Fitzgerald GA, <i>et al<\/i>. Decreased lipidated ApoE-receptor interactions confer protection against pathogenicity of ApoE and its lipid cargoes in lysosomes. Cell. 2025; 188:187-206.e26.","DOI":"10.1016\/j.cell.2024.10.027"},{"key":"68","doi-asserted-by":"crossref","unstructured":"68. Wang S, Li B, Li J, <i>et al<\/i>. Cellular senescence induced by cholesterol accumulation is mediated by lysosomal ABCA1 in APOE4 and AD. Mol Neurodegener. 2025; 20:15.","DOI":"10.1186\/s13024-025-00802-7"},{"key":"69","doi-asserted-by":"crossref","unstructured":"69. Mahley RW. Apolipoprotein E: From cardiovascular disease to neurodegenerative disorders. J Mol Med (Berl). 2016; 94:739-746.","DOI":"10.1007\/s00109-016-1427-y"},{"key":"70","doi-asserted-by":"crossref","unstructured":"70. Wang C, Najm R, Xu Q, Jeong DE, Walker D, Balestra ME, Yoon SY, Yuan H, Li G, Miller ZA, Miller BL, Malloy MJ, Huang Y. Gain of toxic apolipoprotein E4 effects in human iPSC-derived neurons is ameliorated by a small-molecule structure corrector. Nat Med. 2018; 24:647-657.","DOI":"10.1038\/s41591-018-0004-z"},{"key":"71","doi-asserted-by":"crossref","unstructured":"71. Rao A, Chen N, Kim MJ, <i>et al<\/i>. Microglia depletion reduces human neuronal APOE4-related pathologies in a chimeric Alzheimer&apos;s disease model. Cell Stem Cell. 2025; 32:86-104.e7.","DOI":"10.1016\/j.stem.2024.10.005"},{"key":"72","doi-asserted-by":"crossref","unstructured":"72. Marschallinger J, Iram T, Zardeneta M, <i>et al<\/i>. Author Correction: Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain. Nat Neurosci. 2020; 23:294.","DOI":"10.1038\/s41593-020-0595-9"},{"key":"73","doi-asserted-by":"crossref","unstructured":"73. Haney MS, P\u00e1lovics R, Munson CN, <i>et al<\/i>. APOE4\/4 is linked to damaging lipid droplets in Alzheimer&apos;s disease microglia. Nature. 2024; 628:154-161.","DOI":"10.1038\/s41586-024-07185-7"},{"key":"74","doi-asserted-by":"crossref","unstructured":"74. Bassal R, Rivkin-Natan M, Rabinovich A, Michaelson DM, Frenkel D, Pinkas-Kramarski R. APOE4 impairs autophagy and A\u03b2 clearance by microglial cells. Inflamm Res. 2025; 74:61.","DOI":"10.1007\/s00011-025-02016-5"},{"key":"75","doi-asserted-by":"crossref","unstructured":"75. Zhou J, Wang Y, Huang G, Yang M, Zhu Y, Jin C, Jing D, Ji K, Shi Y. LilrB3 is a putative cell surface receptor of APOE4. Cell Res. 2023; 33:116-130.","DOI":"10.1038\/s41422-022-00759-y"},{"key":"76","doi-asserted-by":"crossref","unstructured":"76. Mauerer R, Walczak Y, Langmann T. Comprehensive mRNA profiling of lipid-related genes in microglia and macrophages using taqman arrays. Methods Mol Biol. 2009; 580:187-201.","DOI":"10.1007\/978-1-60761-325-1_10"},{"key":"77","doi-asserted-by":"crossref","unstructured":"77. Wang Q, Lu M, Zhu X, Gu X, Zhang T, Xia C, Yang L, Xu Y, Zhou M. The role of microglia immunometabolism in neurodegeneration: Focus on molecular determinants and metabolic intermediates of metabolic reprogramming. Biomed Pharmacother. 2022; 153:113412.","DOI":"10.1016\/j.biopha.2022.113412"},{"key":"78","doi-asserted-by":"crossref","unstructured":"78. Lee S, Devanney NA, Golden LR, <i>et al<\/i>. APOE modulates microglial immunometabolism in response to age, amyloid pathology, and inflammatory challenge. Cell Rep. 2023; 42:112196.","DOI":"10.1016\/j.celrep.2023.112196"},{"key":"79","doi-asserted-by":"crossref","unstructured":"79. Liu L, Zhang K, Sandoval H, Yamamoto S, Jaiswal M, Sanz E, Li Z, Hui J, Graham BH, Quintana A, Bellen HJ. Glial lipid droplets and ROS induced by mitochondrial defects promote neurodegeneration. Cell. 2015; 160:177-190.","DOI":"10.1016\/j.cell.2014.12.019"},{"key":"80","doi-asserted-by":"crossref","unstructured":"80. Leng L, Yuan Z, Pan R, <i>et al<\/i>. Microglial hexokinase 2 deficiency increases ATP generation through lipid metabolism leading to \u03b2-amyloid clearance. Nat Metab. 