Association of Glycemic Variability With Imaging Markers of Vascular Burden, β-Amyloid, Brain Atrophy, and Cognitive Impairment.
Level 3 - non-randomized controlled study
Retrospective cohort study
PubMed 38165363 · doi:10.1212/WNL.0000000000207806
What was done
This retrospective cohort study evaluated 688 dementia-free patients (mean age 72.2 years, 51.9% female) from a memory clinic who had fasting glucose (FG) measured more than twice. Glycemic variability (GV) was defined as intraindividual visit-to-visit variability in FG. Participants underwent amyloid-beta (Aβ) PET, brain MRI (measuring white matter hyperintensities [WMH], hippocampal volume, and parietal thickness), and standardized neuropsychological testing. Multivariable regression and mediation analyses examined associations between GV, neuroimaging markers, and cognitive performance, adjusting for mean FG, diabetes status, age, sex, hypertension, and APOE4 status.
What was found
Higher GV was significantly associated with severe WMH (coefficient 1.032 [95% CI 1.012–1.054]; p = 0.002) and increased Aβ uptake (coefficient 1.005 [95% CI 1.001–1.008]; p = 0.007). In mediation analyses, WMH partially mediated the effect of GV on frontal-executive dysfunction (direct effect -0.319 [-0.557 to -0.080]; indirect effect -0.050 [-0.091 to -0.008]), whereas Aβ uptake partially mediated the effect of GV on memory dysfunction (direct effect -0.182 [-0.338 to -0.026]; indirect effect -0.067 [-0.119 to -0.015]). Additionally, Aβ uptake fully mediated the relationship between GV and hippocampal volume (indirect effect -1.091 [-2.078 to -0.103]) and partially mediated parietal thickness reduction (direct effect -0.00101 [-0.00185 to -0.00016]; indirect effect -0.00016 [-0.00032 to -0.000002]).
Why it matters
These findings suggest that visit-to-visit fasting glycemic fluctuation relates independently to both cerebral vascular burden and amyloid pathology pathways, which contribute to domain-specific cognitive deficits. Glycemic variability may serve as a modifiable target for dementia prevention.
Limits
The study is limited by its retrospective, single-center memory clinic cohort, potentially introducing selection bias. Glycemic variability was derived from intermittent fasting glucose checks (at least three visits) rather than continuous glucose monitoring. Retrospective observational data cannot establish causality.
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