Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Apolipoprotein E in Alzheimer’s disease trajectories and the next-generation clinical care pathway

Abstract

Alzheimer’s disease (AD) is a complex, progressive primary neurodegenerative disease. Since pivotal genetic studies in 1993, the ε4 allele of the apolipoprotein E gene (APOE ε4) has remained the strongest single genome-wide associated risk variant in AD. Scientific advances in APOE biology, AD pathophysiology and ApoE-targeted therapies have brought APOE to the forefront of research, with potential translation into routine AD clinical care. This contemporary Review will merge APOE research with the emerging AD clinical care pathway and discuss APOE genetic risk as a conduit to genomic-based precision medicine in AD, including ApoE’s influence in the ATX(N) biomarker framework of AD. We summarize the evidence for APOE as an important modifier of AD clinical–biological trajectories. We then illustrate the utility of APOE testing and the future of ApoE-targeted therapies in the next-generation AD clinical–diagnostic pathway. With the emergence of new AD therapies, understanding how APOE modulates AD pathophysiology will become critical for personalized AD patient care.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Structure and function of ApoE in the periphery and the CNS.
Fig. 2: APOE genotype and the risk of AD.
Fig. 3: Effect of APOE on AD biomarkers in AT(N) framework.
Fig. 4: Relationship between ApoE and underlying AD pathophysiology.
Fig. 5: Overview of ApoE-targeted therapies.

Similar content being viewed by others

References

  1. Alzheimer’s Association. 2022 Alzheimer’s disease facts and figures. Alzheimers Dement. 18, 700–789 (2022).

  2. Hampel, H. et al. The amyloid-β pathway in Alzheimer’s disease. Mol. Psychiatry 26, 5481–5503 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Hampel, H. et al. Developing the ATX(N) classification for use across the Alzheimer disease continuum. Nat. Rev. Neurol. 17, 580–589 (2021).

    PubMed  Google Scholar 

  4. Yamazaki, Y., Zhao, N., Caulfield, T. R., Liu, C. C. & Bu, G. Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies. Nat. Rev. Neurol. 15, 501–518 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Genin, E. et al. APOE and Alzheimer disease: a major gene with semi-dominant inheritance. Mol. Psychiatry 16, 903–907 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Corder, E. H. et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261, 921–923 (1993).

    CAS  PubMed  Google Scholar 

  7. Belloy, M. E. et al. APOE genotype and Alzheimer disease risk across age, sex, and population ancestry. JAMA Neurol. 80, 1284–1294 (2023).

    PubMed  PubMed Central  Google Scholar 

  8. Farrer, L. A. et al. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. JAMA 278, 1349–1356 (1997).

    CAS  PubMed  Google Scholar 

  9. Neu, S. C. et al. Apolipoprotein E genotype and sex risk factors for Alzheimer disease: a meta-analysis. JAMA Neurol. 74, 1178–1189 (2017).

    PubMed  PubMed Central  Google Scholar 

  10. Chen, Y., Strickland, M. R., Soranno, A. & Holtzman, D. M. Apolipoprotein E: structural insights and links to Alzheimer disease pathogenesis. Neuron 109, 205–221 (2021).

    CAS  PubMed  Google Scholar 

  11. Linton, M. F. et al. Phenotypes of apolipoprotein B and apolipoprotein E after liver transplantation. J. Clin. Invest. 88, 270–281 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Mahley, R. W. Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science 240, 622–630 (1988).

    CAS  PubMed  Google Scholar 

  13. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Reiman, E. M. et al. Exceptionally low likelihood of Alzheimer’s dementia in APOE2 homozygotes from a 5,000-person neuropathological study. Nat. Commun. 11, 667 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Kaup, A. R. et al. Cognitive resilience to apolipoprotein E ε4: contributing factors in Black and white older adults. JAMA Neurol. 72, 340–348 (2015).

    PubMed  PubMed Central  Google Scholar 

  16. Zheng, L. et al. Gender specific factors contributing to cognitive resilience in APOE ε4 positive older adults in a population-based sample. Sci. Rep. 13, 8037 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Utermann, G., Hees, M. & Steinmetz, A. Polymorphism of apolipoprotein E and occurrence of dysbetalipoproteinaemia in man. Nature 269, 604–607 (1977).

