Circulating Endocannabinoids and Early Markers of Alzheimer’s Disease: Considering the Role of Sex
Shiraz Vered, Alexa S. Beiser, Liron Sulimani, Sharon Sznitman, Mitzi M. Gonzales, Hugo J Aparicio, Gil M Lewitus, David (Dedi) Meiri, Sudha Seshadri, Galit Weinstein- Psychiatry and Mental health
- Cellular and Molecular Neuroscience
- Geriatrics and Gerontology
- Neurology (clinical)
- Developmental Neuroscience
- Health Policy
- Epidemiology
Abstract
Background
Endogenous cannabinoids (i.e. endocannabinoids; eCBs) have an essential role in multiple physiological processes including energy homeostasis, sleep patterns and mood. Moreover, preclinical studies highlight the implication of eCBs in neurodegeneration and Alzheimer’s disease pathogenesis. Yet, observational studies are scarce and limited by small sample sizes and assessment of limited numbers of eCBs. We assessed the relationship of multiple circulating eCBs with cognitive and brain MRI measures and tested for effect‐modification by sex.
Method
We measured serum levels of 44 eCBs and eCB‐like compounds from 237 cognitively healthy participants aged ≥65 years who attended the ninth examination cycle of the Framingham Heart Study Offspring cohort. Linear regressions were used to examine the associations of eCB levels with cognitive and brain MRI, adjusting for age, age2, sex and time between blood draw and cognitive/MRI examination. Bonferroni correction for multiple comparisons was applied, and interactions with sex were assessed by including interaction terms in the models and stratification.
Result
Mean age was 73.3±6.2 years and 95 (40%) were men. Overall, higher levels of N‐Linolenoyl amide and N‐Linoleoyl amide were associated with poorer performance on Logical Memory (β = ‐1.535±0.442; p = 0.0006; β = ‐0.171±0.045; p = 0.0002, respectively) and Trails‐making A (β = ‐0.127±0.036; p = 0.0005; β = ‐0.014±0.004, p = 0.0003, respectively). Higher levels of Linolenic acid and N‐Oleoyl alanine were associated with poorer performance on Trails‐making B‐A (β = ‐0.001±0.0001; p = 0.0007; β = ‐0.787±0.237; p = 0.001; respectively) (Figure 1). Our results further pointed to a potentially important interaction between sex and eCB signaling with regard to cognitive and brain MRI measures. Specifically, significant interactions between eCBs and sex were observed in relation to all the study outcomes except for total cerebral brain volume. Moreover, most associations that differed by sex were in the opposite directions comparing men to women (Figure 2 and 3). The aforementioned associations between specific eCBs and cognitive performance in the total sample were apparent in women but not men.
Conclusion
We identified a wide range of sex‐specific associations between novel eCB compounds and early AD markers among dementia‐free older adults. These findings suggest putative molecular pathways underlying AD pathophysiology, and highlight potential mechanisms behind sex differences in AD susceptibility that need to be further investigated.