Skin advanced glycation end products and the risk of dementia

Abstract Background Conditions such as hyperglycemia and oxidative stress lead to the formation of advanced glycation end products (AGEs), which have also been implicated in neurodegeneration including dementia. Previous studies have shown a link between these AGEs and the occurrence of Alzheimer’s neuropathology and worse cognitive functioning. However, no study examined the association between AGE levels and the risk of dementia. Therefore, we used skin AGE levels, reflecting accumulation of AGEs in long‐lived tissues, to determine the association with the risk of dementia and brain MRI measures. Method Within the Rotterdam Study, we determined skin AGEs using skin autofluorescence (SAF [arbitrary units]) measured at the forearm, between 2013 and 2016 in 2938 participants without dementia. Of them, 1515 also underwent brain MRI. All participants were followed for the incidence of dementia until 2020. The associations of SAF with incident dementia and with brain MRI measures were assessed, adjusting for potential confounders, namely age, sex, education, APOE ε4 carriership, smoking, estimated glomerular filtration rate, fasting glucose level and use of antidiabetic medication. Result Of 2938 participants (mean age 72.6 years, 57% women), 124 developed dementia during a median follow‐up of 4.3 years. Higher SAF was associated with an increased risk of dementia (hazard ratio (HR) 1.22 per standard deviation increase of SAF [95% confidence interval 1.03‐1.45]) and of Alzheimer’s disease (HR 1.21 [1.00‐1.48]). Stronger effects were seen in APOE ε4 carriers with HRs of 1.38 [1.03‐1.84] for all‐cause dementia and 1.51 [1.10‐2.09] for Alzheimer’s disease. Participants with higher SAF also had lower total brain volumes on MRI (difference per standard deviation increase: ‐2.71 mL [‐4.54; ‐0.89]), lower grey matter volumes (‐1.77 mL [‐3.45; ‐0.08]) and lower hippocampus volumes (‐0.04 [‐0.07; ‐0.01]). In addition, they tended to more often have lacunar infarcts and microbleeds (odds ratios: 1.22 [0.99‐1.50] and 1.09 [0.96‐1.25]). Conclusion Higher levels of AGEs in the skin are associated with an increased risk of dementia, especially in APOE ε4 carriers, and with lower brain volumes. These results suggest that AGEs are involved in dementia pathophysiology and may provide potential for prevention.