Plasma Insulin Predicts Early Amyloid-β Pathology Changes in Alzheimer’s Disease

Background: Evidence suggests that type 2 diabetes (T2D) is an independent risk factor for Alzheimer's disease (AD), sharing similar pathophysiological traits like impaired insulin signaling. Objective: To test the association between plasma insulin and cerebrospinal fluid (CSF) AD pathology. Methods: A total of 304 participants were included in the Alzheimer's Disease Neuroimaging Initiative, assessing plasma insulin and CSF AD pathology. We explored the cross-sectional and longitudinal associations between plasma insulin and AD pathology and compared their associations across different AD clinical and pathological stages. Results: In the non-demented group, amyloid-β (Aβ)+ participants (e.g., as reflected by CSF Aβ42) exhibited significantly lower plasma insulin levels compared to non-demented Aβ-participants (p < 0.001). This reduction in plasma insulin was more evident in the A+T+ group (as shown by CSF Aβ42 and pTau181 levels) when compared to the A-T- group within the non-dementia group (p = 0.002). Additionally, higher plasma insulin levels were consistently associated with more normal CSF Aβ42 levels (p < 0.001) across all participants. This association was particularly significant in the Aβ-group (p = 0.002) and among non-demented individuals (p < 0.001). Notably, baseline plasma insulin was significantly correlated with longitudinal changes in CSF Aβ42 (p = 0.006), whereas baseline CSF Aβ42 did not show a similar correlation with changes in plasma insulin over time. Conclusions: These findings suggest an association between plasma insulin and early Aβ pathology in the early stages of AD, indicating that plasma insulin may be a potential predictor of changes in early Aβ pathology.