    CAS  PubMed  Google Scholar 

  18. Corder, E. H. et al. Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease. Nat. Genet. 7, 180–184 (1994).

    CAS  PubMed  Google Scholar 

  19. Naslavsky, M. S. et al. Global and local ancestry modulate APOE association with Alzheimer’s neuropathology and cognitive outcomes in an admixed sample. Mol. Psychiatry 27, 4800–4808 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Chen, Q., Wang, T., Kang, D. & Chen, L. Protective effect of apolipoprotein E ε3 on sporadic Alzheimer’s disease in the Chinese population: a meta-analysis. Sci. Rep. 12, 13620 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Nishita, Y. et al. Effects of APOEε4 genotype on age-associated change in cognitive functions among Japanese middle-aged and older adults: a 20-year follow-up study. Exp. Gerontol. 171, 112036 (2023).

    CAS  PubMed  Google Scholar 

  22. Ali, M. et al. Large multi-ethnic genetic analyses of amyloid imaging identify new genes for Alzheimer disease. Acta Neuropathol. Commun. 11, 68 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Serrano-Pozo, A., Das, S. & Hyman, B. T. APOE and Alzheimer’s disease: advances in genetics, pathophysiology, and therapeutic approaches. Lancet Neurol. 20, 68–80 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Cacace, R., Sleegers, K. & Van Broeckhoven, C. Molecular genetics of early-onset Alzheimer’s disease revisited. Alzheimers Dement. 12, 733–748 (2016).

    PubMed  Google Scholar 

  25. van Duijn, C. M. et al. Apolipoprotein E4 allele in a population-based study of early-onset Alzheimer’s disease. Nat. Genet. 7, 74–78 (1994).

    PubMed  Google Scholar 

  26. Polsinelli, A. J. et al. APOE ε4 is associated with earlier symptom onset in LOAD but later symptom onset in EOAD. Alzheimers Dement. 19, 2212–2217 (2023).

    CAS  PubMed  Google Scholar 

  27. Polsinelli, A. J. et al. APOE ε4 carrier status and sex differentiate rates of cognitive decline in early- and late-onset Alzheimer’s disease. Alzheimers Dement. 19, 1983–1993 (2023).

  28. Bu, G. APOE targeting strategy in Alzheimer’s disease: lessons learned from protective variants. Mol. Neurodegener. 17, 51 (2022).

    PubMed  PubMed Central  Google Scholar 

  29. Arboleda-Velasquez, J. F. et al. Resistance to autosomal dominant Alzheimer’s disease in an APOE3 Christchurch homozygote: a case report. Nat. Med. 25, 1680–1683 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Sepulveda-Falla, D. et al. Distinct tau neuropathology and cellular profiles of an APOE3 Christchurch homozygote protected against autosomal dominant Alzheimer’s dementia. Acta Neuropathol. 144, 589–601 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Fagan, A. M. et al. Human and murine ApoE markedly alters Aβ metabolism before and after plaque formation in a mouse model of Alzheimer’s disease. Neurobiol. Dis. 9, 305–318 (2002).

    CAS  PubMed  Google Scholar 

  32. Holtzman, D. M. et al. Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer’s disease. Proc. Natl Acad. Sci. USA 97, 2892–2897 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Tiraboschi, P. et al. Impact of APOE genotype on neuropathologic and neurochemical markers of Alzheimer disease. Neurology 62, 1977–1983 (2004).

    CAS  PubMed  Google Scholar 

  34. Migliore, L. & Coppede, F. Gene–environment interactions in Alzheimer disease: the emerging role of epigenetics. Nat. Rev. Neurol. 18, 643–660 (2022).

    CAS  PubMed  Google Scholar 

  35. Hampel, H. et al. Designing the next-generation clinical care pathway for Alzheimer’s disease. Nat. Aging 2, 692–703 (2022).

    PubMed  PubMed Central  Google Scholar 

  36. Barthelemy, N. R. et al. A soluble phosphorylated tau signature links tau, amyloid and the evolution of stages of dominantly inherited Alzheimer’s disease. Nat. Med. 26, 398–407 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Therriault, J. et al. Association of phosphorylated tau biomarkers with amyloid positron emission tomography vs tau positron emission tomography. JAMA Neurol. 80, 188–199 (2022).

    PubMed Central  Google Scholar 

  38. Gonzalez-Ortiz, F. et al. Brain-derived tau: a novel blood-based biomarker for Alzheimer’s disease-type neurodegeneration. Brain 146, 1152–1165 (2023).

    PubMed  Google Scholar 

  39. Hampel, H. et al. Blood-based biomarkers for Alzheimer’s disease: current state and future use in a transformed global healthcare landscape. Neuron 111, 2781–2799 (2023).

