Omega 3/6 ratios: Usage and epigenetic changes in health and Alzheimer's disease

Abstract

AbstractBackgroundFrom our previous research, we identified circulating metabolites that are associated with cognitive performance and dementia including polyunsaturated fatty acids (PUFA), in particular plasma levels of Omega‐3. To follow up on this finding, we sought to explore potential mechanism mediating the effect of Omega‐3 and Omega‐6 on these neurodegenerative phenotypes. Herein, we hypothesized that modulation of immune response and inflammation may mediate the effect of PUFA on neurodegenerative diseases.Methods1.Validate our PUFA ratios hypothesis on the MAPT intervention study. 2.Evaluate the epigenetic mechanisms modulation derived from genetics using genome‐wide association studies. 3.Corroborate previous results on real methylation data from the DELCODE study using the EPIC array. 4.Evaluate the biological age derived by epigenetics and its implications in healthy and cognitively affected subjects.ResultsThe effect of the PUFA ratios follows the same trend on the MAPT study as previously described during our first period. We observed that the methylation of the genes coding for key enzymes of PUFA metabolism is modulated by levels of Omega‐3. Likewise, these methylation changes have been described in susceptibility genes for Alzheimer’s disease (AD) that modulate immune response. Finally, methylated signals also enabled the prediction of biological age. We observed that biological age in DELCODE participants differs from chronological age depending on the status of the participants.ConclusionsThe present analysis suggests that PUFA ratios are associated with cognitive decline as we previously described. Moreover, we suggest that genetic signals located in the immune‐related gene cluster MS4A are modulated by changes in DNA methylation. The same epigenetic modulation seems to mediate the genetic effect discovered in the sTREM2 GWAS. Interestingly, methylation modulation in MS4A gene has been previously reported using an independent approach. Likewise, TREM2 locus seems to be affected by methylation changes. Finally, our methylation data allowed us to analyze the biological age of cognitively affected individuals and find some clear differences with their chronological ages. Using our results, we will explore whether PUFA levels, and the ratio built on Omega‐6 and Omega‐3, modulate levels of CSF sTREM2 offering thereby a potential connection between PUFA levels and neuroinflammation in the context of AD.