Assessing the Effect of Combined Humanization of Apolipoprotein E, Amyloid and Tau on Cognition and Alzheimer’s Disease Pathology

Abstract Background Apolipoprotein E (ApoE) exhibits isoform‐specific interactions with Alzheimer’s disease (AD)‐related pathology. In comparison with the more common ApoE3 isoform, ApoE4 promotes amyloid‐β (Aβ) deposition, enhances tau‐mediated neurodegeneration and inflammation. However, the lack of appropriate preclinical models has limited the ability to evaluate the potential synergistic effect of Aβ, tau and ApoE on cognition and disease progression. To overcome this, we developed new mouse models harbouring humanized variants of the ApoE genotypes (ApoE3 or ApoE4), hApp (AppNL or AppNL‐F) and hMAPT (tau) and evaluated whether the interaction among these AD‐related factors influence cognition, brain structure, and pathological load. Method An array of biochemical and imaging techniques including single‐nuclei (sn)RNA sequencing, magnetic resonance imaging (MRI), immunofluorescence microscopy, and Western blots were performed. Attentional demand was assessed, using the cross‐species Continuous Performance Task, an automated touchscreen test. Result Preliminary results indicate that AppNL‐F (ApoE3 or ApoE4), but not AppNL (ApoE3 or ApoE4) mice presented plaque pathology and insoluble Aβ. Moreover, increased levels of insoluble Aβ, plaque burden, plaque size and neuroinflammation were observed in the cortex of AppNL‐F ApoE4 mice in comparison to AppNL‐F ApoE3 at 9 and 12 months of age. At 16 months of age AppNL‐F ApoE3 and ApoE4 mice showed similar levels of insoluble Aβ. In vivo 9.4T MRI analyses indicated reduced grey matter volume in fronto‐cortical regions of AppNL‐F ApoE4 mice when compared to controls. snRNA sequencing also indicated a reduction of excitatory neurons in the cortex and upregulation of gliosis related genes and astrocytic populations at 9 months in AppNL‐F ApoE4 mice. Attentional deficits were observed on the CPT as early as 6 months of age in AppNL‐F ApoE4 mice that were maintained at 9 and 12 months of age. Conclusion Results from this project provide new insights into how amyloid, ApoE, and tau conspire to trigger and accelerate disease progression. We show that amyloid interacts with both ApoE3 and ApoE4 to drive degeneration, but in that the rate of this progression is faster in the ApoE4 background. Our findings also demonstrate that cognitive deficits are detectable much earlier than expected, in putative pre‐plaque stages of disease.

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