APOE ε2 is associated with increased tau pathology in primary tauopathy
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Apolipoprotein E ( APOE ) ε4 allele is the strongest genetic risk factor for late-onset Alzheimer’s disease mainly by modulating amyloid-β pathology. APOE ε4 is also shown to exacerbate neurodegeneration and neuroinflammation in a tau transgenic mouse model. To further evaluate the association of APOE genotype with the presence and severity of tau pathology, we express human tau via an adeno-associated virus gene delivery approach in human APOE targeted replacement mice. We find increased hyperphosphorylated tau species, tau aggregates, and behavioral abnormalities in mice expressing APOE ε2/ε2. We also show that in humans, the APOE ε2 allele is associated with increased tau pathology in the brains of progressive supranuclear palsy (PSP) cases. Finally, we identify an association between the APOE ε2/ε2 genotype and risk of tauopathies using two series of pathologically-confirmed cases of PSP and corticobasal degeneration. Our data together suggest APOE ε2 status may influence the risk and progression of tauopathy.
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One study found that the APOEε2 allele is associated with increased odds of neuropathologically confirmed primary tauopathy (progressive supranuclear palsy and corticobasal degeneration).
“One study found that the APOEε2 allele is associated with increased odds of neuropathologically confirmed primary tauopathy (PSP and corticobasal degeneration)66.”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [66]
The Methods section confirms that the PSP and corticobasal degeneration cases met neuropathologic criteria. The Results section reports increased odds for the APOE ε2/ε2 genotype, not for carrying the ε2 allele generally; the increased odds for corticobasal degeneration in the full sample did not reach statistical significance. (LLM, conf=0.90)
Experimental — accuracy not yet measuredThe APOE ε2 allele is associated with increased tau pathology in the brains of human progressive supranuclear palsy.
“Furthermore, the APOE ε2 allele was associated with increased tau pathology in the brains of human progressive supranuclear palsy, a primary tauopathy.”
From Deletion of neuronal <i>Idol</i> ameliorates Alzheimer's disease–related pathologies via APOE receptors (2025) · cites this paper as [71]
APOE2 mice exhibited more tau pathology compared to APOE3 and APOE4 mice, and behavioral abnormalities in a tauopathy model.
“For example, APOE2 mice exhibited more tau pathology, compared to APOE3 and APOE4 mice, and behavioral abnormalities in a tauopathy model.”
From Deletion of neuronal <i>Idol</i> ameliorates Alzheimer's disease–related pathologies via APOE receptors (2025) · cites this paper as [71]
Hyperphosphorylated tau species, tau aggregates and behavioral abnormalities are observed in APOE ε2/ε2 mice.
“Studies have shown that hyperphosphorylated tau species, tau aggregates and behavioral abnormalities were observed in APOE ε2/ε2 mice [471].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [471]
APOE ε2 is associated with increased pathological tau levels in the presence of amyloid.
“In addition, APOE ε2 is also associated with increased pathological tau levels in the presence of amyloid [471, 472].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [471]
A recent study failed to replicate the neurotoxic effect of ApoE4 in tauopathy mice; in that study ApoE2 mice rather than ApoE4 had enhanced tau pathology, astrogliosis, and behavioral impairment.
“A recent study failed to replicate the neurotoxic effect of ApoE4 in tauopathy mice.”
From Alzheimer Disease: An Update on Pathobiology and Treatment Strategies (2019) · cites this paper as Zhao et al., 2018
A recent preclinical study showed that APOE2 expression via viral delivery exacerbated pathology in tauopathy mice.
“This is especially critical after a recent study in the preclinical literature demonstrated APOE2 expression via viral delivery exacerbated pathology in tauopathy mice (Zhao et al., 2018).”
From Alzheimer Disease: An Update on Pathobiology and Treatment Strategies (2019) · cites this paper as Zhao et al., 2018
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“In addition, ApoE has been shown to directly interact with Ab, tau, and a-synuclein, likely directly contributing to the formation of protein aggregates or the response of the brain to these aggregates in various diseases (Davis et al., 2020; Strittmatter et al., 1993a; Zhao et al., 2018, 2020).”
