Removal of Neuronal APOE4 Alleviates Alzheimer’s in Mice

This gene is the principal risk factor for Alzheimer's in humans.


Genetic erasureGenetic erasure

In a new study published in Nature Aging, scientists have shown that targeted ablation of neuronal APOE4, which produces the ApoE4 protein, significantly protects against Alzheimer’s disease in a mouse model [1].

The dreadful allele

An infamous variant of the APOE gene, APOE4, is the strongest risk factor for late-onset Alzheimer’s disease [2]. People heterozygous for APOE4 are 3.5 times more likely to develop Alzheimer’s than people carrying two copies of APOE3, while people who have two copies of APOE4 are 12 times more vulnerable. Scientists have discovered links between the ApoE4 protein and various AD-related pathologies [3], such as hippocampal volume loss, neuroinflammation, and increase in the burden of tau-protein. However, our mechanistic understanding of these links is limited.

ApoE is produced by cells of various types, mostly astrocytes, and acts in a cell type-dependent manner. Previous research has shown that genetic ablation of APOE4 in astrocytes can alleviate AD-related symptoms [4], but the role of APOE4 in neurons is less understood.

APOE4’s disproportional effect

The researchers created an ingenious mouse model of Alzheimer’s using mice that produced both human tau protein and either human ApoE3 or ApoE4. On top of that, the researchers developed a mechanism for switching off the APOE gene specifically in neurons.

As expected, the APOE4 mice exhibited much more severe AD symptoms than the APOE3 mice. If ApoE4 production in neurons was switched off, overall levels of this protein fell by about 30%, which matches the share of ApoE known to be produced in neurons. However, the reduction in tau pathology was much more substantial: 81%.


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Multiple AD hallmarks alleviated

This led to an investigation of how neuronal APOE4 promotes the tauopathy that gives rise to Alzheimer’s. Disease-associated tau protein is known to spread inside the brain [5]. When the researchers injected additional tau into one part of the brain, it propagated to other connected parts much faster in APOE4 mice than in APOE3 mice. However, ablation of neuronal APOE4 significantly slowed this process, showing that at least one of the mechanisms behind APOE4-related AD pathogenesis is increased tau propagation.

Neuronal APOE4 removal also drastically reduced neurodegeneration, including loss of hippocampal neurons and volume. Untreated APOE4 mice had much more apoptotic (dead) neurons, as shown by elevated levels of cleaved caspase 3. Like other AD symptoms, this one was alleviated by neuronal APOE4 ablation, revealing another possible mechanism by which APOE4 contributes to AD development.

Loss of myelin, the protein that forms protective sheaths over axons, is another AD hallmark. Both myelin levels and the number of oligodendrocytes, the cells that produce it, were significantly decreased in APOE4 mice but rescued by APOE4 ablation. The treatment also prevented gliosis, a growth and proliferation of glial cells that increases neuroinflammation. The same dynamic was observed for neuronal hyperexcitability, which is linked to several neurodegenerative disorders, including Alzheimer’s.

Glial cells, which consist mostly of astrocytes and microglia, have a complex relationship with Alzheimer’s. Some subpopulations of these cells can be disease-inducing, and some can be protective. In this study, removal of neuronal APOE4 increased the number of protective and decreased the number of disease-associated astrocytes and microglia.

Probably the most important finding in this paper is that neuronal APOE, while accounting for only about 30% of the total amount of ApoE protein, has a disproportionate effect on AD-related pathologies. Since complete APOE depletion can have deleterious effects [6], the researchers suggest that currently available CRISPR-based techniques can be utilized to block APOE4 specifically in neurons. Such a strategy can be potentially highly effective against Alzheimer’s.


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In the present study, we investigate the roles of neuronal APOE4 in promoting the development of prominent AD pathologies in a tauopathy mouse model. We demonstrate that the removal of neuronal APOE4 has wide-ranging beneficial effects, leading to drastic reductions (1) in the accumulation and spread of pathological tau throughout the hippocampus; (2) in neurodegeneration and hippocampal neuron loss; (3) in myelin deficits and depletion of oligodendrocytes and OPCs; (4) in neuronal network hyperexcitability; (5) in microgliosis and astrogliosis and (6) in the accumulation of neurodegenerative disease-associated cell subpopulations. These findings illustrate that neuronal APOE4 is a potent driver of these AD-related pathologies and that its removal is sufficient to attenuate these disease phenotypes. Thus, our study reveals a central role of neuronal APOE4 in the pathogenesis of APOE4-driven AD and provides new insights into potential therapeutic targets to combat APOE4-related AD, such as through the removal or reduction of neuronal APOE4.


This study shows the disproportionate importance of neuronal APOE4 in Alzheimer’s disease pathogenesis and offers a glimpse into several possible mechanisms linking APOE4 and AD. This can provide a basis for future gene therapies for Alzheimer’s.

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[1] Koutsodendris, N., Blumenfeld, J., Agrawal, A., Traglia, M., Grone, B., Zilberter, M., … & Huang, Y. (2023). Neuronal APOE4 removal protects against tau-mediated gliosis, neurodegeneration and myelin deficits. Nature Aging, 1-22.

[2] Corder, E. H., Saunders, A. M., Strittmatter, W. J., Schmechel, D. E., Gaskell, P. C., Small, G., … & Pericak-Vance, M. A. (1993). Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science, 261(5123), 921-923.

[3] Raulin, A. C., Doss, S. V., Trottier, Z. A., Ikezu, T. C., Bu, G., & Liu, C. C. (2022). ApoE in Alzheimer’s disease: pathophysiology and therapeutic strategies. Molecular Neurodegeneration, 17(1), 1-26.

[4] Wang, C., Xiong, M., Gratuze, M., Bao, X., Shi, Y., Andhey, P. S., … & Holtzman, D. M. (2021). Selective removal of astrocytic APOE4 strongly protects against tau-mediated neurodegeneration and decreases synaptic phagocytosis by microglia. Neuron, 109(10), 1657-1674.


[5] Zhang, H., Cao, Y., Ma, L., Wei, Y., & Li, H. (2021). Possible mechanisms of tau spread and toxicity in Alzheimer’s disease. Frontiers in Cell and Developmental Biology, 9, 707268.

[6] Li, G., Bien-Ly, N., Andrews-Zwilling, Y., Xu, Q., Bernardo, A., Ring, K., … & Huang, Y. (2009). GABAergic interneuron dysfunction impairs hippocampal neurogenesis in adult apolipoprotein E4 knockin mice. Cell stem cell, 5(6), 634-645.

About the author
Arkadi Mazin

Arkadi Mazin

Arkadi is a seasoned journalist and op-ed author with a passion for learning and exploration. His interests span from politics to science and philosophy. Having studied economics and international relations, he is particularly interested in the social aspects of longevity and life extension. He strongly believes that life extension is an achievable and noble goal that has yet to take its rightful place on the very top of our civilization’s agenda – a situation he is eager to change.