A profile of impaired insulin degradation in relation to late‐life cognitive decline: A preliminary investigation

Abstract Objective Insulin degradation pathways may be related to Alzheimer's disease pathology. In preliminary analyses, we considered the relation of combined lower insulin secretion (c‐peptide) and higher insulin––possibly a phenotype for impaired insulin degradation––to cognitive decline. Method Fasting plasma c‐peptide and insulin were measured in 1,187 non‐diabetic Nurses' Health Study participants (mean age = 64 years). Cognitive testing began 10 years later. Participants completed three repeated assessments (over an average span of 4.4 years) of verbal memory, a strong predictor of Alzheimer disease development. C‐peptide and insulin distributions were dichotomized at their medians to create four cross‐tabulated categories. Multivariable linear mixed effects models were used to relate c‐peptide/insulin categories to cognitive decline. Results Compared to the lower c‐peptide/lower insulin group, women with lower c‐peptide/higher insulin had a significantly faster rate of verbal memory decline: the mean difference was ‐0.05 units/year (95% CI ‐0.09,‐0.01). This mean difference was similar to that which we found for women 5 years apart in age, indicating that having a profile of lower c‐peptide/higher insulin appeared cognitively equivalent to aging by five years on tests of verbal memory. For women with higher c‐peptide/higher insulin, the estimated mean difference in decline compared to those in the lower c‐peptide/lower insulin group was statistically significant, but slightly lower, at −0.04 units/year (95% CI: ‐0.07,‐0.02). Conclusion These preliminary analyses of a possible phenotype of impaired insulin degradation provide supportive evidence that deficits in insulin degradation may be related to late‐life verbal memory decline. Copyright © 2008 John Wiley & Sons, Ltd.