BackgroundSengupta, U., & Kayed, R. (2022) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2022.102270 · Cited by 314 · see citing works
Fernández-Calle, R., Konings, S. C., Frontiñán-Rubio, J., García-Revilla, J., Camprubí-Ferrer, L., Svensson, M., Martinson, I., Boza-Serrano, A., Venero, J. L., Nielsen, H. M., et al. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00566-4 · Cited by 278 · see citing works
Rösler, T. W., Marvian, A. T., Brendel, M., Nykänen, N.-P., Höllerhage, M., Schwarz, S. C., Hopfner, F., Koeglsperger, T., Respondek, G., Schweyer, K., et al. (2019) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2019.101644 · Cited by 230 · see citing works
Cellular and pathological heterogeneity of primary tauopathies
Chung, D. C., Roemer, S. F., Petrucelli, L., & Dickson, D. W. (2021) · Molecular Neurodegeneration · doi:10.1186/s13024-021-00476-x · Cited by 219 · see citing works
Self-citationIntersection of pathological tau and microglia at the synapse
Vogels, T., Murgoci, A.-N., & Hromádka, T. (2019) · Acta Neuropathologica Communications · doi:10.1186/s40478-019-0754-y · Cited by 197 · see citing works
Alzheimer’s Risk Factors Age, APOE Genotype, and Sex Drive Distinct Molecular Pathways
Zhao, N., Ren, Y., Yamazaki, Y., Qiao, W., Li, F., Felton, L. M., Mahmoudiandehkordi, S., Kueider-Paisley, A., Sonoustoun, B., Arnold, M., et al. (2020) · Neuron · doi:10.1016/j.neuron.2020.02.034 · Cited by 225 · see citing works
Self-citationUpdates in Alzheimer's disease: from basic research to diagnosis and therapies
Liu, E., Zhang, Y., & Wang, J. (2024) · Translational Neurodegeneration · doi:10.1186/s40035-024-00432-x · Cited by 229 · see citing works
“However, there is still controversy on the effect of APOEε2 on tau [100, 102– 104].”
BackgroundApolipoprotein E4, inhibitory network dysfunction, and Alzheimer’s disease
Najm, R., Jones, E. A., & Huang, Y. (2019) · Molecular Neurodegeneration · doi:10.1186/s13024-019-0324-6 · Cited by 183 · see citing works
Multifaceted roles of APOE in Alzheimer disease
Jackson, R. J., Hyman, B. T., & Serrano-Pozo, A. (2024) · Nature Reviews Neurology · doi:10.1038/s41582-024-00988-2 · Cited by 193 · see citing works
“One study found that the APOE ε2 allele is associated with increased odds of neuropathologically confirmed primary tauopa-thy (PSP and corticobasal degeneration) 66 .”
Therapeutic approaches targeting Apolipoprotein E function in Alzheimer’s disease
Williams, T., Borchelt, D., & Chakrabarty, P. (2020) · Molecular Neurodegeneration · doi:10.1186/s13024-020-0358-9 · Cited by 166 · see citing works
“worse memory performance and higher Aβ burden than APOE4 non-carriers [10], though the isoform-dependent effects on tauopathy remain unclear [11, 12].”
BackgroundInfluentialApolipoprotein E and Alzheimer's disease
Troutwine, B., Hamid, L., Lysaker, C. R., Strope, T. A., & Wilkins, H. M. (2021) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2021.10.002 · Cited by 115 · see citing works
APOE4 exacerbates α-synuclein pathology and related toxicity independent of amyloid
Zhao, N., Attrebi, O. N., Ren, Y., Qiao, W., Sonustun, B., Martens, Y. A., Meneses, A. D., Li, F., Shue, F., Zheng, J., et al. (2020) · Science Translational Medicine · doi:10.1126/scitranslmed.aay1809 · Cited by 156 · see citing works
“A pathogenic role for -synuclein is supported by the genetic evidence that both point mutations and genomic multiplications (duplications and triplications) of the -synuclein gene (SNCA) cause autosomal dominant familial forms of the LBD (19–23).”
