Association Between U-p53AZ Blood Biomarker and White Matter Microstructure in Early Alzheimer's Disease: A Cross-Sectional Study Using AlzoSure® Predict.

Background and Aims: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by early microstructural white matter (WM) damage, often preceding clinical symptoms. While cerebrospinal fluid (CSF) biomarkers provide valuable insights into AD pathology, they are invasive and may not reflect early WM changes. U-p53AZ, a conformational variant of p53 detected via the AlzoSure® blood assay, has emerged as a potential biomarker for early AD detection. This study aimed to investigate the association between AlzoSure® prediction scores and WM microstructural integrity in cognitively normal (CN) individuals and those with mild cognitive impairment (MCI), using diffusion tensor imaging (DTI). Secondary analyses explored parallels with established CSF biomarkers (Aβ₁₋₄₂, total tau, and p-tau181). Methods: We analyzed data from 106 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants (46 CN, 60 MCI) with available DTI and biomarker data. AlzoSure® scores were derived from plasma samples using immunoprecipitation. DTI metrics (fractional anisotropy, mean, axial, and radial diffusivity) were extracted from atlas-defined WM regions. Linear regression models, stratified by diagnosis and adjusted for age, gender, and polygenic hazard score, were used to examine associations between biomarkers and DTI indices. False discovery rate (FDR) correction was applied for multiple comparisons. Results: In the MCI group, higher AlzoSure® scores were significantly associated with reduced diffusivity metrics in the left cingulum hippocampal bundle, a region implicated in early AD-related disconnection. Parallel associations were observed with CSF t-tau and p-tau181 across other WM tracts in MCI. However, no associations remained significant after FDR adjustment. Conclusion: These findings underscore the potential of U-p53AZ, as measured by AlzoSure®, to capture early WM microstructural alterations particularly in individuals with MCI, aligning with tau-related pathology patterns. While exploratory, the results highlight U-p53AZ as a non-invasive candidate biomarker for early AD-related neurodegeneration. Larger, longitudinal studies are needed to validate its diagnostic and prognostic utility in preclinical and prodromal AD stages.