Advanced Glycation Endproduct Level, Diabetes and Accelerated Cognitive Aging

Abstract

Many studies have suggested that diabetes increases risk of cognitive impairment and higher advanced glycation endproduct(AGE) levels have been hypothesized as a possible mechanism for this link. AGEs are a group of cross-linked products, such as pentosidine, that result from reactions between glucose and proteins. AGEs accumulate in the body with age and have been implicated in several age-related diseases, including Alzheimer's disease. No study has determined the association between peripheral AGE concentration and cognitive aging. We prospectively studied 920 elders, 495 with diabetes and 425 with normal glucose, with a mean age of 74 years. We used mixed models to examine the association between baseline AGE concentration, as measured by urine pentosidine level, and performance on the Modified Mini-Mental State Examination (3MS) and Digit Symbol Subsitution Test (DSST) at baseline and repeatedly over 9 years. Incident cognitive impairment was defined as a decline of >1.0 SD on each test and analyzed with logistic regression. Older adults with a high pentosidine level had poorer baseline DSST scores compared to those in low and mid tertile levels (p = 0.046); no difference was observed on baseline 3MS (p = 0.32). On both tests, there was a more pronounced 9-year decline among those with high and mid pentosidine compared to those in the lowest tertile (3MS 7.0, 5.4 and 2.5 point decline, p overall <0.001; DSST: 5.9, 7.4 and 4.5 decline, p overall = 0.03). Multivariate adjustment for age, sex, education, hypertension, and diabetes led to similar results. Incident cognitive impairment was higher in those with high or mid tertile levels of pentosidine than those in the lowest tertile (3MS: 24% vs. 17%, OR = 1.55; 95% CI 1.07-2.26; DSST: 31%vs 22%, OR = 1.62; 95% CI 1.13-2.33). There was no interaction between pentosidine level, diabetes status and cognitive decline. High peripheral AGE level is associated with greater cognitive decline in older adults with and without diabetes; further studies are needed to determine the utility of urinary pentosidine as a biomarker for cognitive aging.