MethodInfluentialSelf-citationEvolving concepts in progressive supranuclear palsy and other 4-repeat tauopathies
Stamelou, M., Respondek, G., Giagkou, N., Whitwell, J. L., Kovács, G. G., & Höglinger, G. U. (2021) · Nature Reviews Neurology · doi:10.1038/s41582-021-00541-5 · Cited by 143 · see citing works
Huynh, T.-P. V., Wang, C., Tran, A. C., Tabor, G. T., Mahan, T. E., Francis, C. M., Finn, M. B., Spellman, R., Manis, M., Tanzi, R. E., et al. (2019) · Molecular Neurodegeneration · doi:10.1186/s13024-019-0337-1 · Cited by 139 · see citing works
Li, H., Liu, C.-C., Zheng, H., & Huang, T. Y. (2018) · Translational Neurodegeneration · doi:10.1186/s40035-018-0139-3 · Cited by 103 · see citing works
Self-citationHDL from an Alzheimer's disease perspective
Button, E. B., Robert, J., Caffrey, T. M., Fan, J., Zhao, W., & Wellington, C. L. (2019) · Current Opinion in Lipidology · doi:10.1097/mol.0000000000000604 · Cited by 114 · see citing works
López‐Ortiz, S., Pinto-Fraga, J., Valenzuela, P. L., Martín-Hernández, J., Seisdedos, M. M., Garcı́a, Ó., Toschi, N., Giuliano, F. D., Garaci, F. G., Mercuri, N. B., et al. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22062897 · Cited by 107 · see citing works
Tau at the interface between neurodegeneration and neuroinflammation
Didonna, A. (2020) · Genes & Immunity · doi:10.1038/s41435-020-00113-5 · Cited by 82 · see citing works
Lipoproteins in the Central Nervous System: From Biology to Pathobiology
Raulin, A.-C., Martens, Y. A., & Bu, G. (2022) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-032620-104801 · Cited by 89 · see citing works
Self-citationAssociation of APOE e2 genotype with Alzheimer’s and non-Alzheimer’s neurodegenerative pathologies
Goldberg, T. E., Huey, E. D., & Devanand, D. P. (2020) · Nature Communications · doi:10.1038/s41467-020-18198-x · Cited by 82 · see citing works
The extracellular chaperone Clusterin enhances Tau aggregate seeding in a cellular model
Yuste‐Checa, P., Trinkaus, V. A., Riera-Tur, I., Imamoglu, R., Schaller, T., Wang, H., Dudanova, I., Hipp, M. S., Bracher, A., & Hartl, F. U. (2021) · Nature Communications · doi:10.1038/s41467-021-25060-1 · Cited by 76 · see citing works
Primary Tau Pathology, Not Copathology, Correlates With Clinical Symptoms in PSP and CBD
Robinson, J. L., Yan, N., Caswell, C., Xie, S. X., Suh, E. R., Deerlin, V. M. V., Gibbons, G. S., Irwin, D. J., Grossman, M., Lee, E. B., et al. (2019) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/nlz141 · Cited by 75 · see citing works
Astrocytic propagation of Tau in the context of Alzheimer's disease
Fleeman, R. M., & Proctor, E. A. (2021) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2021.645233 · Cited by 75 · see citing works
“Finally, APOE ε2 has been shown to increase primary tauopathy pathology when Aβ is not present (Zhao et al., 2018) and thus, effects of APOE may be dependent on the presence of Aβ pathology.”
BackgroundHuang, S., Zhang, Z., Cao, J., Yu, Y., & Pei, G. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01006-x · Cited by 72 · see citing works
“However, it is also associated with increased tau pathology, suggesting the intricate role of ApoE2 in regulating tau and Aβ.(42) It will be very interesting to verify the effect of APOE2 neurons or astrocytes on AD-associated pathologies in chCOs.”
BackgroundRamanan, V. K., Castillo, A. M., Knopman, D. S., Graff‐Radford, J., Lowe, V. J., Petersen, R. C., Jack, C. R., Mielke, M. M., & Vemuri, P. (2019) · JAMA Network Open · doi:10.1001/jamanetworkopen.2019.13909 · Cited by 71 · see citing works
Lewandowski, C. T., Maldonado Weng, J., & LaDu, M. J. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.104811 · Cited by 72 · see citing works
Vascular ApoE4 impairs behavior by modulating gliovascular function
Yamazaki, Y., Liu, C.-C., Yamazaki, A., Shue, F., Martens, Y. A., Chen, Y., Qiao, W., Kurti, A., Oue, H., Ren, Y., et al. (2021) · Neuron · doi:10.1016/j.neuron.2020.11.019 · Cited by 71 · see citing works
“Cognitive and Behavioral Tests—Contextual and cued fear conditioning (CFC), Morris water maze (MWM), open-field assay (OFA) and elevated plus maze (EPM) tests were performed as described (Kang et al., 2018; Sakae et al., 2016; Zhao et al., 2018).”
MethodSelf-citationApolipoprotein E in Alzheimer’s disease trajectories and the next-generation clinical care pathway
Narasimhan, S., Holtzman, D. M., Apostolova, L. G., Cruchaga, C., Masters, C. L., Hardy, J., Villemagne, V. L., Bell, J. S., Cho, M., & Hampel, H. J. (2024) · Nature Neuroscience · doi:10.1038/s41593-024-01669-5 · Cited by 70 · see citing works
“…events, while expression of APOE ε2 in the CNS may have adverse con sequences given the association of APOE ε2 with CAArelated intracer ebral hemorrhage 103 , primary tauopathy 143 and possibly glaucoma 144 , necessitating monitoring for these events in future trials of these therapies.”
