APOE Antibody Inhibits Aβ‐Associated Tau Seeding and Spreading in a Mouse Model
Open accessAbstract
APOE is the strongest genetic factor for late‐onset Alzheimer's disease (AD). A specific conformation of the ApoE protein is present in amyloid‐β (Aβ) containing plaques. Immunotherapy targeting ApoE in plaques reduces brain Aβ deposits in mice. Here, we evaluated the effects of the anti‐human APOE antibody HAE‐4 on amyloid plaques, Aβ‐mediated tau seeding and spreading, and neuritic dystrophy in the 5XFAD amyloid mice expressing human ApoE4. HAE‐4 reduced Aβ plaques as well as Aβ‐driven tau seeding/spreading and neuritic dystrophy. These results demonstrate that HAE‐4 may provide therapeutic effects on amyloid removal and Aβ driven downstream consequences such as tauopathy. ANN NEUROL 2022;91:847–852
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Several groups have suggested lowering of APOE expression with APOE-antibodies or using antisense therapy as a therapeutic option for AD.
“Several groups have suggested lowering of APOE expression with APOE-antibodies (Gratuze et al, 2022; Liao et al, 2018; Xiong et al, 2021) or using antisense therapy (Huynh et al, 2017) as a therapeutic option for AD.”
From APOE from astrocytes restores Alzheimer’s Aβ-pathology and DAM-like responses in APOE deficient microglia (2024) · cites this paper as Gratuze et al, 2022
The Discussion supports investigating the anti-ApoE antibody HAE-4 as a potential AD therapy, but explicitly says it does not lower overall ApoE levels. It identifies antisense oligonucleotides—not HAE-4—as an approach to lowering brain ApoE levels. The antisense-therapy clause in the citing sentence is attributed to a different citation. (LLM, conf=0.90)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredAn antibody against non-lipidated APOE, which is the version most likely to oligomerize, has shown promise in multiple Alzheimer disease mouse models.
“Along this line, an antibody against non-lipidated APOE, which is the version most likely to oligomerize, has shown promise in multiple AD mouse models136–139.”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [138]
The Introduction (page unavailable) identifies HAE-4 as an antibody targeting non-lipidated ApoE and describes beneficial effects in amyloid mice; the Results report reduced Aβ plaques and tau pathology in 5XE4 mice. Our copy does not say that non-lipidated ApoE is the form most likely to oligomerize, and this paper tests only one mouse model, although it describes earlier mouse studies. (LLM, conf=0.86)
Experimental — accuracy not yet measuredAn antibody that preferentially binds to non-lipidated APOE4 has shown promise in reducing Aβ plaques and CAA in a mouse model of β-amyloidosis, as well as decreasing Aβ-driven tau seeding in mice.
“An antibody that preferentially binds to non-lipidated APOE4 has shown promise in reducing Aβ plaques and CAA in a mouse model of β-amyloidosis, as well as decreasing Aβ-driven tau seeding in mice137–139.”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [138]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Oakley, H., Cole, S. L., Logan, S., Maus, E., Shao, P., Craft, J., Guillozet-Bongaarts, A., Ohno, M., Disterhoft, J., Van Eldik, L., et al. (2006) · The Journal of Neuroscience · doi:10.1523/jneurosci.1202-06.2006 · Cited by 3,530 · see citing works
Alzheimer Disease: An Update on Pathobiology and Treatment Strategies
Long, J. M., & Holtzman, D. M. (2019) · Cell · doi:10.1016/j.cell.2019.09.001 · Cited by 3,204 · see citing works
Self-citationNelson, P. T., Alafuzoff, I., Bigio, E. H., Bouras, C., Braak, H., Cairns, N. J., Castellani, R. J., Crain, B. J., Davies, P., Tredici, K. D., et al. (2012) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e31825018f7 · Cited by 2,050 · cited 6× · see citing works
“Roses AD.”
