Apolipoprotein E ε4 and type 2 diabetes cooperatively accelerate amyloid beta and tau neurodegeneration

Both type 2 diabetes mellitus (T2DM) and Apolipoprotein E (APOE) ɛ4 allele are recognized risk factors for Alzheimer's disease (AD). However, the impact of the APOE ɛ4 allele on the accumulation of AD-related neuropathology in patients with T2DM remains unclear.

We analyzed amyloid beta (Aβ) and tau deposition patterns via positron emission tomography (PET) imaging in 163 T2DM patients (64 ɛ4 carriers) and 1654 normal glucose metabolism subjects (687 ɛ4 carriers).

Findings reveal that Aβ deposition has a broader range of influence in diabetics carrying the ɛ4 allele, especially in the deep cortical areas. In terms of tau accumulation, diabetic carriers exhibit progression to the posterior and frontal cortices. Specifically, a greater Aβ PET burden is associated with higher levels of plasma Aβ42 and lower levels of cerebrospinal fluid (CSF) Aβ42, Aβ42/40, and Aβ42/38. A significant positive correlation was observed between tau PET burden and CSF tau and phosphorylated tau (pTau), and plasma pTau181. Importantly, higher Aβ and tau standardized uptake value ratio were associated with poorer memory performance and lower scores on the Montreal Cognitive Assessment.

These findings highlight the allele's region-specific synergism with T2DM in driving AD-related pathology, potentially informing the development of a neuroimaging-based grading system to evaluate diabetic neuropathology severity and progression dynamics.