Dias, D., Portugal, C. C., Relvas, J. B., & Socodato, R. (2025) · Cells · doi:10.3390/cells14040243 · Cited by 66 · see citing works
Panitch, R., Hu, J., Chung, J., Zhu, C., Meng, G., Xia, W., Bennett, D. A., Lunetta, K. L., Ikezu, T., Au, R., et al. (2021) · Molecular Psychiatry · doi:10.1038/s41380-021-01266-z · Cited by 58 · see citing works
Chernick, D., Ortiz-Valle, S., Jeong, A., Qu, W., & Li, L. (2019) · Neuroscience Letters · doi:10.1016/j.neulet.2019.134306 · Cited by 54 · see citing works
The role of APOE in transgenic mouse models of AD
Balu, D., Karstens, A. J., Loukenas, E., Maldonado Weng, J., York, J. M., Valencia-Olvera, A. C., & LaDu, M. J. (2019) · Neuroscience Letters · doi:10.1016/j.neulet.2019.134285 · Cited by 81 · see citing works
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Self-citationCholesterol determines the cytosolic entry and seeded aggregation of tau
Tuck, B. J., Miller, L. V. C., Katsinelos, T., Smith, A. E., Wilson, E. L., Keeling, S., Cheng, S., Vaysburd, M. J., Knox, C., Tredgett, L., et al. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.110776 · Cited by 56 · see citing works
ApoE4 attenuates autophagy via FoxO3a repression in the brain
Sohn, H.-Y., Kim, S.-I., Park, J.-Y., Park, S.-H., Koh, Y. H., Kim, J., & Jo, C. (2021) · Scientific Reports · doi:10.1038/s41598-021-97117-6 · Cited by 54 · see citing works
Clusterin ameliorates tau pathology in vivo by inhibiting fibril formation
Wojtas, A., Carlomagno, Y., Sens, J. P., Kang, S. S., Jensen, T. D., Kurti, A., Baker, K. E., Berry, T. J., Phillips, V. R., Castanedes, M. C., et al. (2020) · Acta Neuropathologica Communications · doi:10.1186/s40478-020-01079-1 · Cited by 53 · see citing works
Self-citationEarly- and Late-Onset Alzheimer’s Disease: Two Sides of the Same Coin?
Valdez-Gaxiola, C. A., Rosales-Leycegui, F., Gaxiola-Rubio, A., Moreno-Ortíz, J. M., & Figuera, L. E. (2024) · Diseases · doi:10.3390/diseases12060110 · Cited by 55 · see citing works
“…compared to ApoE3 [163,164]. is little interaction between ApoE and tau in vivo, studies in transgenic mice suggest that isoforms indirectly affect tau pathology through their influence on microglia phenotype ApoE4 promoting tau-induced neurodegeneration compared to ApoE3 [163,164].”
BackgroundApoE4 inhibition of VMAT2 in the locus coeruleus exacerbates Tau pathology in Alzheimer’s disease
Kang, S. S., Ahn, E. H., Liu, X., Bryson, M., Miller, G. W., Weinshenker, D., & Ye, K. (2021) · Acta Neuropathologica · doi:10.1007/s00401-021-02315-1 · Cited by 48 · see citing works
Koriath, C., Lashley, T., Taylor, W., Druyeh, R., Dimitriadis, A., Denning, N., Williams, J. H., Warren, J. D., Fox, N. C., Schott, J. M., et al. (2019) · Alzheimer s & Dementia Diagnosis Assessment & Disease Monitoring · doi:10.1016/j.dadm.2019.01.010 · Cited by 44 · see citing works
Apolipoprotein E Genotype e2: Neuroprotection and Its Limits
Kim, H., Devanand, D. P., Carlson, S., & Goldberg, T. E. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.919712 · Cited by 36 · see citing works
The Role of HDL and HDL Mimetic Peptides as Potential Therapeutics for Alzheimer’s Disease
Chernick, D., Zhong, R., & Li, L. (2020) · Biomolecules · doi:10.3390/biom10091276 · Cited by 38 · see citing works
Jun, G., You, Y., Zhu, C., Meng, G., Chung, J., Panitch, R., Hu, J., Xia, W., Bennett, D. A., Foroud, T., et al. (2022) · Alzheimer s & Dementia · doi:10.1002/alz.12607 · Cited by 35 · see citing works
Jablonski, A. M., Warren, L., Usenovic, M., Zhou, H. H., Sugam, J. A., Parmentier‐Batteur, S., & Voleti, B. (2021) · Scientific Reports · doi:10.1038/s41598-021-82901-1 · Cited by 35 · see citing works
The Impact of Apolipoprotein E (APOE) Epigenetics on Aging and Sporadic Alzheimer’s Disease
Lozupone, M., Dibello, V., Sardone, R., Castellana, F., Zupo, R., Lampignano, L., Bortone, I., Daniele, A., Bellomo, A., Solfrizzi, V., et al. (2023) · Biology · doi:10.3390/biology12121529 · Cited by 36 · see citing works
“ApoE also can affect tau-mediated neurodegeneration and tauopathy by modulating microglial responses to A β plaque pathology [36–38].”