2022; 4:1287-1305.","DOI":"10.1038\/s42255-022-00643-4"},{"key":"81","doi-asserted-by":"crossref","unstructured":"81. Liu CC, Wang N, Chen Y, <i>et al<\/i>. Cell-autonomous effects of APOE4 in restricting microglial response in brain homeostasis and Alzheimer&apos;s disease. Nat Immunol. 2023; 24:1854-1866.","DOI":"10.1038\/s41590-023-01640-9"},{"key":"82","doi-asserted-by":"crossref","unstructured":"82. Muth C, Hartmann A, Sepulveda-Falla D, Glatzel M, Krasemann S. Phagocytosis of apoptotic cells is specifically upregulated in ApoE4 expressing microglia <i>in vitro<\/i>. Front Cellular Neurosci. 2019; 13:181.","DOI":"10.3389\/fncel.2019.00181"},{"key":"83","doi-asserted-by":"crossref","unstructured":"83. Serrano-Pozo A, Li Z, Noori A, Nguyen HN, Mezlini A, Li L, Hudry E, Jackson RJ, Hyman BT, Das S. Effect of APOE alleles on the glial transcriptome in normal aging and Alzheimer&apos;s disease. Nat Aging. 2021; 1:919-931.","DOI":"10.1038\/s43587-021-00123-6"},{"key":"84","doi-asserted-by":"crossref","unstructured":"84. Krasemann S, Madore C, Cialic R, <i>et al<\/i>. The TREM2-APOE pathway drives the transcriptional phenotype of dysfunctional microglia in Neurodegenerative diseases. Immunity. 2017; 47:566-581.e9.","DOI":"10.1016\/j.immuni.2017.08.008"},{"key":"85","doi-asserted-by":"crossref","unstructured":"85. Yin Z, Rosenzweig N, Kleemann KL, <i>et al<\/i>. APOE4 impairs the microglial response in Alzheimer&apos;s disease by inducing TGF\u03b2-mediated checkpoints. Nat Immunol. 2023; 24:1839-1853.","DOI":"10.1038\/s41590-023-01627-6"},{"key":"86","doi-asserted-by":"crossref","unstructured":"86. Millet A, Ledo JH, Tavazoie SF. An exhausted-like microglial population accumulates in aged and APOE4 genotype Alzheimer&apos;s brains. Immunity. 2024; 57:153-170.e6.","DOI":"10.1016\/j.immuni.2023.12.001"},{"key":"87","doi-asserted-by":"crossref","unstructured":"87. Alzheimer A, Stelzmann RA, Schnitzlein HN, Murtagh FR. An English translation of Alzheimer&apos;s 1907 paper, &quot;Uber eine eigenartige Erkankung der Hirnrinde&quot;. Clin Anat. 1995; 8:429-431.","DOI":"10.1002\/ca.980080612"},{"key":"88","doi-asserted-by":"crossref","unstructured":"88. Flury A, Aljayousi L, Park HJ, <i>et al<\/i>. A neurodegenerative cellular stress response linked to dark microglia and toxic lipid secretion. Neuron. 2025; 113:554-571.e14.","DOI":"10.1016\/j.neuron.2024.11.018"},{"key":"89","doi-asserted-by":"crossref","unstructured":"89. Prakash P, Manchanda P, Paouri E, <i>et al<\/i>. Amyloid \u03b2 induces lipid droplet-mediated microglial dysfunction <i>via<\/i> the enzyme DGAT2 in Alzheimer&apos;s disease. bioRxiv : the preprint server for biology. 2023; <i>https:\/\/www.biorxiv.org\/content\/10.1101\/2023.06.04.543525v2.full.pdf<\/i>","DOI":"10.1002\/alz.075938"},{"key":"90","doi-asserted-by":"crossref","unstructured":"90. Zhao Y, Wu X, Li X, <i>et al<\/i>. TREM2 is a receptor for \u03b2-amyloid that mediates microglial function. Neuron. 2018; 97:1023-1031.e7.","DOI":"10.1016\/j.neuron.2018.01.031"},{"key":"91","doi-asserted-by":"crossref","unstructured":"91. Claes C, Danhash EP, Hasselmann J, Chadarevian JP, Shabestari SK, England WE, Lim TE, Hidalgo JLS, Spitale RC, Davtyan H, Blurton-Jones M. Plaque-associated human microglia accumulate lipid droplets in a chimeric model of Alzheimer&apos;s disease. Mol Neurodegener. 