Plasma endocannabinoid alterations as a link in the comorbidity of Alzheimer's disease and type 2 diabetes mellitus.

Abstract

Over the last several years, studies have suggested a role of endocannabinoids such as 2-AG and 2-OG in the impairment of β-cell function and insulin secretion, as well as in the control of lipid and glucose metabolism in the periphery. Besides, alterations in the endocannabidiome are associated with the development of dementia. Since type 2 diabetes mellitus (T2DM) is an established risk factor for late-life cognitive decline, we sought to evaluate the possible link between the alterations in plasma endocannabinoids as potential biomarkers of cognitive decline in elderly patients with T2DM. In the present study, we evaluated the plasma levels of endocannabinoids in a cohort of elder controls and patients suffering from T2DM, with either mild cognitive impairment (MCI) or Alzheimer’s disease (AD). The cognitive performance of these patients was evaluated at the beginning of the study and their regional brain metabolic activity was assessed by PET-18FDG. We found that T2DM patients showed decreased levels of brain metabolic activity determined by PET-18FDG in the inferior parietal lobe, caudate, and thalamus, which were decreased and related to poor cognitive performance shown by both BLESSED and MMSE tests. Segregation of patients according to their cognitive status (MCI or AD) showed lower basal metabolism in the aforementioned regions, which was exacerbated in patients with AD and T2DM comorbidity. Correlation analysis showed plasma levels of the endocannabinoids 2-AG, 2-LG, and 2-OG were inversely related to brain metabolism in these areas, as well as to worse BLESSED and MMSE scores. Our results depict that plasma endocannabinoids are potential biomarkers linking the development of cognitive decline to the occurrence of T2DM.