BackgroundGenetics of Chronic Traumatic Encephalopathy
Abdolmohammadi, B., Dupre, A., Evers, L., & Mez, J. (2020) · Seminars in Neurology · doi:10.1055/s-0040-1713631 · Cited by 35 · see citing works
Relevance of transgenic mouse models for Alzheimer's disease
Tai, L. M., Weng, J. M., LaDu, M. J., & Brady, S. T. (2020) · Progress in molecular biology and translational science · doi:10.1016/bs.pmbts.2020.07.007 · Cited by 39 · see citing works
Tau Seeding Mouse Models with Patient Brain-Derived Aggregates
Robert, A., Schöll, M., & Vogels, T. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22116132 · Cited by 35 · see citing works
“Fourthly, they have the considerable advantage of being able to induce tau pathology in a range of genetic backgrounds, thus circumventing the costly and slow process of cross-breeding [101].”
BackgroundIacono, D., & Feltis, G. C. (2019) · Aging · doi:10.18632/aging.101757 · Cited by 32 · see citing works
“Curiously, however, newer investigations both in animals and humans showed a “paradoxical” (due to actually to the AP?) effect of APOE2, specifically in case of APOE2 homozygosis (APOE2/E2) [287].”
BackgroundWang, H., Chang, T. S., Dombroski, B. A., Cheng, P., Patil, V., Valiente‐Banuet, L., Farrell, K. W., McLean, C., Molina‐Porcel, L., Rajput, A. H., et al. (2024) · Molecular Neurodegeneration · doi:10.1186/s13024-024-00747-3 · Cited by 35 · see citing works
“Notably, both ε2 allele and ε4 allele have been associated with tau pathology burden in the brain of mice models [47, 72], which raises the question of distinct tau species in 4R-PSP versus 3R-4R-AD.”
BackgroundInfluentialSelf-citationAdvances in Modeling Alzheimer's Disease In Vitro
Sharma, N. S., Karan, A., Lee, D.-H., Yan, Z., & Xie, J. (2021) · Advanced NanoBiomed Research · doi:10.1002/anbr.202100097 · Cited by 28 · see citing works
Are apolipoprotein E fragments a promising new therapeutic target for Alzheimer’s disease?
Vecchio, F. L., Bisceglia, P., Imbimbo, B. P., Lozupone, M., Latino, R. R., Resta, E., Leone, M., Solfrizzi, V., Greco, A., Daniele, A., et al. (2022) · Therapeutic Advances in Chronic Disease · doi:10.1177/20406223221081605 · Cited by 28 · see citing works
“Mouse J20 line of hAPPFAD and overexpressing APOE 272-299 ApoE4 (1-271)1 (N-terminal) Decreases Aβ clearance and increases Aβ deposition In vivo/ In vitro Full-length ApoE3 and ApoE4 expressing mice were able to stimulate Aβ clearance Bien-Ly et al.”
BackgroundAssessment of APOE in atypical parkinsonism syndromes
Sabir, M. S., Blauwendraat, C., Ahmed, S., Serrano, G. E., Beach, T. G., Perkins, M., Rice, A. C., Masliah, E., Morris, C. M., Pihlstrom, L., et al. (2019) · Neurobiology of Disease · doi:10.1016/j.nbd.2019.02.016 · Cited by 28 · see citing works
Influence of APOE genotype in primary age-related tauopathy
Robinson, A., Davidson, Y. S., Roncaroli, F., Minshull, J., Tinkler, P., Horan, M. A., Payton, A., Pendleton, N., & Mann, D. M. A. (2020) · Acta Neuropathologica Communications · doi:10.1186/s40478-020-01095-1 · Cited by 27 · see citing works
Beyond the amyloid cascade: An update of Alzheimer's disease pathophysiology
Gouilly, D., Rafiq, M., Nogueira, L., Salabert, A., Payoux, P., Péran, P., & Pariente, J. (2023) · Revue Neurologique · doi:10.1016/j.neurol.2022.12.006 · Cited by 30 · see citing works
Variants inPPP2R2BandIGF2BP3are associated with higher tau deposition
Ramanan, V. K., Wang, X., Przybelski, S. A., Raghavan, S., Heckman, M. G., Batzler, A. J., Kosel, M., Hohman, T. J., Knopman, D. S., Graff‐Radford, J., et al. (2020) · Brain Communications · doi:10.1093/braincomms/fcaa159 · Cited by 23 · see citing works
“…in whether a mechanistic relationship exists between APOE and brain parenchymal tau that is independent of amyloid, as has been suggested by analyses of primary tauopathies and selected studies using cellular and animal model systems (Shi et al., 2017; Zhao et al., 2018; Wadhwani et al., 2019).”