2021; 16:50.","DOI":"10.1186\/s13024-021-00473-0"},{"key":"92","doi-asserted-by":"crossref","unstructured":"92. Andreone BJ, Przybyla L, Llapashtica C, Rana A, Davis SS, van Lengerich B, Lin K, Shi J, Mei Y, Astarita G, Di Paolo G, Sandmann T, Monroe KM, Lewcock JW. Alzheimer&apos;s-associated PLC\u03b32 is a signaling node required for both TREM2 function and the inflammatory response in human microglia. Nat Neurosci. 2020; 23:927-938.","DOI":"10.1038\/s41593-020-0650-6"},{"key":"93","doi-asserted-by":"crossref","unstructured":"93. Zhang J, Liu Q. Cholesterol metabolism and homeostasis in the brain. Protein Cell. 2015; 6:254-264.","DOI":"10.1007\/s13238-014-0131-3"},{"key":"94","doi-asserted-by":"crossref","unstructured":"94. Li B, Wang S, Kerman B, Hugo C, Shwab EK, Shu C, Chiba-Falek O, Arvanitakis Z, Yassine H. Microglia states are susceptible to senescence and cholesterol dysregulation in Alzheimer&apos;s disease. 2024; <i>https:\/\/www.biorxiv.org\/content\/10.1101\/2024.11.18.624141v1<\/i>","DOI":"10.1101\/2024.11.18.624141"},{"key":"95","doi-asserted-by":"crossref","unstructured":"95. Komatsu C, Komatsu RS. Alzheimer&apos;s Disease (AD): High cholesterol is associated with lower Mini\u2010Mental State Exam (MMSE) scores. Alzheimer&apos;s &amp; Dementia. 2023; 19. <i>https:\/\/doi.org\/10.1002\/alz.065868<\/i>","DOI":"10.1002\/alz.065868"},{"key":"96","doi-asserted-by":"crossref","unstructured":"96. Lu J, Wu K, Sha X, Lin J, Chen H, Yu Z. TRPV1 alleviates APOE4-dependent microglial antigen presentation and T cell infiltration in Alzheimer&apos;s disease. Transl Neurodegener. 2024; 13:52.","DOI":"10.1186\/s40035-024-00445-6"},{"key":"97","doi-asserted-by":"crossref","unstructured":"97. Lee CY, Tse W, Smith JD, Landreth GE. Apolipoprotein E promotes \u03b2-amyloid trafficking and degradation by modulating microglial cholesterol levels. J Biol Chem. 2012; 287:2032-2044.","DOI":"10.1074\/jbc.M111.295451"},{"key":"98","doi-asserted-by":"crossref","unstructured":"98. Egawa J, Pearn ML, Lemkuil BP, Patel PM, Head BP. Membrane lipid rafts and neurobiology: Age-related changes in membrane lipids and loss of neuronal function. J Physiol. 2016; 594:4565-4579.","DOI":"10.1113\/JP270590"},{"key":"99","doi-asserted-by":"crossref","unstructured":"99. Rudajev V, Novotny J. Cholesterol-dependent amyloid \u03b2 production: Space for multifarious interactions between amyloid precursor protein, secretases, and cholesterol. Cell Biosci. 2023; 13:171.","DOI":"10.1186\/s13578-023-01127-y"},{"key":"100","doi-asserted-by":"crossref","unstructured":"100. Wang C, Lu J, Sha X, Qiu Y, Chen H, Yu Z. TRPV1 regulates ApoE4-disrupted intracellular lipid homeostasis and decreases synaptic phagocytosis by microglia. Exp Mol Med. 2023; 55:347-363.","DOI":"10.1038\/s12276-023-00935-z"},{"key":"101","doi-asserted-by":"crossref","unstructured":"101. Cser\u00e9p C, Schwarcz AD, P\u00f3sfai B, L\u00e1szl\u00f3 ZI, Kellermayer A, K\u00f6rnyei Z, Kisfali M, Nyerges M, Lele Z, Katona I, \u00c1d\u00e1m D. Microglial control of neuronal development <i>via<\/i> somatic purinergic junctions. Cell Rep. 2022; 40:111369.","DOI":"10.1016\/j.celrep.2022.111369"},{"key":"102","doi-asserted-by":"crossref","unstructured":"102. Marinelli S, Basilico B, Marrone MC, Ragozzino D. Microglia-neuron crosstalk: Signaling mechanism and control of synaptic transmission. Semin Cell Dev Biol. 2019; 94:138-151.","DOI":"10.1016\/j.semcdb.2019.05.017"},{"key":"103","doi-asserted-by":"crossref","unstructured":"103. Victor