Neurodegeneration mediates link between diabetes, cognitive status

Diabetes correlated with decreased cognition through neurodegeneration, regardless of small vessel disease and Alzheimer’s disease biomarkers, according to a cross-sectional analysis of MEMENTO, a large clinical cohort study.

“Previous studies have suggested a mediating role of neurodegeneration and small vessel disease biomarkers on the association between diabetes and cognition,” Eric Frison, MD, PhD, a clinical epidemiologist at Center Hospital University of Bordeaux, and colleagues wrote. “However, the mediating role of AD-specific lesions (amyloid plaques and neurofibrillary tangles), and the correlation between those different brain features have not been considered so far.”

Frison and colleagues looked at the mediating effect of biomarkers of AD, neurodegeneration and small vessel disease (SVD) in to the link between diabetes and cognition. Their analysis of the MEMENTO cohort included 2,288 participants (median age, 71.6 years; 61.8% women) from the French national network of university hospital-based memory clinics, of whom 254 patients (11.1%) had diabetes. Each participant had a Clinical Dementia Rating scale score of statistical significance (P < .001) and expressed cognitive symptoms or subjective cognitive complaints between April 2011 and June 2014. At baseline, 65.3% of the patients with diabetes were taking antidiabetic medications. Additionally, each participant underwent neuropsychological battery administration, clinical examinations, brain MRI, cerebrospinal samples and fluorodeoxyglucose and amyloid PET examinations.

The researchers used structural equation modelling to determine if latent variables of AD pathology (PET mean amyloid uptake, amyloid beta 42/amyloid beta 40 ratio and CSF phosphorylated tau), SVD (white matter hyperintensities volume and visual grading), and neurodegeneration (mean cortical thickness, brain parenchymal fraction, hippocampal volume, and mean fluorodeoxyglucose uptake) causes the association between diabetes and a latent variable of cognition (five neuropsychological tests) after adjusting for potential confounders.

Frison and colleagues found that the link between diabetes and lower cognition was “significantly mediated” by greater neurodegeneration (standardized indirect effect, -0.061; 95% CI, -0.089 to -0.032), but not mediated by SVD and AD markers. Researchers also found, in complementary analysis that took into account specific cognitive functions, that associations between diabetes and lower memory or lower executive functioning were often mediated by higher neurodegeneration (standardized beta = -0.058, 95% CI, -0.088 to -0.029 and standardized beta = -0.034, 95% CI, -0.051 to -0.016, respectively).

“Although it needs to be replicated in longitudinal studies, our finding that neurodegeneration mediates the association between diabetes and cognitive performances, independently of biomarkers of AD and small vessel disease, supports the hypothesis of a direct role of diabetes-related insulin resistance in the development of cognitive impairment in older adults with diabetes,” Frison and colleagues wrote. “The current results suggest that the detrimental effect of diabetes on cognition is mediated by neurodegeneration, independently of AD and small vessel disease pathologies, in a population of older adults at risk for dementia. Longitudinal studies are now needed to reinforce and confirm these findings.”