Prediction value of the genetic risk of type 2 diabetes on the amnestic mild cognitive impairment conversion to Alzheimer's disease.

Amnestic mild cognitive impairment (aMCI) and Type 2 diabetes mellitus (T2DM) are both important risk factors for Alzheimer's disease (AD). We aimed to investigate whether a T2DM-specific polygenic risk score (PRS sT2DM ) can predict the conversion of aMCI to AD and further explore the underlying neurological mechanism. All aMCI patients were from the Alzheimer's disease Neuroimaging Initiative (ADNI) database and were divided into conversion (aMCI-C, n = 164) and stable (aMCI-S, n = 222) groups. PRS sT2DM was calculated by PRSice-2 software to explore the predictive efficacy of the aMCI conversion to AD. We found that PRS sT2DM could independently predict the aMCI conversion to AD after removing the common variants of these two diseases. PRS sT2DM was significantly negatively correlated with gray matter volume (GMV) of the right superior frontal gyrus in the aMCI-C group. In all aMCI patients, PRS sT2DM was significantly negatively correlated with the cortical volume of the right superior occipital gyrus. The cortical volume of the right superior occipital gyrus could significantly mediate the association between PRS sT2DM and aMCI conversion. Gene-based analysis showed that T2DM-specific genes are highly expressed in cortical neurons and involved in ion and protein binding, neural development and generation, cell junction and projection, and PI3K-Akt and MAPK signaling pathway, which might increase the aMCI conversion by affecting the Tau phosphorylation and amyloid-beta (Aβ) accumulation. Therefore, the PRS sT2DM could be used as a measure to predict the conversion of aMCI to AD.