MB, Leary N, Luna X, <i>et al<\/i>. Lipid accumulation induced by APOE4 impairs microglial surveillance of neuronal-network activity. Cell Stem Cell. 2022; 29:1197-1212.e8.","DOI":"10.1016\/j.stem.2022.07.005"},{"key":"104","doi-asserted-by":"crossref","unstructured":"104. Young JE, Jayadev S. Neighborhood matters: Altered lipid metabolism in APOE4 microglia causes problems for neurons. Cell Stem Cell. 2022; 29:1159-1160.","DOI":"10.1016\/j.stem.2022.07.001"},{"key":"105","doi-asserted-by":"crossref","unstructured":"105. Li Y, Munoz-Mayorga D, Nie Y, Kang N, Tao Y, Lagerwall J, Pernaci C, Curtin G, Coufal NG, Mertens J, Shi L, Chen X. Microglial lipid droplet accumulation in tauopathy brain is regulated by neuronal AMPK. Cell Metab. 2024; 36:1351-1370.e8.","DOI":"10.1016\/j.cmet.2024.03.014"},{"key":"106","doi-asserted-by":"crossref","unstructured":"106. Huynh TV, Wang C, Tran AC, Tabor GT, Mahan TE, Francis CM, Finn MB, Spellman R, Manis M, Tanzi RE, Ulrich JD, Holtzman DM. Lack of hepatic apoE does not influence early A\u03b2 deposition: observations from a new APOE knock-in model. Mol Neurodegener. 2019; 14:37.","DOI":"10.1186\/s13024-019-0337-1"},{"key":"107","doi-asserted-by":"crossref","unstructured":"107. Leng F, Edison P. Neuroinflammation and microglial activation in Alzheimer disease: where do we go from here? Nat Rev Neurol. 2021; 17:157-172.","DOI":"10.1038\/s41582-020-00435-y"},{"key":"108","doi-asserted-by":"crossref","unstructured":"108. Zhang R, Ding RQ, Wang Q, Zhang LK, Fan XC, Guo FY, Chen XM, Jiang C, Cao J, Wang JM, Zang WD, Wang J. Inflammation in intracerebral hemorrhage: A bibliometric perspective. Brain Hemorrhages. 2024; 5:107-116.","DOI":"10.1016\/j.hest.2024.01.003"},{"key":"109","doi-asserted-by":"crossref","unstructured":"109. Goel P, Chakrabarti S, Goel K, Bhutani K, Chopra T, Bali S. Neuronal cell death mechanisms in Alzheimer&apos;s disease: An insight. Front Mol Neurosci. 2022; 15:937133.","DOI":"10.3389\/fnmol.2022.937133"},{"key":"110","doi-asserted-by":"crossref","unstructured":"110. Amelimojarad M, Amelimojarad M, Cui X. The emerging role of brain neuroinflammatory responses in Alzheimer&apos;s disease. Front Aging Neurosci. 2024; 16:1391517.","DOI":"10.3389\/fnagi.2024.1391517"},{"key":"111","doi-asserted-by":"crossref","unstructured":"111. Wong MY, Lewis M, Doherty JJ, Shi Y, Cashikar AG, Amelianchik A, Tymchuk S, Sullivan PM, Qian M, Covey DF, Petsko GA, Holtzman DM, Paul SM, Luo W. 25-Hydroxycholesterol amplifies microglial IL-1\u03b2 production in an apoE isoform-dependent manner. J Neuroinflammation. 2020; 17:192.","DOI":"10.1186\/s12974-020-01869-3"},{"key":"112","doi-asserted-by":"crossref","unstructured":"112. Pollock TB, Mack JM, Day RJ, Isho NF, Brown RJ, Oxford AE, Morrison BE, Hayden EJ, Rohn TT. A fragment of apolipoprotein E4 leads to the downregulation of a CXorf56 homologue, a novel ER-associated protein, and activation of BV2 microglial cells. Oxid Med Cell Longev. 2019; 2019:5123565.","DOI":"10.1155\/2019\/5123565"},{"key":"113","doi-asserted-by":"crossref","unstructured":"113. Mhatre-Winters I, Eid A, Han Y, Tieu K, Richardson JR. Sex and APOE genotype alter the basal and induced inflammatory states of primary microglia from APOE targeted replacement mice. Int J Mol Sci. 2022; 23:9829.","DOI":"10.3390\/ijms23179829"},{"key":"114","doi-asserted-by":"crossref","unstructured":"114. Liu XT, Chen X, Zhao N, Geng F, Zhu MM, Ren QG. Synergism of ApoE4 and systemic infectious burden is mediated by the APOE-NLRP3 axis in Alzheimer&apos;s disease. Psychiatry Clin Neurosci. 