Self-citationAssociation of CD2AP neuronal deposits with Braak neurofibrillary stage in Alzheimer’s disease
Camacho, J., Rábano, A., Marazuela, P., Bonaterra‐Pastra, A., Serna, G., Moliné, T., y Cajal, S. R., Martínez-Sáez, E. A., & Hernández‐Guillamón, M. (2021) · Brain Pathology · doi:10.1111/bpa.13016 · Cited by 23 · see citing works
“Finally, because the APOE genotype is linked to Aβ brain accumulation [68,69] but is also a risk factor for tau neurodegeneration independent of Aβ [57,70,71,72,73,74], future studies analyzing the effect of APOE on CD2AP neuronal deposition in tauopathies are required.”
BackgroundLozupone, M., Imbimbo, B. P., Balducci, C., Vecchio, F. L., Bisceglia, P., Latino, R. R., Leone, M. A., Dibello, V., Solfrizzi, V., Greco, A., et al. (2022) · Alzheimer s & Dementia · doi:10.1002/alz.12728 · Cited by 26 · see citing works
Associations Between APOE Variants, Tau and α-Synuclein
Rodriguez‐Vieitez, E., & Nielsen, H. M. (2019) · Advances in experimental medicine and biology · doi:10.1007/978-981-32-9358-8_15 · Cited by 24 · see citing works
Noori, M., Mahboobi, R., Nabavi-Rad, A., Jamshidizadeh, S., Fakharian, F., Yadegar, A., & Zali, M. R. (2023) · Heliyon · doi:10.1016/j.heliyon.2023.e19607 · Cited by 23 · see citing works
Impact of APOE genotype on prion-type propagation of tauopathy
Williams, T., Ruiz, A. J., Ruiz, A. M., Vo, Q., Tsering, W., Xu, G. M., McFarland, K. N., Giasson, B. I., Sullivan, P. M., Borchelt, D., et al. (2022) · Acta Neuropathologica Communications · doi:10.1186/s40478-022-01359-y · Cited by 21 · see citing works
Apolipoprotein E Facilitates Amyloid-β Oligomer-Induced Tau Phosphorylation
Hou, T.-T., Han, Y.-D., Cong, L., Liu, C.-C., Liang, X.-Y., Xue, F.-Z., & Du, Y.-F. (2020) · Journal of Alzheimer’s Disease · doi:10.3233/jad-190711 · Cited by 20 · see citing works
Self-citationEisenbaum, M., Pearson, A., Ortiz, C., Koprivica, M., Cembran, A., MULLAN, M. J., Crawford, F., Ojo, J. O., & Bachmeier, C. J. (2024) · Experimental Neurology · doi:10.1016/j.expneurol.2024.114702 · Cited by 17 · see citing works
Лю, Ч., Liu, J., Wang, Y., Xu, S.-F., & Yu, L.-M. (2025) · Molecular Neurobiology · doi:10.1007/s12035-025-05629-3 · Cited by 21 · see citing works
Dilliott, A. A., Sunderland, K. M., McLaughlin, P. M., Roberts, A., Evans, E. C., Abrahão, A., Binns, M. A., Black, S. E., BORRIE, M. J., Casaubon, L. K., et al. (2021) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2021.04.011 · Cited by 16 · see citing works
Williams, T., Bathe, T., Vo, Q., Sacilotto, P., McFarland, K. N., Ruiz, A. J., Hery, G. P., Sullivan, P. M., Borchelt, D., Prokop, S., et al. (2023) · Acta Neuropathologica Communications · doi:10.1186/s40478-023-01581-2 · Cited by 16 · see citing works
ApoE-calypse tau: ApoE–tau synergy in Alzheimer’s disease
Lennol, M. P., Bordier, C., Kamelher, L., Ulrich, J. D., Holtzman, D. M., & Gratuze, M. (2025) · The Journal of Experimental Medicine · doi:10.1084/jem.20250965 · Cited by 14 · see citing works
Koller, E. J., Cruz, E. G. D. L., Weinrich, M. J., Williams, T., Cruz, P. E., Ryu, D. H., Golde, T. E., Sullivan, P. M., Lewis, J. M., Borchelt, D., et al. (2020) · Molecular Neurobiology · doi:10.1007/s12035-019-01859-4 · Cited by 13 · see citing works