BackgroundInfluentialDonanemab in Early Alzheimer’s Disease
Mintun, M. A., Lo, A. C., Duggan Evans, C., Wessels, A. M., Ardayfio, P. A., Andersen, S. W., Shcherbinin, S., Sparks, J., Sims, J. R., Brys, M., et al. (2021) · New England Journal of Medicine · doi:10.1056/nejmoa2100708 · Cited by 1,728 · see citing works
Swanson, C. J., Zhang, Y., Dhadda, S., Wang, J., Kaplow, J., Lai, R. Y. K., Lannfelt, L., Bradley, H., Rabe, M., Koyama, A., et al. (2021) · Alzheimer's Research & Therapy · doi:10.1186/s13195-021-00813-8 · Cited by 847 · see citing works
He, Z., Guo, J. L., McBride, J. D., Narasimhan, S., Kim, H., Changolkar, L., Zhang, B., Gathagan, R. J., Yue, C., Dengler, C., et al. (2018) · Nature Medicine · doi:10.1038/nm.4443 · Cited by 645 · see citing works
Sperling, R., Salloway, S., Brooks, D. J., Tampieri, D., Barakos, J., Fox, N. C., Raskind, M., Sabbagh, M., Honig, L. S., Porsteinsson, A. P., et al. (2012) · The Lancet Neurology · doi:10.1016/s1474-4422(12)70015-7 · Cited by 512 · see citing works
Guo, J. L., Narasimhan, S., Changolkar, L., He, Z., Stieber, A., Zhang, B., Gathagan, R. J., Iba, M., McBride, J. D., Trojanowski, J. Q., et al. (2016) · Journal of Experimental Medicine · doi:10.1084/jem.20160833 · Cited by 440 · see citing works
Xiong, M., Jiang, H., Serrano, J. R., Gonzales, E. R., Wang, C., Gratuze, M., Hoyle, R., Bien-Ly, N., Silverman, A. P., Sullivan, P. M., et al. (2021) · Science Translational Medicine · doi:10.1126/scitranslmed.abd7522 · Cited by 179 · see citing works
Self-citationTargeting of nonlipidated, aggregated apoE with antibodies inhibits amyloid accumulation
Liao, F., Li, A., Xiong, M., Bien-Ly, N., Jiang, H., Zhang, Y., Finn, M. B., Hoyle, R., Keyser, J., Lefton, K. B., et al. (2018) · Journal of Clinical Investigation · doi:10.1172/jci96429 · Cited by 178 · see citing works
Self-citationLitvinchuk, A., Huynh, T. V., Shi, Y., Jackson, R. J., Finn, M. B., Manis, M., Francis, C. M., Tran, A. C., Sullivan, P. M., Ulrich, J. D., et al. (2021) · Annals of Neurology · doi:10.1002/ana.26043 · Cited by 91 · see citing works
Self-citation
Flagged first, then by citations
Research works printed but not linked: 11
- [1]Holtzman DM, Morris JC, Goate AM. Alzheimer’s disease: The challenge of the second century. Sci. Transl. Med 2011; 3(77) PMC3130546 21471435
- [2]Castellani RJ, Rolston RK, Smith MA. Alzheimer disease. Disease-a-Month 2010; 56(9): 484– 546. 20831921 PMC2941917
- [3]Roses AD. Apolipoprotein E alleles as risk factors in Alzheimer’s disease. Annu. Rev. Med 1996; 47: 387– 400. 8712790
- [5]Musiek ES, Holtzman DM. Three dimensions of the amyloid hypothesis: time, space and “wingmen.” Nat. Neurosci 2015; 18(6): 800– 806. 26007213 PMC4445458
- [11]Huynh TPV, Wang C, Tran AC, Lack of hepatic apoE does not influence early Aβ deposition: Observations from a new APOE knock-in model. Mol. Neurodegener 2019; 14(1): 1– 23. 31623648 PMC6796484
- [12]Gratuze M, Chen Y, Parhizkar S, Activated microglia mitigate Aβ-associated tau seeding and spreading. J. Exp. Med 2021; 218(8): e20210542. 34100905 PMC8190588
- [14]Leyns CEG, Gratuze M, Narasimhan S, TREM2 function impedes tau seeding in neuritic plaques. Nat. Neurosci 2019; 22(8): 1217– 1222. 31235932 PMC6660358
