Circulating Endocannabinoids and Cognitive Function in Older Adults

The role of endogenous cannabinoids (endocannabinoids; eCBs) in cognitive-related processes has been demonstrated in preclinical studies. However, observational studies are lacking. We examined the associations of multiple circulating eCBs and eCB-like molecules with cognitive function in a sample of dementia-free older adults. In this exploratory, cross-sectional study, serum levels of 44 eCBs were analyzed in 237 older participants of the Framingham Heart Study Offspring cohort who attended examination cycle 9 (2011-2014). Linear regression models were used to examine the associations of eCB levels with cognitive function while adjusting for potential confounders and correcting for multiple testing. Effect modification by sex and apolipoprotein ɛ4 (ApoEɛ4) was additionally examined. Participants' mean age was 73.3±6.2y and 40% were men. After correction for multiple comparisons, increased levels of linoleic acid, linolenic acid, oleic acid, oleoyl alanine and palmitoyl alanine were associated with poorer executive function (B±SE=-0.0002±0.0001, p=0.002; B±SE=-0.0005±0.0001, p<0.001; B±SE=-0.0002±0.0001, p=0.003; B±SE=-0.74±0.25, p=0.003 and B±SE=-1.75±0.62, p=0.005, respectively). In addition, elevated levels of linolenoyl amide and linoleoyl amide were associated with poorer verbal memory (B±SE=-1.45±0.44, p=0.001 and B±SE=-0.16±0.05, p<0.001, respectively) and attention (B±SE=-0.12±0.04, p<0.001 and B±SE=-0.013±0.004, p<0.001, respectively). A significant interaction with sex was observed such that most of the above associations were present only among women. Furthermore, associations between several eCBs and perceptual organization were observed only among participants with ApoEɛ4 genotype. We identified novel eCB compounds that may be related to cognitive function. Validation of these findings is warranted and should consider sex and ApoEɛ4 interactions.