Valentino, R. R., Tamvaka, N., Heckman, M. G., Johnson, P. W., Soto‐Beasley, A. I., Walton, R. L., Koga, S., Uitti, R. J., Wszołek, Z. K., Dickson, D. W., et al. (2020) · Acta Neuropathologica Communications · doi:10.1186/s40478-020-01035-z · Cited by 13 · see citing works
Self-citationGenetics of progressive supranuclear palsy in a Chinese population
Xiao, X., Yang, Q., Wen, Y., Jiao, B., Liao, X., Zhou, Y., Weng, L., Liu, H., Xu, T., Zhu, Y., et al. (2022) · Neurobiology of Disease · doi:10.1016/j.nbd.2022.105819 · Cited by 11 · see citing works
Meneses, A. D., Koga, S., Li, Z., O'Leary, J., Li, F., Chen, K., Murakami, A., Qiao, W., Kurti, A., Heckman, M. G., et al. (2023) · Annals of Neurology · doi:10.1002/ana.26580 · Cited by 11 · see citing works
Self-citationTau polygenic risk scoring: a cost-effective aid for prognostic counseling in Alzheimer’s disease
Ramanan, V. K., Heckman, M. G., Lesnick, T. G., Przybelski, S. A., Cahn, E. J., Kosel, M., Murray, M. E., Mielke, M. M., Botha, H., Graff‐Radford, J., et al. (2022) · Acta Neuropathologica · doi:10.1007/s00401-022-02419-2 · Cited by 10 · see citing works
Self-citationVogels, T., Vargová, G., Brezováková, V., Quint, W. H., & Hromádka, T. (2020) · Journal of Alzheimer s Disease · doi:10.3233/jad-200047 · Cited by 11 · see citing works
The interaction effects of age, APOE and common environmental risk factors on human brain structure
Chen, J., Li, T., Zhao, B., Chen, H., Yuan, C., Garden, G. A., Guorong Wu, A., & Hongtu Zhu, B. (2023) · Cerebral Cortex · doi:10.1093/cercor/bhad472 · Cited by 10 · see citing works
Valentino, R. R., Koga, S., Heckman, M. G., Brushaber, D. E., Diehl, N. N., Walton, R. L., Dickson, D. W., & Ross, O. A. (2020) · Movement Disorders · doi:10.1002/mds.28010 · Cited by 10 · see citing works
Self-citationMultifactorial etiology of progressive supranuclear palsy (PSP): the genetic component
Müller, U., Höglinger, G. U., & Dickson, D. W. (2025) · Acta Neuropathologica · doi:10.1007/s00401-025-02898-z · Cited by 10 · see citing works
“The opposite is true for Alzheimer disease (AD) where APOE-ε2 is protective and ε4 is a major risk factor [114].”
Self-citationPasqualotto, A., da Silva, V., Pellenz, F. M., Schuh, A. F. S., Schwartz, I. V. D., & Siebert, M. (2024) · Metabolic Brain Disease · doi:10.1007/s11011-024-01342-7 · Cited by 8 · see citing works
“Hub genes in purple and bottleneck genes in yellow still controversial (Zhao et al. 2018; Sabir et al. 2019).”
Mahanta, A. K., Chaulagain, B., Gothwal, A., & Singh, J. (2025) · ACS Biomaterials Science & Engineering · doi:10.1021/acsbiomaterials.5c00465 · Cited by 9 · see citing works
Savignac, C., Villeneuve, S., Badhwar, A., Saltoun, K., Shafighi, K., Zajner, C., Sharma, V., Taliun, S. A. G., Farhan, S. M. K., Poirier, J., et al. (2022) · PLoS Biology · doi:10.1371/journal.pbio.3001863 · Cited by 10 · see citing works
Wang, H., Chang, T. S., Dombroski, B. A., Cheng, P., Patil, V., Valiente‐Banuet, L., Farrell, K. W., McLean, C., Molina‐Porcel, L., Rajput, A. H., et al. (2023) · medRxiv · doi:10.1101/2023.12.28.23300612 · Cited by 7 · see citing works
“Notably, both 2 allele and 4 allele have been associated with tau pathology burden in the brain of mice models [46,71], which raises the question of distinct tau species in 4R-PSP versus 3R-4R-AD.”