    CAS  PubMed  Google Scholar 

  40. Bradley, J. et al. Genetic architecture of plasma Alzheimer disease biomarkers. Hum. Mol. Genet. 32, 2532–2543 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Elias-Sonnenschein, L. S., Viechtbauer, W., Ramakers, I. H., Verhey, F. R. & Visser, P. J. Predictive value of APOE-ε4 allele for progression from MCI to AD-type dementia: a meta-analysis. J. Neurol. Neurosurg. Psychiatry 82, 1149–1156 (2011).

    PubMed  Google Scholar 

  42. Vermunt, L. et al. Duration of preclinical, prodromal, and dementia stages of Alzheimer’s disease in relation to age, sex, and APOE genotype. Alzheimers Dement. 15, 888–898 (2019).

    PubMed  Google Scholar 

  43. Leonenko, G. et al. Genetic risk for Alzheimer disease is distinct from genetic risk for amyloid deposition. Ann. Neurol. 86, 427–435 (2019).

    CAS  PubMed  Google Scholar 

  44. Tomassen, J. et al. Amyloid-β and APOE genotype predict memory decline in cognitively unimpaired older individuals independently of Alzheimer’s disease polygenic risk score. BMC Neurol. 22, 484 (2022).

    CAS  PubMed  Google Scholar 

  45. Emrani, S., Arain, H. A., DeMarshall, C. & Nuriel, T. APOE4 is associated with cognitive and pathological heterogeneity in patients with Alzheimer’s disease: a systematic review. Alzheimers Res. Ther. 12, 141 (2020).

    PubMed  Google Scholar 

  46. Buckley, R. F. et al. Sex, amyloid, and APOE ε4 and risk of cognitive decline in preclinical Alzheimer’s disease: findings from three well-characterized cohorts. Alzheimers Dement. 14, 1193–1203 (2018).

    PubMed  Google Scholar 

  47. Kumar, A. et al. Genetic effects on longitudinal cognitive decline during the early stages of Alzheimer’s disease. Sci. Rep. 11, 19853 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Shi, Y. et al. ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature 549, 523–527 (2017).

    PubMed  PubMed Central  Google Scholar 

  49. Steward, A. et al. ApoE4 and connectivity-mediated spreading of tau pathology at lower amyloid levels. JAMA Neurol. 80, 1295–1306 (2023).

    PubMed  Google Scholar 

  50. Morris, J. C. et al. APOE predicts amyloid-β but not tau Alzheimer pathology in cognitively normal aging. Ann. Neurol. 67, 122–131 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Burnham, S. C. et al. Impact of APOE-ε4 carriage on the onset and rates of neocortical Aβ-amyloid deposition. Neurobiol. Aging 95, 46–55 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Jansen, W. J. et al. Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis. JAMA 313, 1924–1938 (2015).

    PubMed  PubMed Central  Google Scholar 

  53. Lim, Y. Y., Mormino, E. C. & Alzheimer’s Disease Neuroimaging Initiative. APOE genotype and early β-amyloid accumulation in older adults without dementia. Neurology 89, 1028–1034 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Serrano-Pozo, A., Qian, J., Monsell, S. E., Betensky, R. A. & Hyman, B. T. APOEε2 is associated with milder clinical and pathological Alzheimer disease. Ann. Neurol. 77, 917–929 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Deming, Y. et al. Genome-wide association study identifies four novel loci associated with Alzheimer’s endophenotypes and disease modifiers. Acta Neuropathol. 133, 839–856 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. West, T. et al. A blood-based diagnostic test incorporating plasma Aβ42/40 ratio, ApoE proteotype, and age accurately identifies brain amyloid status: findings from a multi cohort validity analysis. Mol. Neurodegener. 16, 30 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Castellano, J. M. et al. Human ApoE isoforms differentially regulate brain amyloid-β peptide clearance. Sci. Transl. Med. 3, 89ra57 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Liu, C. C. et al. ApoE4 accelerates early seeding of amyloid pathology. Neuron 96, 1024–1032 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Koffie, R. M. et al. Apolipoprotein E4 effects in Alzheimer’s disease are mediated by synaptotoxic oligomeric amyloid-β. Brain 135, 2155–2168 (2012).

