Apolipoprotein E and sex modulate fatty acid metabolism in a prospective observational study of cognitive decline

Background Fatty acids play prominent roles in brain function as they participate in structural, metabolic and signaling processes. The homeostasis of fatty acids and related pathways is known to be impaired in cognitive decline and dementia, but the relationship between these metabolic disturbances and common risk factors, namely the e4 allele of the apolipoprotein E (ApoE-e4) gene and sex, remains elusive. Methods In order to investigate early alterations associated with cognitive decline in the fatty acid-related serum metabolome, we here applied targeted metabolomics analysis on a nested case-control study (N=368), part of a prospective population cohort on dementia. Results When considering the entire study population, circulating levels of free fatty acids, acyl-carnitines and pantothenic acid were found to be increased among those participants who had greater odds of cognitive decline over a 12-year follow-up. Interestingly, stratified analyses indicated that these metabolomic alterations were specific for ApoE-e4 non-carriers and women. Conclusions Altogether, our results highlight that the regulation of fatty acids and related metabolic pathways during ageing and cognitive decline depends on complex inter-relationships between the ApoE-epsilon 4 genotype and sex. A better understanding of the ApoE-e4 and sex dependent modulation of metabolism is essential to elucidate the individual variability in the onset of cognitive decline, which would help develop personalized therapeutic approaches.

Automated summary

This study reveals that fatty acids and related pathways are impaired in cognitive decline and dementia, and the relationship is dependent on the complex inter-relationships between the ApoE-e4 genotype and sex. Understanding this relationship is crucial for developing personalized therapeutic approaches for cognitive decline.