Elevation of Plasma 2-Arachidonoylglycerol Levels in Alzheimer's Disease Patients as a Potential Protective Mechanism against Neurodegenerative Decline

J Alzheimers Dis. 2015;46(2):497-506. doi: 10.3233/JAD-142349.


Background: Growing evidence suggests that the endocannabinoid system is involved in the pathogenesis of Alzheimer's disease (AD) and atherosclerosis.

Objective: The purpose of this study was to investigate the activation of the endocannabinoid system in AD in vivo and the possible intermediate role of atherosclerosis.

Methods: We enrolled 41 patients with probable AD, and 30 age- and gender-matched controls. All subjects underwent: ultrasound examination of cerebral and neck vessels (including intima-media thickness and plaque stenosis evaluation); blood sampling to measure levels of endocannabinoid [anandamide (AEA), 2-arachidonoylglycerol (2-AG)] and endogenous AEA analogues [N-palmitoyl-ethanolamide (PEA); N-oleoyl-ethanolamide]; neuropsychological evaluation and brain MRI (atrophy, white matter hyperintensity volume).

Results: 2-AG levels were higher in AD patients compared to controls (Mann-Whitney test p = 0.021). In the AD group, 2-AG correlated to white matter hyperintensity volume (r = 0.415, p = 0.015) and was higher in patients with chronic heart ischemic disease (p = 0.023). In AD patients, 2-AG was also positively related to memory (r = 0.334, p = 0.05) and attention (r = 0.423, p = 0.018) performances. Constructional praxia test scores were lower in patients with higher levels of PEA (r =-0.389, p = 0.019).

Conclusion: AD patients present high plasma 2-AG levels, also in relation to heart ischemic disease and cerebral leukoaraiosis. This may be a protective mechanism hindering neurodegeneration, but it may also play an ambivalent role on cerebrovascular circulation. The increase in 2-AG and PEA levels observed with ongoing pathological processes may differently modulate cognitive performances.

Keywords: Alzheimer’s disease; atherosclerosis; endocannabinoids; leukoaraiosis.

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / blood*
  • Alzheimer Disease / diagnostic imaging
  • Arachidonic Acids / blood*
  • Attention
  • Biomarkers
  • Brain / blood supply*
  • Carotid Intima-Media Thickness*
  • Case-Control Studies
  • Cerebrovascular Circulation
  • Cross-Sectional Studies
  • Endocannabinoids / blood*
  • Female
  • Glycerides / blood*
  • Humans
  • Magnetic Resonance Imaging
  • Male
  • Memory
  • Neuropsychological Tests


  • Arachidonic Acids
  • Biomarkers
  • Endocannabinoids
  • Glycerides
  • glyceryl 2-arachidonate