    PubMed  PubMed Central  Google Scholar 

  60. Hashimoto, T. et al. Apolipoprotein E, especially apolipoprotein E4, increases the oligomerization of amyloid β peptide. J. Neurosci. 32, 15181–15192 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Hori, Y., Hashimoto, T., Nomoto, H., Hyman, B. T. & Iwatsubo, T. Role of apolipoprotein E in β-amyloidogenesis: isoform-specific effects on protofibril to fibril conversion of Aβ in vitro and brain Aβ deposition in vivo. J. Biol. Chem. 293, 7267 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Kanekiyo, T., Xu, H. & Bu, G. ApoE and Aβ in Alzheimer’s disease: accidental encounters or partners? Neuron 81, 740–754 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Deane, R. et al. ApoE isoform-specific disruption of amyloid β peptide clearance from mouse brain. J. Clin. Invest. 118, 4002–4013 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Castellano, J. M. et al. Low-density lipoprotein receptor overexpression enhances the rate of brain-to-blood Aβ clearance in a mouse model of β-amyloidosis. Proc. Natl Acad. Sci. USA 109, 15502–15507 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Hawkes, C. A. et al. Disruption of arterial perivascular drainage of amyloid-β from the brains of mice expressing the human APOE ε4 allele. PLoS ONE 7, e41636 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Huang, Y. A., Zhou, B., Wernig, M. & Sudhof, T. C. ApoE2, ApoE3, and ApoE4 differentially stimulate APP transcription and Aβ secretion. Cell 168, 427–441 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Lin, Y. T. et al. APOE4 causes widespread molecular and cellular alterations associated with Alzheimer’s disease phenotypes in human iPSC-derived brain cell types. Neuron 98, 1141–1154 (2018).

    Google Scholar 

  68. Nuriel, T. et al. The endosomal–lysosomal pathway is dysregulated by APOE4 expression in vivo. Front. Neurosci. 11, 702 (2017).

    PubMed  PubMed Central  Google Scholar 

  69. Hou, X. et al. Differential and substrate-specific inhibition of γ-secretase by the C-terminal region of ApoE2, ApoE3, and ApoE4. Neuron 111, 1898–1913 (2023).

    CAS  PubMed  Google Scholar 

  70. Lim, Y. Y. et al. Association of β-amyloid and apolipoprotein E ε4 with memory decline in preclinical Alzheimer disease. JAMA Neurol. 75, 488–494 (2018).

    PubMed  Google Scholar 

  71. Ghisays, V. et al. Brain imaging measurements of fibrillar amyloid-β burden, paired helical filament tau burden, and atrophy in cognitively unimpaired persons with two, one, and no copies of the APOE ε4 allele. Alzheimers Dement. 16, 598–609 (2020).

    CAS  PubMed  Google Scholar 

  72. Cruchaga, C. et al. GWAS of cerebrospinal fluid tau levels identifies risk variants for Alzheimer’s disease. Neuron 78, 256–268 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 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 β-amyloid. Neurobiol. Aging 37, 19–25 (2016).

    CAS  PubMed  Google Scholar 

  74. Goldberg, T. E., Huey, E. D. & Devanand, D. P. Association of APOE e2 genotype with Alzheimer’s and non-Alzheimer’s neurodegenerative pathologies. Nat. Commun. 11, 4727 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Wang, Y. T. et al. Interactive rather than independent effect of APOE and sex potentiates tau deposition in women. Brain Commun. 3, fcab126 (2021).

    Google Scholar 

  76. Dincer, A. et al. APOE ε4 genotype, amyloid-β, and sex interact to predict tau in regions of high APOE mRNA expression. Sci. Transl. Med. 14, eabl7646 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Yan, S. et al. Sex modifies APOE ε4 dose effect on brain tau deposition in cognitively impaired individuals. Brain 144, 3201–3211 (2021).