2024; 78:517-526.","DOI":"10.1111\/pcn.13704"},{"key":"115","doi-asserted-by":"crossref","unstructured":"115. Huynh TN, Fikse EN, De La Torre AL, Havrda MC, Chang CCY, Chang TY. Inhibiting the cholesterol storage enzyme ACAT1\/SOAT1 in aging apolipoprotein E4 mice alters their brains&apos; inflammatory profiles. Int J Mol Sci. 2024; 25:13690.","DOI":"10.3390\/ijms252413690"},{"key":"116","doi-asserted-by":"crossref","unstructured":"116. Fitz NF, Nam KN, Wolfe CM, Letronne F, Playso BE, Iordanova BE, Kozai TDY, Biedrzycki RJ, Kagan VE, Tyurina YY, Han X, Lefterov I, Koldamova R. Phospholipids of APOE lipoproteins activate microglia in an isoform-specific manner in preclinical models of Alzheimer&apos;s disease. Nat Commun. 2021; 12:3416.","DOI":"10.1038\/s41467-021-23762-0"},{"key":"117","doi-asserted-by":"crossref","unstructured":"117. Bogie JF, Jorissen W, Mailleux J, Nijland PG, Zelcer N, Vanmierlo T, Van Horssen J, Stinissen P, Hellings N, Hendriks JJ. Myelin alters the inflammatory phenotype of macrophages by activating PPARs. Acta Neuropathol Commun. 2013; 1:43.","DOI":"10.1186\/2051-5960-1-43"},{"key":"118","doi-asserted-by":"crossref","unstructured":"118. Park JC, Han JW, Lee W, <i>et al<\/i>. Microglia Gravitate toward Amyloid Plaques Surrounded by Externalized Phosphatidylserine <i>via<\/i> TREM2. Adv Sci (Weinh). 2024; 11:e2400064.","DOI":"10.1002\/advs.202400064"},{"key":"119","doi-asserted-by":"crossref","unstructured":"119. Rosenzweig N, Kleemann KL, Rust T, <i>et al<\/i>. Sex-dependent APOE4 neutrophil-microglia interactions drive cognitive impairment in Alzheimer&apos;s disease. Nat Med. 2024; 30:2990-3003.","DOI":"10.1038\/s41591-024-03122-3"},{"key":"120","doi-asserted-by":"crossref","unstructured":"120. Vogels T, Murgoci AN, Hrom\u00e1dka T. Intersection of pathological tau and microglia at the synapse. Acta Neuropathol Commun. 2019; 7:109.","DOI":"10.1186\/s40478-019-0754-y"},{"key":"121","doi-asserted-by":"crossref","unstructured":"121. Wu X, Miller JA, Lee BTK, Wang Y, Ruedl C. Reducing microglial lipid load enhances \u03b2 amyloid phagocytosis in an Alzheimer&apos;s disease mouse model. Sci Adv. 2025; 11:eadq6038.","DOI":"10.1126\/sciadv.adq6038"},{"key":"122","doi-asserted-by":"crossref","unstructured":"122. Asai H, Ikezu S, Tsunoda S, Medalla M, Luebke J, Haydar T, Wolozin B, Butovsky O, K\u00fcgler S, Ikezu T. Depletion of microglia and inhibition of exosome synthesis halt tau propagation. Nat Neurosci. 2015; 18:1584-1593.","DOI":"10.1038\/nn.4132"},{"key":"123","doi-asserted-by":"crossref","unstructured":"123. Ferrari-Souza JP, Lussier FZ, Leffa DT, <i>et al<\/i>. APOE\u03b54 associates with microglial activation independently of A\u03b2 plaques and tau tangles. Sci Adv. 2023; 9:eade1474.","DOI":"10.1126\/sciadv.ade1474"},{"key":"124","doi-asserted-by":"crossref","unstructured":"124. Nelson MR, Liu P, Agrawal A, <i>et al<\/i>. The APOE-R136S mutation protects against APOE4-driven Tau pathology, neurodegeneration and neuroinflammation. Nat Neurosci. 2023; 26:2104-2121.","DOI":"10.1038\/s41593-023-01480-8"},{"key":"125","doi-asserted-by":"crossref","unstructured":"125. Tzioras M, McGeachan RI, Durrant CS, Spires-Jones TL. Synaptic degeneration in Alzheimer disease. Nat Rev Neurol. 2023; 19:19-38.","DOI":"10.1038\/s41582-022-00749-z"},{"key":"126","doi-asserted-by":"crossref","unstructured":"126. Tzioras M, Daniels MJD, Davies C, <i>et al<\/i>. Human astrocytes and microglia show augmented ingestion of synapses in Alzheimer&apos;s disease <i>via<\/i> MFG-E8. Cell Rep Med. 2023; 4:101175.","DOI":"10.1016\/j.xcrm.2023.101175"},{"key":"127","doi-asserted-by":"crossref","unstructured":"127. Chen Y, Jin H, Chen J, Li J, G\u0103man MA, Zou Z. The multifaceted roles of apolipoprotein E4 in Alzheimer&apos;s disease pathology and potential therapeutic strategies. Cell Death Discov. 