Is ApoE the key to an Alzheimer's cure?

Alzheimer’s disease has gained a lot of attention in the past week or so due to new findings about Apolipoprotein E (ApoE) published in Nature¹. ApoE genotype has long been known to be a major risk factor for Alzheimer disease. Of the four known alleles of this gene, one variant (ApoE4) increases Alzheimer’s severity and risk, while the ApoE2 allele is protective².

The new research from Shi et al. overturns the idea that ApoE affects Alzheimer’s pathology by affecting amyloid-β plaque formation³. Instead, these researchers show that ApoE affects inflammation and tau-mediated neurodegeneration independently of amyloid-β pathology. Their data suggest that the ApoE4 variant is a gain-of-function mutation that causes increased neurodegeneration in response to tau neurofibrillary tangles. The other ApoE variants have reduced neurodegeneration, while mice lacking ApoE entirely showed virtually no Alzheimer’s-like neurodegeneration.

This research made use of a series of two-part mouse models³. Transgenic mice expressing a mutant form of the human tau gene (P301S) develop neurofibrillary tangles, and recapitulate many aspects of human Alzheimer’s disease. Shi et al. introduced this P301S tau transgene into ApoE knockout mice or into humanized, knockin mice carrying the human ApoE gene of one of the three variants (ApoE2, ApoE3, or ApoE4).

Not only did Shi et al. find that P301S/ApoE4 mice had much less brain tissue loss and inflammation than P301S/ApoE2 and P301S/ApoE3 mice, but they also showed that P301S/ApoE-KO mice had no brain damage. In vitro co-culturing studies suggested that ApoE (particularly ApoE4) mediates neurodegeneration by initiating a harmful immune response.

Together, these data suggest that inactivation of ApoE in the brain may be an effective way to prevent neurodegeneration in Alzheimer’s disease and in other tau-associated neuropathies. Reassuringly, individuals lacking functional ApoE due to mutations show no obvious neurological defects, suggesting that ApoE may not be necessary in the human brain⁴.

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References

1. Shi Y, Yamada K, Liddelow SA, et al.. ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature. 2017 Sep 20.
2. Roses AD. Apolipoprotein E alleles as risk factors in Alzheimer's disease. Annu Rev Med. 1996;47:387-400.
3. Holtzman DM, Herz J, Bu G. Apolipoprotein E and apolipoprotein E receptors: normal biology and roles in Alzheimer disease. Cold Spring Harb Perspect Med. 2012 Mar;2(3):a006312.
4. Mak AC, Pullinger CR, Tang LF, et al. Effects of the absence of apolipoprotein e on lipoproteins, neurocognitive function, and retinal function. JAMA Neurol. 2014 Oct;71(10):1228-36.