An elusive link between blood measures of advanced glycation end products and their receptors and cognitive impairment syndromes in people with diabetes: A scoping review

Advanced glycation end products (AGEs), which are glycated forms of proteins and lipids, are increased in diabetes resulting from chronic hyperglycemia. AGEs and their receptor (RAGE) have been linked to cognitive impairment syndromes and may increase the risk of cognitive decline and impairment in people with diabetes who experience chronic hyperglycemia. The objective of this scoping review was to comprehensively document the current evidence concerning the relationship between AGEs and RAGE, measured in the blood, and cognitive function and cognitive impairment syndromes in people with diabetes. MEDLINE, Embase, Cochrane Library, Web of Science Core Collection, APA PsycInfo, and the Psychology and Behavioral Sciences Collection were queried, and the PRISMA Extension for Scoping Reviews guidelines were followed for reporting of methods and results. Twenty-two articles were included in the current scoping review. Among the included articles, we found largely mixed results, whereby both higher and lower levels of AGEs/RAGE were associated with worse cognition or presence of cognitive impairment syndromes in people with diabetes; however, due to notable differences in the methodologies employed to quantify AGEs/RAGE in blood, it is challenging to interpret the factors driving the observed variability. Methodological differences that are likely relevant to AGEs/RAGE quantification include use of plasma vs. serum and selection of AGEs/RAGE studied (e.g., total AGEs/RAGE, pentosidine, carboxymethyl lysine, etc.). Given the observed inconsistencies, currently, there is insufficient evidence to conclude that blood-based AGEs and/or RAGE are indicators of risk for cognitive impairment and decline in people with diabetes. Moreover, it remains undetermined as to which AGEs species or RAGE isoform is most predictive of cognitive impairment or decline in people with diabetes. More studies are needed that include larger sample sizes and well-described and validated methodology to measure AGEs/RAGE.