2025; 11:312.","DOI":"10.1038\/s41420-025-02600-y"},{"key":"128","doi-asserted-by":"crossref","unstructured":"128. Jung ES, Choi H, Mook-Jung I. Decoding microglial immunometabolism: A new frontier in Alzheimer&apos;s disease research. Mol Neurodegener. 2025; 20:37.","DOI":"10.1186\/s13024-025-00825-0"},{"key":"129","doi-asserted-by":"crossref","unstructured":"129. Valencia-Olvera AC, Balu D, Bellur S, McNally T, Saleh Y, Pham D, Ghura S, York J, Johansson JO, LaDu MJ, Tai L. A novel apoE-mimetic increases brain apoE levels, reduces A\u03b2 pathology and improves memory when treated before onset of pathology in male mice that express APOE3. Alzheimers Res Ther. 2023; 15:216.","DOI":"10.1186\/s13195-023-01353-z"},{"key":"130","doi-asserted-by":"crossref","unstructured":"130. Boehm-Cagan A, Michaelson DM. Reversal of apoE4-driven brain pathology and behavioral deficits by bexarotene. J Neurosci. 2014; 34:7293-7301.","DOI":"10.1523\/JNEUROSCI.5198-13.2014"},{"key":"131","doi-asserted-by":"crossref","unstructured":"131. Boehm-Cagan A, Bar R, Liraz O, Bielicki JK, Johansson JO, Michaelson DM. ABCA1 agonist reverses the ApoE4- driven cognitive and brain pathologies. J Alzheimers Dis. 2016; 54:1219-1233.","DOI":"10.3233\/JAD-160467"},{"key":"132","doi-asserted-by":"crossref","unstructured":"132. Prakash P, Manchanda P, Paouri E, <i>et al<\/i>. Amyloid-\u03b2 induces lipid droplet-mediated microglial dysfunction <i>via<\/i> the enzyme DGAT2 in Alzheimer&apos;s disease. Immunity. 2025; 58:1536-1552.e8.","DOI":"10.1016\/j.immuni.2025.04.029"},{"key":"133","doi-asserted-by":"crossref","unstructured":"133. Loix M, Wouters E, Vanherle S, Dehairs J, McManaman JL, Kemps H, Swinnen JV, Haidar M, Bogie JFJ, Hendriks JJA. Perilipin-2 limits remyelination by preventing lipid droplet degradation. Cell Mol Life Sci. 2022; 79:515.","DOI":"10.1007\/s00018-022-04547-0"},{"key":"134","doi-asserted-by":"crossref","unstructured":"134. Sangineto M, Ciarnelli M, Cassano T, Radesco A, Moola A, Bukke VN, Romano A, Villani R, Kanwal H, Capitanio N, Duda L, Avolio C, Serviddio G. Metabolic reprogramming in inflammatory microglia indicates a potential way of targeting inflammation in Alzheimer&apos;s disease. Redox Biol. 2023; 66:102846.","DOI":"10.1016\/j.redox.2023.102846"},{"key":"135","doi-asserted-by":"crossref","unstructured":"135. Yin J, Zhao F, Chojnacki JE, Fulp J, Klein WL, Zhang S, Zhu X. NLRP3 inflammasome inhibitor ameliorates amyloid pathology in a mouse model of Alzheimer&apos;s disease. Mol Neurobiol. 2018; 55:1977-1987.","DOI":"10.1007\/s12035-017-0467-9"},{"key":"136","doi-asserted-by":"crossref","unstructured":"136. Feng J, Wang JX, Du YH, Liu Y, Zhang W, Chen JF, Liu YJ, Zheng M, Wang KJ, He GQ. Dihydromyricetin inhibits microglial activation and neuroinflammation by suppressing NLRP3 inflammasome activation in APP\/PS1 transgenic mice. CNS Neurosci Ther. 2018; 24:1207-1218.","DOI":"10.1111\/cns.12983"},{"key":"137","doi-asserted-by":"crossref","unstructured":"137. Park MH, Lee M, Nam G, <i>et al<\/i>. N,N&apos;-Diacetyl-p-phenylenediamine restores microglial phagocytosis and improves cognitive defects in Alzheimer&apos;s disease transgenic mice. Proc Natl Acad Sci U S A. 2019; 116:23426-23436.","DOI":"10.1073\/pnas.1916318116"},{"key":"138","doi-asserted-by":"crossref","unstructured":"138. Lonnemann