Insulin sensitivity predicts cognitive decline in individuals with prediabetes

Epidemiological evidence links type 2 diabetes to cognitive dysfunction, with changes already emerging in the prediabetic stage. While cross-sectional studies associate insulin resistance with impaired cognition, its longitudinal predictive value independent of overt diabetes and treatment effects remains unclear.

We analyzed longitudinal data from the Tübinger Evaluation of Risk Factors for Early Detection of Neurodegeneration (TREND) study. Participants underwent repeated neurocognitive assessments using the CERAD Plus battery at baseline and every two years (median follow-up 4.0 years). Individuals with prediabetic HbA1c levels (5.6–6.5%) completed 75 g oral glucose tolerance tests to assess insulin sensitivity and secretion (n = 175). Participants with newly diagnosed diabetes or severe depression were excluded. Mixed-effects models were applied, with sex, age, and glycemic traits as fixed effects and subject and time as random effects.

Lower insulin sensitivity was associated with a time-dependent decline in overall cognitive performance, as reflected by the CERAD sum score (p = 0.0057). This effect was primarily driven by a steeper decline in memory performance among individuals with lower insulin sensitivity (p = 0.029). The interaction between age and insulin sensitivity was independent of glycemic levels, and no association was found between insulin secretion and cognition.

These findings suggest that insulin resistance, rather than elevated blood glucose alone, predicts cognitive decline—particularly in memory—in individuals with prediabetes. Interventions targeting insulin sensitivity may therefore help delay or prevent cognitive decline in diabetes.