BackgroundInfluentialSelf-citationSantamaría‐García, H. A., Ogonowski, N. S., Báez, S., Palacio, N., Reyes, P. A., Schulte, M., López, A., Matallana, D., & Ibáñez, A. M. (2022) · BMC Neurology · doi:10.1186/s12883-022-02954-1 · Cited by 9 · see citing works
“Association of APOE gene polymorphisms with primary open angle glaucoma in Brazilian patients”
Occhiutto, M. L., de Melo, M. B., de Vasconcellos, J. P. C., Rodrigues, T. A. R., Bajano, F. F., Costa, F. F., & Costa, V. P. (2020) · Ophthalmic Genetics · doi:10.1080/13816810.2020.1849314 · Cited by 6 · see citing works
Unraveling APOE4's Role in Alzheimer's Disease: Pathologies and Therapeutic Strategies
Tripathi, S., Sharma, Y., & Kumar, D. (2024) · Current Protein and Peptide Science · doi:10.2174/0113892037326839241014054430 · Cited by 4 · see citing works
Exploring Protein Structure with RasMol, a Free Online Tool
Fraley, A. D., Odegaard, K. E., Vilchiz, V. H., Kang, C., & Lee, C. (2022) · The American Biology Teacher · doi:10.1525/abt.2022.84.6.369 · Cited by 4 · see citing works
“Scientists have shown that one key difference between APOE3 and APOE4 is the substitution of a cysteine in place of an arginine in one position (Frieden & Garai, 2012).”
BackgroundInfluentialTau processing and tau-mediated inflammation differ in human APOEε2 and APOEε4 astrocytes
Mothes, T., Konstantinidis, E., Eltom, K., Dakhel, A., Rostami, J., & Erlandsson, A. (2024) · iScience · doi:10.1016/j.isci.2024.111163 · Cited by 5 · see citing works
“10 However, it is worth noting that this was performed using the bare proteins in isolation.”
Wan, Z., & Ma, T. (2025) · PLoS ONE · doi:10.1371/journal.pone.0303486 · Cited by 4 · see citing works
Perez, C. M., Gong, Z., Yoo, C., Roy, D., Deoraj, A., & Felty, Q. H. (2023) · Molecular Neurobiology · doi:10.1007/s12035-023-03541-2 · Cited by 4 · see citing works
“The strong causality between CAA and APOE4 in the male CAA network amongst NRF1 regulated genes confirms the significance of both NRF1 targeting of the APOE4 allele amongst male CAA cases, reported in previous studies examing the transcription factor and its targeting of an exon of APOE4 [17, 33].”
InfluentialApolipoprotein E Alleles and Motor Signs in Older Adults with Alzheimer’s Dementia
Liampas, I., Demiri, S., Siokas, V., Tsika, A., Marogianni, C., Stamati, P., Nasios, G., Messinis, L., Lyketsos, C. G., & Dardiotis, E. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26178562 · Cited by 3 · see citing works
Cheng, Y., Liao, Y., Chen, C., Chung, C., Fann, C. S. J., Chang, C.-S., Lee, Y., & Tang, S. (2023) · Journal of the American Heart Association · doi:10.1161/jaha.123.032689 · Cited by 3 · see citing works
- Authors
- Zhao, N., Liu, C.-C., Van Ingelgom, A. J., Linares, C., Kurti, A., Knight, J. A., Heckman, M. G., Diehl, N. N., Shinohara, M., Martens, Y. A., Attrebi, O. N., Petrucelli, L., Fryer, J. D., Wszolek, Z. K., Graff-Radford, N. R., Caselli, R. J., Sanchez-Contreras, M. Y., Rademakers, R., Murray, M. E., Koga, S., Dickson, D. W., Ross, O. A., & Bu, G.
- Affiliations
- Mayo Clinic (US)
- Mayo Clinic in Florida (US)
- Corresponding author
- Liu, Chia-Chen
- Bu, Guojun
- ORCID
- Venue
- Nature Communications
- Published
- 2018-10-22
- Volume
- 9
- Issue
- 1
- Pages
- 4388-4388
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC6197187
- OpenAlex
- W2897709706
- Cited by
- 139
- References
- 59
- Citations by year
- 2026: 14 · 2025: 11 · 2024: 13 · 2023: 15 · 2022: 20 · 2021: 20 · 2020: 30 · 2019: 15 · 2018: 1
- FWCI
- 11.35
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- Funders
- U.S. Department of Health & Human Services | NIH | National Institute on Aging (R01AG046205, R37AG027924, RF1AG051504, P50AG016574)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Keywords
- APOE ε2, apolipoprotein E, tau pathology, primary tauopathies, progressive supranuclear palsy, corticobasal degeneration, tau hyperphosphorylation, tau aggregates, AAV gene delivery, genetic risk, neurodegeneration, behavioral abnormalities
- MeSH terms
- Alleles, Alzheimer Disease, Animals, Humans, Supranuclear Palsy, Progressive, Disease Progression, Tauopathies, Mice, Apolipoprotein E4, Apolipoprotein E2
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