Midlife insulin resistance, APOE genotype, and change in late‐life brain amyloid accumulation – a 5‐year follow‐up ¹¹C‐PIB‐PET study

Abstract

Background Midlife insulin resistance has been associated with an increased risk for cognitive decline (1) and amyloid accumulation (2). We hypothesized that midlife insulin resistance would predict amyloid accumulation 20 years later, and the change in brain amyloid accumulation during the 5‐year imaging follow‐up. Methods We studied 60 cognitively normal participants from the Finnish population‐based Health2000 study in 2014‐2016 with 11C‐PIB‐PET (2). They were recruited according to their homeostatic model assessment of insulin resistance (HOMA‐IR) values measured 15 years earlier in 2000, and their APOEε4 genotype. The insulin resistance group (IR+, HOMA‐IR <1.25) and the control group (IR−, HOMA‐IR > 2.17) both included 30 participants and 50% APOEε4 carriers. In 2019‐2021 43 participants took part in the 5‐year 11C‐PIB‐PET‐imaging follow‐up. Here, we report the change in amyloid accumulation in the IR+ group (n = 19, 57% APOE ε4 carriers) and the IR‐ group (n = 24, 46% APOEε4 carriers) during this 5‐year interval. 11C‐PIB‐PET images were analyzed with an in‐house pipeline and standard uptake value ratio (SUVR) composite scores were calculated. Kruskal‐Wallis test and the Steel‐Dwass method was used to analyze the difference in amyloid accumulation rates between groups, and Spearman’s correlation was utilized to assess the association between HOMA‐IR and amyloid accumulation. Result At the 20‐year follow‐up, amyloid accumulation was significantly higher in the IR+ group than the IR‐ group (composite SUVR 2.43 vs. 1.96, p = 0.03) (Fig. 1). The change in amyloid accumulation during 5 years was significantly higher in the IR+/APOEε4+ group than in either IR−/APOEε4− (mean change in composite SUVR 0.79 vs. 0.32, p = 0.02) or IR+/APOEε4− groups (mean change in composite SUVR 0.79 vs. 0.26, p = 0.046,) (Fig. 2). HOMA‐IR in 2000 (rS = 0.39, p = 0.01) and 2014‐2016 (rS = 0.34, p = 0.03), but not in 2019‐2021 (rS = 0.24, p = 0.13), correlated with 11C‐PIB composite SUVR at the 20‐year follow‐up. Conclusion These results suggest that IR could be an additive risk factor for late‐life amyloid accumulation in APOEε4 carriers, and that midlife, but not late‐life IR associates with amyloid accumulation. 1) Ekblad et al., Diabetes Care 2017 2) Ekblad et al., Neurology 2018