Targeting of nonlipidated, aggregated apoE with antibodies inhibits amyloid accumulation
Open accessAbstract
The apolipoprotein E E4 allele of the APOE gene is the strongest genetic factor for late-onset Alzheimer disease (LOAD). There is compelling evidence that apoE influences Alzheimer disease (AD) in large part by affecting amyloid β (Aβ) aggregation and clearance; however, the molecular mechanism underlying these findings remains largely unknown. Herein, we tested whether anti-human apoE antibodies can decrease Aβ pathology in mice producing both human Aβ and apoE4, and investigated the mechanism underlying these effects. We utilized APPPS1-21 mice crossed to apoE4-knockin mice expressing human apoE4 (APPPS1-21/APOE4). We discovered an anti-human apoE antibody, anti-human apoE 4 (HAE-4), that specifically recognizes human apoE4 and apoE3 and preferentially binds nonlipidated, aggregated apoE over the lipidated apoE found in circulation. HAE-4 also binds to apoE in amyloid plaques in unfixed brain sections and in living APPPS1-21/APOE4 mice. When delivered centrally or by peripheral injection, HAE-4 reduced Aβ deposition in APPPS1-21/APOE4 mice. Using adeno-associated virus to express 2 different full-length anti-apoE antibodies in the brain, we found that HAE antibodies decreased amyloid accumulation, which was dependent on Fcγ receptor function. These data support the hypothesis that a primary mechanism for apoE-mediated plaque formation may be a result of apoE aggregation, as preferentially targeting apoE aggregates with therapeutic antibodies reduces Aβ pathology and may represent a selective approach to treat AD.
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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 Liao et al, 2018
The cited paper supports anti-apoE antibodies as a potential therapeutic approach, but not as a way to lower APOE expression. Its Discussion (p. 7) says HAE-4 did not significantly alter total apoE levels, and the Discussion (p. 8) explicitly distinguishes antibody targeting from simply lowering apoE levels. The antisense-therapy clause is attributed to a different citation. (LLM, conf=0.90)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredThe apoE found within Aβ plaques is non-lipidated or poorly lipidated.
“In addition, the apoE found within Aβ plaques is non‐lipidated or poorly lipidated. 60”
From Deletion of miR-33, a regulator of the ABCA1–APOE pathway, ameliorates neuropathological phenotypes in APP/PS1 mice (2024) · cites this paper as [60]
The Discussion (p. 8) says HAE-4 preferentially binds nonlipidated apoE and may recognize poorly lipidated, aggregated apoE in plaques of APPPS1-21/APOE4 mice. This supports the presence of such apoE in those plaques, but does not establish that apoE in Aβ plaques generally is non-lipidated or poorly lipidated; the authors say its frequency in patients with Alzheimer’s disease remains to be determined. (LLM, conf=0.86)
Experimental — accuracy not yet measuredTargeting the non-lipidated version of APOE4 is predicted to be more successful than targeting the lipidated version, as non-lipidated APOE is more likely to co-deposit with Aβ plaques and also to self-associate.
“Targeting of the non-lipidated version of APOE4 is predicted to be more successful than targeting the lipidated version, as non-lipidated APOE is more likely to co-deposit with Aβ plaques and also to self-associate139”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [139]
The Discussion (pp. 7–8) reports that HAE-4 preferentially binds nonlipidated, aggregated apoE in plaques and reduces Aβ accumulation in mice expressing human apoE4. It also proposes that poorly lipidated apoE may be more prone to aggregation. The paper does not establish that nonlipidated apoE is more likely than lipidated apoE to co-deposit with plaques or self-associate, or directly show that targeting it is more successful than targeting lipidated apoE. (LLM, conf=0.84)
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 [139]
The Discussion (p. 7) reports that HAE-4 preferentially binds nonlipidated apoE and reduces Aβ plaque load in APP transgenic mice expressing human apoE4. It does not support the CAA or Aβ-driven tau-seeding parts of the sentence: the Discussion (p. 8) says this mouse model had very little amyloid angiopathy, and our copy reports no tau-seeding result. (LLM, conf=0.90)
Experimental — accuracy not yet measuredApoE antibodies can suppress amyloidosis progression, alleviate amyloid pathology and improve cognitive function through multiple mechanisms including modification of glia responses, regulation of proinflammatory cytokines, amendment of apoE4-induced apoER2 reduction, and improvement of cerebrovascular function.