    PubMed  PubMed Central  Google Scholar 

  78. Ferrari-Souza, J. P. et al. APOEε4 associates with microglial activation independently of Aβ plaques and tau tangles. Sci. Adv. 9, eade1474 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Shi, Y. et al. Microglia drive APOE-dependent neurodegeneration in a tauopathy mouse model. J. Exp. Med. 216, 2546–2561 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Wang, C. et al. Selective removal of astrocytic APOE4 strongly protects against tau-mediated neurodegeneration and decreases synaptic phagocytosis by microglia. Neuron 109, 1657–1674 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Seo, D. O. et al. ApoE isoform- and microbiota-dependent progression of neurodegeneration in a mouse model of tauopathy. Science 379, eadd1236 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Koutsodendris, N. et al. Neuronal APOE4 removal protects against tau-mediated gliosis, neurodegeneration and myelin deficits. Nat. Aging 3, 275–296 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Parhizkar, S. & Holtzman, D. M. APOE mediated neuroinflammation and neurodegeneration in Alzheimer’s disease. Semin. Immunol. 59, 101594 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Shi, Y. & Holtzman, D. M. Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight. Nat. Rev. Immunol. 18, 759–772 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Ulrich, J. D. et al. ApoE facilitates the microglial response to amyloid plaque pathology. J. Exp. Med. 215, 1047–1058 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Serrano-Pozo, A. et al. Effect of APOE alleles on the glial transcriptome in normal aging and Alzheimer’s disease. Nat. Aging 1, 919–931 (2021).

    PubMed  PubMed Central  Google Scholar 

  87. Stephen, T. L. et al. APOE genotype and sex affect microglial interactions with plaques in Alzheimer’s disease mice. Acta Neuropathol. Commun. 7, 82 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Rodriguez, G. A., Tai, L. M., LaDu, M. J. & Rebeck, G. W. Human APOE4 increases microglia reactivity at Aβ plaques in a mouse model of Aβ deposition. J. Neuroinflammation 11, 111 (2014).

    Google Scholar 

  89. Parhizkar, S. et al. Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE. Nat. Neurosci. 22, 191–204 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Gratuze, M. et al. Activated microglia mitigate Aβ-associated tau seeding and spreading. J. Exp. Med. 218, e20210542 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Fitz, N. F. et al. Phospholipids of APOE lipoproteins activate microglia in an isoform-specific manner in preclinical models of Alzheimer’s disease. Nat. Commun. 12, 3416 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Chen, X. et al. Microglia-mediated T cell infiltration drives neurodegeneration in tauopathy. Nature 615, 668–677 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Shi, Y. et al. Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to ApoE-linked mechanisms. Neuron 109, 2413–2426 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Litvinchuk, A. et al. Apolipoprotein E4 reduction with antisense oligonucleotides decreases neurodegeneration in a tauopathy model. Ann. Neurol. 89, 952–966 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Nugent, A. A. et al. TREM2 regulates microglial cholesterol metabolism upon chronic phagocytic challenge. Neuron 105, 837–854 (2020).

    CAS  PubMed  Google Scholar 

  96. Victor, M. B. et al. Lipid accumulation induced by APOE4 impairs microglial surveillance of neuronal-network activity. Cell Stem Cell 29, 1197–1212 (2022).

    CAS  Google Scholar 

  97. Tcw, J. et al. Cholesterol and matrisome pathways dysregulated in astrocytes and microglia. Cell 185, 2213–2233 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Qi, G. et al. ApoE4 impairs neuron–astrocyte coupling of fatty acid metabolism. Cell Rep. 34, 108572 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Blanchard, J. W. et al. APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes. Nature 611, 769–779 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Chatterjee, P. et al. Diagnostic and prognostic plasma biomarkers for preclinical Alzheimer’s disease. Alzheimers Dement. 18, 1141–1154 (2022).

    CAS  PubMed  Google Scholar 

  101. Stevenson-Hoare, J. et al. Plasma biomarkers and genetics in the diagnosis and prediction of Alzheimer’s disease. Brain 146, 690–699 (2023).

  102. Bonomi, C. G. et al. Cerebrospinal fluid sTREM-2, GFAP, and β-S100 in symptomatic sporadic Alzheimer’s disease: microglial, astrocytic, and APOE contributions along the Alzheimer’s disease continuum. J. Alzheimers Dis. 92, 1385–1397 (2023).

    CAS  PubMed  Google Scholar 

  103. Greenberg, S. M. et al. Cerebral amyloid angiopathy and Alzheimer disease — one peptide, two pathways. Nat. Rev. Neurol. 16, 30–42 (2020).

    CAS  PubMed  Google Scholar 

  104. Jakel, L., De Kort, A. M., Klijn, C. J. M., Schreuder, F. & Verbeek, M. M. Prevalence of cerebral amyloid angiopathy: a systematic review and meta-analysis. Alzheimers Dement. 18, 10–28 (2022).

