Biomarkers

Background: The renin angiotensin system (RAS) has been proposed as a potential modifier of the development of Alzheimer's disease (AD). However, prospective studies of RAS are sparse especially among cognitively normal individuals with type 2 diabetes mellitus (T2DM) and other vascular risk factors. We aimed to determine whether plasma levels or activity of the RAS marker ACE-1 predicts cognitive decline over an 8-year period in this population.

Method: We performed a secondary data analysis of the Action for Health in Diabetes (Look AHEAD) study among community-dwelling, non-demented adults with overweight/obesity and T2DM aged 45-76 years at baseline observed over a 12-year period. Of 5,145 participants, we included 310 participants who were not using medications affecting the RAS system, had blood available at years 1, 4 and 10 and had undergone cognitive testing at least once and up to 4 times between years 8 and 16. Plasma ACE-1 was measured using by ELISA (R&D systems) and ACE-1 activity using immunocapture fluorogenic peptide assay. Cognitive tests included the Modified Mini-Mental State Examination (3MSE), the Trail Making Test Parts A and B, the Stroop Color-Word Test, the Digit Symbol Substitution Test, and the Rey Auditory Verbal Learning (RAVLT) Immediate and Delayed test. A cognitive composite score was derived by averaging standardized cognitive test scores. Mixed effects models were used to relate log converted ACE-1 levels and activity to performance in cognitive test scores after adjusting for potential confounders.

Result: Participants included in the analyses were more likely to be female (65%), White (76%), and were more likely to have obesity (34%), have lower HgbA1C, LDL and systolic blood pressure control compared to the excluded particpants. Higher mean ACE-1 levels measured at Y1, 4 and 10 was significantly associated with 3MSE (β=0.1774; p=0.02) and RAVLT-delayed recall (β=0.1600; p=0.05). The cognitive composite score was not associated with ACE-1 level. There was no association between ACE-1 activity and cognitive function.

Conclusion: In this sample with T2DM and dementia free at baseline, we observed longitudinal associations between mean ACE-1 levels and global cognition and memory.