“ApoE antibodies can suppress amyloidosis progression, alleviate amyloid pathology and improve cognitive function through multiple mechanisms including modification of glia responses”
From ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease (2022) · cites this paper as Liao et al 2018
The Discussion (pp. 7–8) reports that anti-apoE antibodies reduced amyloid accumulation in mice and that the effect appeared to require a microglial response. It does not establish improved cognitive function. The longer supplied claim also attributes effects on cytokines, apoER2, and cerebrovascular function that this paper does not report. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Complete depletion of apoE expression could be harmful for neuronal maintenance, repair, and brain homeostasis.
“There is always a concern that complete depletion of apoE expression could be harmful for neuronal maintenance, repair, and brain homeostasis”
From ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease (2022) · cites this paper as Liao et al 2018
The Discussion (p. 8) contrasts targeting apoE in plaques with lowering apoE levels, but does not say that complete depletion could harm neuronal maintenance, repair, or brain homeostasis. Searches for complete depletion and apoE’s roles in repair and homeostasis found no passage addressing that concern. (LLM, conf=0.72)
Experimental — accuracy not yet measuredData suggest that HAE-4 mediates its effect by binding apoE in plaques followed by antibody-mediated opsonization by microglia, likely promoting peri-plaque Aβ phagocytosis.
“Instead, data suggests the antibody mediates its effect by binding apoE in plaques followed by antibody mediated plaque opsonization by microglia, likely promoting peri-plaque Aβ phagocytosis (Liao et al., 2018).”
From Alzheimer Disease: An Update on Pathobiology and Treatment Strategies (2019) · cites this paper as Liao et al., 2018
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- Authors
- Liao, F., Li, A., Xiong, M., Bien-Ly, N., Jiang, H., Zhang, Y., Finn, M. B., Hoyle, R., Keyser, J., Lefton, K. B., Robinson, G. O., Serrano, J. R., Silverman, A. P., Guo, J. L., Getz, J., Henne, K., Leyns, C. E. G., Gallardo, G., Ulrich, J. D., Sullivan, P. M., Lerner, E. P., Hudry, E., Sweeney, Z. K., Dennis, M. S., Hyman, B. T., Watts, R. J., & Holtzman, D. M.
- Affiliations
- Washington University in St. Louis (US)
- Denali Therapeutics (United States) (US)
- Duke University (US)
- Harvard University (US)
- Corresponding author
- Holtzman, David M.
- ORCID
- Liao, Fan
- Li, Aimin
- Xiong, Monica
- Jiang, Hong
- Zhang, Yin
- Finn, Mary Beth
- Hoyle, Rosa
- Lefton, Katheryn B.
- Serrano, Javier Remolina
- Silverman, Adam P.
- Guo, Jing L.
- Getz, Jennifer
- Henne, Kirk
- Leyns, Cheryl E.G.
- Gallardo, Gilbert
- Ulrich, Jason D.
- Sullivan, Patrick M.
- Lerner, Eli Paul
- Sweeney, Zachary K.
- Dennis, Mark S.
- Hyman, Bradley T.
- Watts, Ryan J.
- Holtzman, David M.
- Venue
- Journal of Clinical Investigation
- Published
- 2018-03-30
- Volume
- 128
- Issue
- 5
- Pages
- 2144-2155
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC5919821
- OpenAlex
- W2794553092
- Cited by
- 178
- References
- 41
- Citations by year
- 2026: 18 · 2025: 23 · 2024: 24 · 2023: 23 · 2022: 21 · 2021: 15 · 2020: 21 · 2019: 19 · 2018: 14
- FWCI
- 11.83
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
- Funders
- National Insitiutes of Health (AG047644)
- Denali (characterization of the effects of apoE antibodies)
- BrightFocus Foundation (Effects of anti-apoE antibodies in APP mice)
- National Institutes of Health (P50 AG05681, P01 AG03991, P01 AG026276)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- apolipoprotein E, APOE ε4, Alzheimer's disease, amyloid-beta, antibody therapy, amyloid plaques, Fc gamma receptor, AAV gene delivery, amyloid accumulation
- MeSH terms
- Alzheimer Disease, Animals, Humans, Amyloid beta-Peptides, Mice, Knockout, Mice, Apolipoprotein E3, Apolipoprotein E4, Plaque, Amyloid, Antibodies, Monoclonal, Murine-Derived
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