    CAS  PubMed  Google Scholar 

  105. Tai, L. M. et al. The role of APOE in cerebrovascular dysfunction. Acta Neuropathol. 131, 709–723 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Montagne, A. et al. APOE4 leads to blood–brain barrier dysfunction predicting cognitive decline. Nature 581, 71–76 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Barisano, G. et al. A ‘multi-omics’ analysis of blood–brain barrier and synaptic dysfunction in APOE4 mice. J. Exp. Med. 219, e20221137 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Liu, C. C. et al. Peripheral ApoE4 enhances Alzheimer’s pathology and impairs cognition by compromising cerebrovascular function. Nat. Neurosci. 25, 1020–1033 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Fryer, J. D. et al. Apolipoprotein E markedly facilitates age-dependent cerebral amyloid angiopathy and spontaneous hemorrhage in amyloid precursor protein transgenic mice. J. Neurosci. 23, 7889–7896 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Fryer, J. D. et al. Human apolipoprotein E4 alters the amyloid-β 40:42 ratio and promotes the formation of cerebral amyloid angiopathy in an amyloid precursor protein transgenic model. J. Neurosci. 25, 2803–2810 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Xiong, M. et al. Astrocytic APOE4 removal confers cerebrovascular protection despite increased cerebral amyloid angiopathy. Mol. Neurodegener. 18, 17 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Chwalisz, B. K. Cerebral amyloid angiopathy and related inflammatory disorders. J. Neurol. Sci. 424, 117425 (2021).

    CAS  PubMed  Google Scholar 

  113. Filippi, M. et al. Amyloid-related imaging abnormalities and β-amyloid-targeting antibodies: a systematic review. JAMA Neurol. 79, 291–304 (2022).

    PubMed  Google Scholar 

  114. Hampel, H. et al. Amyloid-related imaging abnormalities (ARIA): radiological, biological and clinical characteristics. Brain 146, 4414–4424 (2023).

    PubMed  PubMed Central  Google Scholar 

  115. Liu, C. C., Liu, C. C., Kanekiyo, T., Xu, H. & Bu, G. Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat. Rev. Neurol. 9, 106–118 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Cruchaga, C. et al. Proteogenomic analysis of human cerebrospinal fluid identifies neurologically relevant regulation and informs causal proteins for Alzheimer’s disease. Preprint at Reseach Square https://doi.org/10.21203/rs.3.rs-2814616/v1 (2023).

  117. Tible, M. et al. Dissection of synaptic pathways through the CSF biomarkers for predicting Alzheimer disease. Neurology 95, e953–e961 (2020).

    CAS  PubMed  Google Scholar 

  118. Roberts, J. S. & Uhlmann, W. R. Genetic susceptibility testing for neurodegenerative diseases: ethical and practice issues. Prog. Neurobiol. 110, 89–101 (2013).

    PubMed  Google Scholar 

  119. Largent, E. A. et al. Disclosing genetic risk of Alzheimer’s disease to cognitively unimpaired older adults: findings from the study of knowledge and reactions to APOE testing (SOKRATES II). J. Alzheimers Dis. 84, 1015–1028 (2021).

    PubMed  PubMed Central  Google Scholar 

  120. Blasco, D. & Roberts, J. S. Editorial: implications of emerging uses of genetic testing for Alzheimer’s disease. J. Prev. Alzheimers Dis. 10, 359–361 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Goldman, J. S. et al. ADDENDUM: genetic counseling and testing for Alzheimer disease: joint practice guidelines of the American College of Medical Genetics and the National Society of Genetic Counselors. Genet. Med. 21, 2404 (2019).

    PubMed  Google Scholar 

  122. Galluzzi, S. et al. Disclosure of genetic risk factors for Alzheimer’s disease to cognitively healthy individuals—from current practice towards a personalised medicine scenario. Biomedicines 10, 3177 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Batra, P. & Huang, K. L. Genotype concordance and polygenic risk score estimation across consumer genetic testing data. Ann. Hum. Genet. 84, 352–356 (2020).

    CAS  PubMed  Google Scholar 

  124. Cummings, J. et al. Lecanemab: appropriate use recommendations. J. Prev. Alzheimers Dis. 10, 362–377 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Bertram, L. & Hampel, H. The role of genetics for biomarker development in neurodegeneration. Prog. Neurobiol. 95, 501–504 (2011).

    CAS  PubMed  Google Scholar 

  126. Tolar, M., Abushakra, S., Hey, J. A., Porsteinsson, A. & Sabbagh, M. Aducanumab, gantenerumab, BAN2401, and ALZ-801—the first wave of amyloid-targeting drugs for Alzheimer’s disease with potential for near term approval. Alzheimers Res. Ther. 12, 95 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Abushakra, S. et al. Clinical effects of tramiprosate in APOE4/4 homozygous patients with mild Alzheimer’s disease suggest disease modification potential. J. Prev. Alzheimers Dis. 4, 149–156 (2017).

