. An Alzheimer's-disease-protective APOE mutation. Nat Med. 2019 Nov;25(11):1648-1649. PubMed.


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  1. We’d like to pick up on several of the interesting themes raised in these studies as based on our own work in this area.

    In a study of 1,557 brains in the NACC v 10 database (which we presented  at AAIC, 2019, and which we’ve now submitted) we found that E2 was associated with significantly reduced risk of neuritic plaques, diffuse plaques, and Braak stage. Odds Ratios in E2 v E3/E3 contrasts were around .50 for these three neuropathologies  and ORs in E2 v E4 contrasts were around .90, again for the three AD pathologies. In a mediation analysis we found that E2 had direct effects on tau Braak stage, as well as indirect effects via amyloid.

    However, there were sharp limits to E2 neuroprotection. When the E2 isoform was in the presence of the e4 isoform, i.e., in the E2/E4 genotype, E2 was not protective (see also Oveisgharan et al., 2018). This genotype “behaved” like other E4 carrier cases in terms of promoting pathology. Second and unexpectedly, E2 demonstrated trends for increases in FTLD related pathologies (including TDP-43 and select tauopathies).

    We’ve also conducted microarray transcriptional profiling studies in human postmortem neocortex to identify E2-associated pathways. We found that E2 was linked to increased expression of transcripts in an integrin/extracellular matrix KYOTO pathway (Conejero-Goldberg et al., 2014). The potential importance of this finding (and the HSPG binding related to the APOE mutation) is that matrix neurobiology might play a role in tau propagation as suggested by Lendvai et al., 2012


    . APOE2 enhances neuroprotection against Alzheimer's disease through multiple molecular mechanisms. Mol Psychiatry. 2014 Feb 4; PubMed.

    . Neurochemical mapping of the human hippocampus reveals perisynaptic matrix around functional synapses in Alzheimer's disease. Acta Neuropathol. 2012 Sep 9; PubMed.

    . APOE ε2ε4 genotype, incident AD and MCI, cognitive decline, and AD pathology in older adults. Neurology. 2018 Jun 12;90(24):e2127-e2134. Epub 2018 May 11 PubMed.

    View all comments by Terry Goldberg
  2. This is a very interesting finding, and parallels recent findings from the Kaczorowski lab (in mice). In our recent study, we took the approach to map modifiers that protect/delay onset of cognitive deficits in a genetically diverse population of transgenic mice carrying human familial AD mutations in APP and PSEN1 (Neuner et al., 2019). In this way, we identified genetic variants in the receptor binding domain of mouse Apoe associated with cognitive resilience (Figure 2). Specifically, strains of mice with ADAD mutations that were resilient to cognitive decline despite high amyloid burden had two copies of the C57BL/6J allele at the ApoE locus. Our results are consistent with the present report, that variants in ApoE modify the impact on ADAD mutations on cognition (even absent effects on amyloid).

    Perhaps more importantly, since most AD mouse models are maintained on a pure C57BL/6J background, we speculate that preclinical studies that failed to translate to human clinical trials may be due to studies being run in mice that harbor protective variants at ApoE that modify the impact of ADAD mutations.


    . Harnessing Genetic Complexity to Enhance Translatability of Alzheimer's Disease Mouse Models: A Path toward Precision Medicine. Neuron. 2019 Feb 6;101(3):399-411.e5. Epub 2018 Dec 27 PubMed.

    View all comments by Catherine Kaczorowski

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  1. Can an ApoE Mutation Halt Alzheimer’s Disease?