N, Hosseini S, Marchetti C, Skouras DB, Stefanoni D, D&apos;Alessandro A, Dinarello CA, Korte M. The NLRP3 inflammasome inhibitor OLT1177 rescues cognitive impairment in a mouse model of Alzheimer&apos;s disease. Proc Natl Acad Sci U S A. 2020; 117:32145-32154.","DOI":"10.1073\/pnas.2009680117"},{"key":"139","doi-asserted-by":"crossref","unstructured":"139. Ndoja A, Reja R, Lee SH, Webster JD, Ngu H, Rose CM, Kirkpatrick DS, Modrusan Z, Chen YJ, Dugger DL, Gandham V, Xie L, Newton K, Dixit VM. Ubiquitin ligase COP1 suppresses neuroinflammation by degrading c\/EBP\u03b2 in microglia. Cell. 2020; 182:1156-1169.e12.","DOI":"10.1016\/j.cell.2020.07.011"},{"key":"140","doi-asserted-by":"crossref","unstructured":"140. Feng L, Zhang L. Resveratrol suppresses A\u03b2-induced microglial activation through the TXNIP\/TRX\/NLRP3 signaling pathway. DNA Cell Biol. 2019; 38:874-879.","DOI":"10.1089\/dna.2018.4308"},{"key":"141","doi-asserted-by":"crossref","unstructured":"141. Abozaid OAR, Sallam MW, El-Sonbaty S, Aziza S, Emad B, Ahmed ESA. Resveratrol-selenium nanoparticles alleviate neuroinflammation and neurotoxicity in a rat model of Alzheimer&apos;s disease by regulating Sirt1\/miRNA-134\/GSK3\u03b2 expression. Biol Trace Elem Res. 2022; 200:5104-5114.","DOI":"10.1007\/s12011-021-03073-7"},{"key":"142","doi-asserted-by":"crossref","unstructured":"142. Qiao P, Ma J, Wang Y, Huang Z, Zou Q, Cai Z, Tang Y. Curcumin prevents neuroinflammation by inducing microglia to transform into the M2-phenotype <i>via<\/i> CaMKK\u03b2-dependent activation of the AMP-activated protein kinase signal pathway. Curr Alzheimer Res. 2020; 17:735-752.","DOI":"10.2174\/1567205017666201111120919"},{"key":"143","doi-asserted-by":"crossref","unstructured":"143. Lu J, Zhang C, Lv J, Zhu X, Jiang X, Lu W, Lu Y, Tang Z, Wang J, Shen X. Antiallergic drug desloratadine as a selective antagonist of 5HT(2A) receptor ameliorates pathology of Alzheimer&apos;s disease model mice by improving microglial dysfunction. Aging cell. 2021; 20:e13286.","DOI":"10.1111\/acel.13286"},{"key":"144","doi-asserted-by":"crossref","unstructured":"144. Pan RY, Ma J, Kong XX, Wang XF, Li SS, Qi XL, Yan YH, Cheng J, Liu Q, Jin W, Tan CH, Yuan Z. Sodium rutin ameliorates Alzheimer&apos;s disease-like pathology by enhancing microglial amyloid-\u03b2 clearance. Sci Adv. 2019; 5:eaau6328.","DOI":"10.1126\/sciadv.aau6328"},{"key":"145","doi-asserted-by":"crossref","unstructured":"145. Lv J, Wang W, Zhu X, Xu X, Yan Q, Lu J, Shi X, Wang Z, Zhou J, Huang X, Wang J, Duan W, Shen X. DW14006 as a direct AMPK\u03b11 activator improves pathology of AD model mice by regulating microglial phagocytosis and neuroinflammation. Brain Behav Immun. 2020; 90:55-69.","DOI":"10.1016\/j.bbi.2020.07.041"},{"key":"146","doi-asserted-by":"crossref","unstructured":"146. Wang S, Mustafa M, Yuede CM, <i>et al<\/i>. Anti-human TREM2 induces microglia proliferation and reduces pathology in an Alzheimer&apos;s disease model. J Exp Med. 2020; 217:e20200785.","DOI":"10.1084\/jem.20200785"},{"key":"147","unstructured":"147. A Phase I Study Evaluating the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Immunogenicity of Single and Multiple Doses of AL002 in Healthy Participants and in Participants With Mild to Moderate Alzheimer&apos;s Disease. 