Apolipoprotein E4 and Insulin Resistance Interact to Impair Cognition and Alter the Epigenome and Metabolome

Apolipoprotein E4 (E4) and type 2 diabetes are major risk factors for cognitive decline and late onset Alzheimer’s disease (AD). E4-associated phenotypes and insulin resistance (IR) share several features and appear to interact in driving cognitive dysfunction. However, shared mechanisms that could explain their overlapping pathophysiology have yet to be found. We hypothesized that, compared to E3 mice, E4 mice would be more susceptible to the harmful cognitive effects of high fat diet (HFD)-induced IR due to apoE isoform-specific differences in brain metabolism. While both E3 and E4 mice fed HFD displayed impairments in peripheral metabolism and cognition, deficits in hippocampal-dependent spatial learning and memory were exaggerated in E4 mice. Combining genome-wide measures of DNA hydroxymethylation with comprehensive untargeted metabolomics, we identified novel alterations in purine metabolism, glutamate metabolism, and the pentose phosphate pathway. Finally, in E4 mice, the metabolic and cognitive deficiencies caused by HFD were rescued by switching to a low fat diet for one month, suggesting a functional role was associated with reversal of the same metabolic pathways described above. These results suggest a susceptibility of E4 carriers to metabolic impairments brought on by IR, and may guide development of novel therapies for cognitive decline and dementia.

Protocol publication

[…] Hippocampi were dissected and homogenized in RIPA (500 μl). Metabolites were extracted from 100 μl of hippocampal homogenate and untargeted metabolomics was completed as described. Metabolomics data was processed using MarkerView and Peakview software (AB SCIEX) and Metaboanalyst. Metabolite identification was based on mass error (<30 ppm) and MS/MS fragment ions. Many metabolites were further confirmed using retention time and comparison to authentic standards ( ± 1 min) from an in-house library (IROA Technologies). LipidMaps, METLIN and HMDB databases were used for MS and MS/MS matching. Metaboanalyst heatmap and pathway analyses were performed as described. For integrated pathway analyses, the parameters were set to ‘global test’ and ‘relative betweenness centrality’. […]