Biomarkers

Altered plasma sphingomyelin levels have been associated with Alzheimer's disease (AD), indicating disruptions in lipid metabolism and their potential link with AD pathogenesis. Meanwhile, tau-related neuronal damage and neurodegeneration result in the release of neuronal tau protein into the bloodstream, reflected predominantly as plasma total-Tau. Exploring the relationship between sphingomyelin metabolism and tau release before symptom onset could offer valuable insights into the biochemical pathways linked to AD and support the development of improved diagnostic and therapeutic strategies.

The current study embraced plasma sample analysis using a Biocrates-based targeted mass-spectrometry platform to measure sphingomyelin levels and a single-molecule array (Simoa) platform to quantify total-Tau levels. The participants involved in this study were from the KARVIAH cohort -100 cognitively normal (CN; MoCA≥26 & MMSE≥26) older adults who underwent positron emission tomography (PET) to assess cortical amyloid-beta (Aβ) load and were grouped as CN Aβ- (normal cortical-Aβ load) and CN Aβ+ (higher cortical-Aβ load). This study examined cross-sectional correlations between plasma sphingomyelins and total-Tau levels within each group. Sphingomyelins associated with total-Tau were further analysed for their relationship with cortical-Aβ load. All statistically significant correlations were assessed for correction for AD-related confounding variables, containing gender, age, body mass index (BMI), and APOE ε4 status, with additional amendments for the false discovery rate (FDR).

Statistically significant positive correlations between sphingomyelins and total-Tau levels were observed exclusively in CN Aβ+ individuals. These associations remained robust after adjusting for AD-related confounding variables and correcting for the FDR. Further analysis revealed significant inverse associations between total-Tau-associated sphingomyelins and cortical-Aβ load, observed only in CN Aβ+ individuals, both with and without adjustment for confounding variables and FDR correction.

Elevated plasma total-Tau levels were associated with higher plasma sphingomyelins exclusively in CN Aβ+ individuals, suggesting a link between tau release from neuronal damage and sphingomyelin-associated biochemical pathways in the presymptomatic stage of AD. Furthermore, higher levels of total-Tau-associated sphingomyelins in plasma were correlated with lower cortical-Aβ load in CN Aβ+ individuals, likely reflecting early sphingomyelin-mediated compensatory mechanisms against AD pathogenesis. These findings highlight the potential of total-Tau-associated sphingomyelins as markers for understanding the mechanisms involved in presymptomatic AD.