    CAS  PubMed  Google Scholar 

  128. Walsh, T. et al. Outreach, screening, and randomization of APOE ε4 carriers into an Alzheimer’s prevention trial: a global perspective from the API Generation Program. J. Prev. Alzheimers Dis. 10, 453–463 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Solomon, A. et al. Effect of the apolipoprotein E genotype on cognitive change during a multidomain lifestyle intervention: a subgroup analysis of a randomized clinical trial. JAMA Neurol. 75, 462–470 (2018).

    PubMed  PubMed Central  Google Scholar 

  130. Stocker, H., Mollers, T., Perna, L. & Brenner, H. The genetic risk of Alzheimer’s disease beyond APOE ε4: systematic review of Alzheimer’s genetic risk scores. Transl. Psychiatry 8, 166 (2018).

    PubMed  PubMed Central  Google Scholar 

  131. Jung, S. H. et al. Transferability of Alzheimer disease polygenic risk score across populations and its association with Alzheimer disease-related phenotypes. JAMA Netw. Open 5, e2247162 (2022).

    PubMed  PubMed Central  Google Scholar 

  132. Green, R. C. et al. Disclosure of APOE genotype for risk of Alzheimer’s disease. N. Engl. J. Med. 361, 245–254 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Lineweaver, T. T., Bondi, M. W., Galasko, D. & Salmon, D. P. Effect of knowledge of APOE genotype on subjective and objective memory performance in healthy older adults. Am. J. Psychiatry 171, 201–208 (2014).

    PubMed  PubMed Central  Google Scholar 

  134. Chao, S. et al. Health behavior changes after genetic risk assessment for Alzheimer disease: the REVEAL Study. Alzheimer Dis. Assoc. Disord. 22, 94–97 (2008).

    PubMed  PubMed Central  Google Scholar 

  135. Zick, C. D. et al. Genetic testing for Alzheimer’s disease and its impact on insurance purchasing behavior. Health Aff. 24, 483–490 (2005).

    Google Scholar 

  136. Cook, L. et al. Tools for communicating risk for Parkinson’s disease. NPJ Parkinsons Dis. 8, 164 (2022).

    Google Scholar 

  137. Hampel, H. et al. The foundation and architecture of precision medicine in neurology and psychiatry. Trends Neurosci. 46, 176–198 (2023).

  138. Jansen, I. E. et al. Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer’s disease risk. Nat. Genet. 51, 404–413 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Kunkle, B. W. et al. Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing. Nat. Genet. 51, 414–430 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Xiong, M. et al. APOE immunotherapy reduces cerebral amyloid angiopathy and amyloid plaques while improving cerebrovascular function. Sci. Transl. Med. 13, eabd7522 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Huynh, T. V. et al. Age-dependent effects of ApoE reduction using antisense oligonucleotides in a model of β-amyloidosis. Neuron 96, 1013–1023 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Pankiewicz, J. E. et al. Blocking the ApoE/Aβ interaction ameliorates Aβ-related pathology in APOE ε2 and ε4 targeted replacement Alzheimer model mice. Acta Neuropathol. Commun. 2, 75 (2014).

    PubMed  PubMed Central  Google Scholar 

  143. Zhao, N. et al. APOE ε2 is associated with increased tau pathology in primary tauopathy. Nat. Commun. 9, 4388 (2018).

    PubMed  PubMed Central  Google Scholar 

  144. Margeta, M. A. et al. Association of APOE with primary open-angle glaucoma suggests a protective effect for APOE ε4. Invest. Ophthalmol. Vis. Sci. 61, 3 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Marino, C. et al. APOE Christchurch-mimetic therapeutic antibody reduces APOE-mediated toxicity and tau phosphorylation. Alzheimers Dement. 20, 819–836 (2023).

    PubMed  PubMed Central  Google Scholar 

  146. Jack, C. R. Jr. et al. Hypothetical model of dynamic biomarkers of the Alzheimer’s pathological cascade. Lancet Neurol. 9, 119–128 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Gratuze, M. et al. APOE antibody inhibits Aβ-associated tau seeding and spreading in a mouse model. Ann. Neurol. 91, 847–852 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. 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).