- [15]Sadleir KR, Kandalepas PC, Buggia-Prévot V, Presynaptic dystrophic neurites surrounding amyloid plaques are sites of microtubule disruption, BACE1 elevation, and increased Aβ generation in Alzheimer’s disease. Acta Neuropathol 2016; 132(2): 235– 256. 26993139 PMC4947125
- [18]Chantran Y, Capron J, Alamowitch S, Aucouturier P. Anti-Aβ antibodies and cerebral amyloid angiopathy complications. Front. Immunol 2019; 10(07): 1534. 31333665 PMC6620823
- [19]Laversenne V, Nazeeruddin S, Källstig EC, Anti-Aβ antibodies bound to neuritic plaques enhance microglia activity and mitigate tau pathology. Acta Neuropathol. Commun 2020; 8(1) PMC7681991 33225991
- [20]Lathuilière A, Laversenne V, Astolfo A, A subcutaneous cellular implant for passive immunization against amyloid-β reduces brain amyloid and tau pathologies. Brain 2016; 139(Pt 5): 1587– 1604. 26956423
Cited by
Sorted by citations
ApoE in Alzheimer’s disease: pathophysiology and therapeutic strategies
Raulin, A.-C., Doss, S. V., Trottier, Z. A., Ikezu, T. C., Bu, G., & Liu, C.-C. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00574-4 · Cited by 756 · 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
Preman, P., Moechars, D., Fertan, E., Wolfs, L., Serneels, L., Shah, D., Lamote, J., Poovathingal, S., Snellinx, A., Mancuso, R., et al. (2024) · EMBO Molecular Medicine · doi:10.1038/s44321-024-00162-7 · Cited by 32 · see citing works
Lymphoid gene expression supports neuroprotective microglia function
Ayata, P., Crowley, J. M., Challman, M. F., Sahasrabuddhe, V., Gratuze, M., Werneburg, S., Ribeiro, D., Hays, E. C., Durán-Laforet, V., Faust, T. E., et al. (2025) · Nature · doi:10.1038/s41586-025-09662-z · Cited by 32 · see citing works
Self-citationCurrent insights into apolipoprotein E and the immune response in Alzheimer's disease
Lin, P. B., & Holtzman, D. M. (2024) · Immunological Reviews · doi:10.1111/imr.13414 · Cited by 19 · see citing works
Self-citation
- Authors
- Gratuze, M., Jiang, H., Wang, C., Xiong, M., Bao, X., & Holtzman, D. M.
- Affiliations
- Washington University in St. Louis (US)
- Corresponding author
- Holtzman, David M.
- Venue
- Annals of Neurology
- Publisher
- Wiley
- Published
- 2022-03-31
- Volume
- 91
- Issue
- 6
- Pages
- 847-852
- ISSN
- 0364-5134 (ISSN-L)
- 1531-8249
- PMC
- PMC9285984
- OpenAlex
- W4221126716
- Cited by
- 41
- References
- 11
- Citations by year
- 2026: 4 · 2025: 11 · 2024: 11 · 2023: 12 · 2022: 3
- FWCI
- 5.72
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Annals of Neurology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- HAL (submittedVersion)
- Funders
- National Institutes of Health (AG047644)
- Hope Center for Neurological Disorders
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- apolipoprotein E, amyloid-beta, tau seeding, tau propagation, tauopathy, amyloid plaques, immunotherapy, Alzheimer's disease, APOE ε4, 5xFAD mice, neuritic dystrophy, amyloid-beta immunotherapy
- MeSH terms
- Alzheimer Disease, Animals, Antibodies, Apolipoproteins E, Brain, Disease Models, Animal, Humans, Mice, Transgenic, Amyloid beta-Peptides, tau Proteins, Mice, Apolipoprotein E4, Plaque, Amyloid
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
