Diabetes Mellitus contributes to higher cerebrospinal fluid tau levels selectively in Alzheimer's disease patients with APOE4 genotype

Background: Diabetes mellitus (DM) is considered a risk factor for Alzheimer's disease (AD), sharing some pathological pathways such as activation of amyloid cascade and tau phosphorylation. In the present work, we investigated to what extent DM could impact on neurodegeneration within the AD continuum, using β amyloid (A: Aβ1-42 ) and phosphorylated tau (T: p-Tau) biomarkers to discriminate patients into Alzheimer's pathologic change (A+/T-) and AD (A+/T+), according to the National Institute on Aging and Alzheimer's Association. Moreover, we aimed at evaluating whether APOE genotype interacts with tau protein and glucose metabolism dysfunctions to affect the pathological process. Methods: For this retrospective observational study, 1350 patients were recruited and underwent a complete clinical investigation, neuropsychological assessment, lumbar puncture for CSF biomarkers analysis and APOE genotyping. Results: 607 patients fulfilled the clinical criteria of mild cognitive impairment or early dementia. In A+T- patients (n=350) DM did not influence CSF biomarkers levels, while among A+T+ patients (n=257) those with DM showed increased t-Tau levels compared to non-DM patients (DM: 919.4±444 vs non-DM: 773.1±348.2; p=0.04), but similar p-Tau (p=0.72) and Aβ1-42 levels (p=0.83). Furthermore, multivariable regression analyses showed a significant association between diabetes and t-Tau CSF levels, adjusting for age and sex, in APOE E4+ carriers (Coef. 222.83, CI 95% 47.49-398.1, p=0.01) but not in APOE E4- (p=0.53). Conclusions: Our work shows a clear dependency of CSF t-Tau levels on diabetes for APOE E4+ AD patients, suggesting important differences between APOE E4 related and non-related disease, with key implications for AD pathophysiology and treatment.