APOE variant in the receptor binding domain confers cognitive resilience to familial Alzheimer's mutations and cell‐type specific gene expression changes in the hippocampus.

Background: Cognitive resilience to familial Alzheimer's Disease (FAD) is a phenomenon whereby cognitive functioning is better than predicted based on highly penetrant mutations in APP and PS1. This resilience is likely mediated by unidentified genetic factors, and we hypothesize that these factors provide key targets for treatment and prevention of AD. We previously discovered that the most commonly used background strain in AD model research (C57BL/6J, B6) is resilient to AD‐related cognitive decline. Method: Using genetic mapping, we determined that cognitive resilience is associated with a variant in the Apoe receptor binding domain and utilized CRISPR to generate a novel Apoe knockin mouse (Apoe KIB6/E163D). Contextual fear conditioning (CFC), tau pathology, and single‐nuclear RNAseq hippocampi analyses were performed in male and female Apoe KIB6/E163D x 5XFAD progeny that differed by only a single variant in Apoe leading to the E163D base pair change in the protein. Result: We found that, indeed, cognitive resilience to the 5XFAD transgene was conferred in ApoeB6/B6 mice compared to Apoe KIB6/E163D mice tested on CFC. Although minimal differences in hyperphosphorylated tau abundance were observed between 5XFAD‐ApoeWT/WT mice compared to 5XFAD‐Apoe KIB6/E163D, we uncovered robust differences in the transcriptomes of hippocampal excitatory and inhibitory neurons and microglia using single‐nuclear sequencing. Gene enrichment and pathway analyses of differentially expressed genes suggest that the 5XFAD‐ApoeB6/B6 genotype promotes cation transport and suppression of amyloid fibril formation in excitatory neurons, promotes genes involved in ribosome assembly and protein translation in inhibitory neurons, and enhances gene expression associated with stress response in microglia. Conclusion: Our results suggest that 5XFAD‐ApoeB6/B6 homozygotes exhibit cognitive resilience to causal FAD mutations that involve dynamic regulation of gene networks across multiple cell types, emphasizing the need for well‐aligned cell culture models of cognitive resilience to validate targets and screen resilience‐based interventions. Future work leveraging in vivo electrophysiology and imaging will establish mechanisms whereby Apoe variants alter neural and synaptic function. Understanding the relationship between protective genetic factors and cognitive resilience are crucial for determining mechanisms of resilience and uncovering novel targets for intervention. [ABSTRACT FROM AUTHOR]