2018; <i>https:\/\/clinicaltrials.gov\/study\/NCT03635047<\/i>"},{"key":"148","unstructured":"148. A Phase 2 Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to Evaluate the Efficacy and Safety of AL002 in Participants With Early Alzheimer&apos;s Disease. AbbVie, ed. 2020; <i>https:\/\/clinicaltrials.gov\/study\/NCT04592874<\/i>"},{"key":"149","doi-asserted-by":"crossref","unstructured":"149. Kuszczyk MA, Sanchez S, Pankiewicz J, Kim J, Duszczyk M, Guridi M, Asuni AA, Sullivan PM, Holtzman DM, Sadowski MJ. Blocking the interaction between apolipoprotein E and A\u03b2 reduces intraneuronal accumulation of A\u03b2 and inhibits synaptic degeneration. Am J Pathol. 2013; 182:1750-1768.","DOI":"10.1016\/j.ajpath.2013.01.034"},{"key":"150","doi-asserted-by":"crossref","unstructured":"150. Krishnamurthy K, Cantillana V, Wang H, Sullivan PM, Kolls BJ, Ge X, Lin Y, Mace B, Laskowitz DT. ApoE mimetic improves pathology and memory in a model of Alzheimer&apos;s disease. Brain Res. 2020; 1733:146685.","DOI":"10.1016\/j.brainres.2020.146685"},{"key":"151","doi-asserted-by":"crossref","unstructured":"151. Liu S, Breitbart A, Sun Y, Mehta PD, Boutajangout A, Scholtzova H, Wisniewski T. Blocking the apolipoprotein E\/amyloid \u03b2 interaction in triple transgenic mice ameliorates Alzheimer&apos;s disease related amyloid \u03b2 and tau pathology. J Neurochem. 2014; 128:577-591.","DOI":"10.1111\/jnc.12484"},{"key":"152","doi-asserted-by":"crossref","unstructured":"152. Gratuze M, Jiang H, Wang C, Xiong M, Bao X, Holtzman DM. APOE antibody inhibits A\u03b2-associated Tau seeding and spreading in a mouse model. Ann Neurol. 2022; 91:847-852.","DOI":"10.1002\/ana.26351"},{"key":"153","doi-asserted-by":"crossref","unstructured":"153. Xiong M, Jiang H, Serrano JR, Gonzales ER, Wang C, Gratuze M, Hoyle R, Bien-Ly N, Silverman AP, Sullivan PM, Watts RJ, Ulrich JD, Zipfel GJ, Holtzman DM. APOE immunotherapy reduces cerebral amyloid angiopathy and amyloid plaques while improving cerebrovascular function. Sci Transl Med. 2021; 13:eabd7522.","DOI":"10.1126\/scitranslmed.abd7522"},{"key":"154","doi-asserted-by":"crossref","unstructured":"154. Zhao L, Gottesdiener AJ, Parmar M, Li M, Kaminsky SM, Chiuchiolo MJ, Sondhi D, Sullivan PM, Holtzman DM, Crystal RG, Paul SM. Intracerebral adeno-associated virus gene delivery of apolipoprotein E2 markedly reduces brain amyloid pathology in Alzheimer&apos;s disease mouse models. Neurobiol Aging. 2016; 44:159-172.","DOI":"10.1016\/j.neurobiolaging.2016.04.020"},{"key":"155","doi-asserted-by":"crossref","unstructured":"155. Rosenberg JB, Kaplitt MG, De BP, <i>et al<\/i>. AAVrh.10-mediated APOE2 central nervous system gene therapy for APOE4-associated Alzheimer&apos;s disease. Hum Gene Ther Clin Dev. 2018; 29:24-47.","DOI":"10.1089\/humc.2017.231"},{"key":"156","unstructured":"156. A 52-Week, Multicenter, Phase 1\/2 Open-label Study to Evaluate the Safety of LX1001 in Participants With APOE4 Homozygote Alzheimer&apos;s Disease.Alzheimer&apos;s Drug Discovery F, Weill Medical College of Cornell U, eds.), 2018; <i>https:\/\/clinicaltrials.gov\/study\/NCT03634007<\/i>"},{"key":"157","unstructured":"157. Long-Term Follow-Up to Evaluate the Safety of LX1001 in Participants With APOE4 Homozygote Alzheimer&apos;s Disease. 2022; <i>https:\/\/clinicaltrials.gov\/study\/NCT05400330<\/i>"},{"key":"158","doi-asserted-by":"crossref","unstructured":"158. Li T, Yang Y, Qi H, Cui W, Zhang L, Fu X, He X, Liu M, Li PF, Yu T. CRISPR\/Cas9 therapeutics: Progress and prospects. Signal Transduct Target Ther. 2023; 8:36.","DOI":"10.1038\/s41392-023-01309-7"},{"key":"159","doi-asserted-by":"crossref","unstructured":"159. Blumenfeld J, Yip O, Kim MJ, Huang Y. Cell type-specific roles of APOE4 in Alzheimer disease. 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