    PubMed  PubMed Central  Google Scholar 

  149. Rosenberg, J. B. et al. AAVrh.10-mediated APOE2 central nervous system gene therapy for APOE4-associated Alzheimer’s disease. Hum. Gene Ther. Clin. Dev. 29, 24–47 (2018).

    CAS  Google Scholar 

Download references

Acknowledgements

Figure rendering under the direction and schema devised by the authors was provided by Y. Henderson of MediTech Media and was funded by Eisai, in accordance with Good Publication 20 Practice (GPP3) guidelines.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Harald Hampel.

Ethics declarations

Competing interests

H.H. is an employee of Eisai. He serves as a reviewing editor for the journal Alzheimer’s & Dementia. He is an inventor of 11 patents and has received no royalties: In Vitro Multiparameter Determination Method for the Diagnosis and Early Diagnosis of Neurodegenerative Disorders, patent number 8916388; In Vitro Procedure for Diagnosis and Early Diagnosis of Neurodegenerative Diseases, patent number 8298784; Neurodegenerative Markers for Psychiatric Conditions, publication number 20120196300; In Vitro Multiparameter Determination Method for the Diagnosis and Early Diagnosis of Neurodegenerative Disorders, publication number 20100062463; In Vitro Method for the Diagnosis and Early Diagnosis of Neurodegenerative Disorders, publication number 20100035286; In Vitro Procedure for Diagnosis and Early Diagnosis of Neurodegenerative Diseases, publication number 20090263822; In Vitro Method for the Diagnosis of Neurodegenerative Diseases, patent number 7547553; CSF Diagnostic In Vitro Method for Diagnosis of Dementias and Neuroinflammatory Diseases, publication number 20080206797; In Vitro Method for the Diagnosis of Neurodegenerative Diseases, publication number 20080199966; Neurodegenerative Markers for Psychiatric Conditions, publication number 20080131921; Method for diagnosis of dementias and neuroinflammatory diseases based on an increased level of procalcitonin in cerebrospinal fluid, publication number: United States patent 10921330. D.M.H. cofounded, has equity in and is on the scientific advisory board of C2N Diagnostics. He is on the scientific advisory board of Denali, Cajal Neuroscience and Genentech and consults for Alector. He is an inventor on US patent application US-20190270794-A1, ‘Anti-ApoE antibodies’. Anti-ApoE antibodies and this patent application have been licensed by Washington University the NextCure. L.G.A. receives research support from the NIH, the Alzheimer Association, AVID Pharmaceuticals, Life Molecular Imaging, Roche Diagnostics and Eli Lilly. L.G.A. has served as a consultant for Biogen, Two Labs, IQVIA, the NIH, the Florida Department of Health, Siemens, Corium, the NIH Biobank, Eli Lilly, Eisai, GE Healthcare, Roche Diagnostics, Alnylam and Genentech. L.G.A. is a member of various data and safety monitoring boards and advisory boards for IQVIA, NIA R01 AG061111, the UAB Nathan Schick Center, the FDA PCNS Advisory Board and the University New Mexico ADRC. L.G.A. serves in a leadership or fiduciary role at the Medical and Scientific Council of the Alzheimer’s Association Greater Indiana Chapter, the Alzheimer’s Association Science Program Committee, the FDA PCNS Advisory Committee and the Beeson Program Committee. L.G.A. has received equipment, materials, drugs, medical writing, gifts or other services from AVID Pharmaceuticals, Life Molecular Imaging and Roche Diagnostics. L.G.A. owns stock in Cassava Neurosciences and Golden Seeds. C.C. has received research support from GSK. C.C. is a member of the advisory board of Vivid Genomics and Circular Genomics and owns stocks. C.L.M. has no competing interests to declare. J.H. has consulted for Eisai and Eli Lilly. V.L.V. serves as a senior associate editor for the Journal of Neurochemistry. He has been a consultant for IXICO and Life Molecular Imaging and has received speaker honoraria from GE Healthcare, Piramal Lifesciences and Eli Lilly. M.C., J.B. and S.N. are employees of Eisai.

Peer review

Peer review information

Nature Neuroscience thanks David Bennett and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Narasimhan, S., Holtzman, D.M., Apostolova, L.G. et al. Apolipoprotein E in Alzheimer’s disease trajectories and the next-generation clinical care pathway. Nat Neurosci 27, 1236–1252 (2024). https://doi.org/10.1038/s41593-024-01669-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41593-024-01669-5

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing