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

Raúl González-Domínguez*, Pol Castellano-Escuder, Sophie Lefèvre-Arbogast, Dorrain Y. Low, Andrea Du Preez, Silvie R. Ruigrok, Hyunah Lee, Catherine Helmer, Mercè Pallàs, Mireia Urpi-Sarda, Alex Sánchez-Pla, Aniko Korosi, Paul J. Lucassen, Ludwig Aigner, Claudine Manach, Sandrine Thuret, Cécilia Samieri, Cristina Andres-Lacueva

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

13 Citations (Scopus)


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 ɛ4 allele of the apolipoprotein E (ApoE-ɛ4) 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-ɛ4 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-ε4 genotype and sex. A better understanding of the ApoE-ɛ4 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.

Original languageEnglish
Article number1
JournalAlzheimer's Research and Therapy
Issue number1
Early online date3 Jan 2022
Publication statusPublished - Dec 2022


  • Acyl-carnitines
  • Apolipoprotein E
  • Cognitive decline
  • Fatty acids
  • Metabolomics
  • Sex


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