medRxiv (Medicine)
2026-06-24
DOI: HASH:660c4180edd5d5d939b0eb19d25ade8b
Background Greater cognitive intra-individual variability (IIV) reflects increased heterogeneous performance across cognitive domains and has been linked to a higher risk of Alzheimer's disease (AD). However, it remains unclear whether cognitive IIV is linked to heterogeneous dispersion of regional AD pathology. Hence, we aimed to examine the association between cognitive IIV and AD neuroimaging biomarker IIV. Methods This study included participants with normal cognition (CN) and mild cognitive impairment (MCI) from the Alzheimer's Disease Neuroimaging Initiative. Cognitive IIV was computed as the within-person standard deviation of five domain-specific neuropsychological test z-scores. Four neuroimaging biomarker IIV metrics were similarly derived using regional amyloid-{beta} (n = 1,021), tau (n = 719), cortical thickness (n = 2,148), and combined amyloid-tau-neurodegeneration (ATN, n = 258). Associations between cognitive IIV and each biomarker IIV were evaluated using linear regression models, adjusted for relevant covariates. Results Higher cognitive IIV was associated with greater biomarker IIV across amyloid-{beta} ({beta} = 0.039, SE = 0.014, p = .006), tau ({beta} = 0.196, SE = 0.033, p < .001), cortical thinning ({beta} = 0.036, SE = 0.008, p < .001), and ATN ({beta} = 0.176, SE = 0.043, p < .001). Interaction analyses revealed that the associations of cognitive IIV with tau IIV, cortical thickness IIV, and ATN IIV were stronger in MCI than CN individuals. Significant interactions between cognitive IIV and biomarker positivity status showed that the effect with amyloid-{beta} IIV was attenuated in A- ({beta} = 0.004, SE = 0.014, p = .78) but that the effect with tau IIV remained robust even in T- individuals ({beta} = 0.088, SE = 0.022, p < .001). Conclusion Elevated cognitive IIV is associated with greater heterogeneity in cortical dispersion of AD-related pathology, particularly in prodromal AD and in the presence of abnormal pathology. As a novel measure that captures variation in topographical scattering of AD pathological burden across the cortex, AD biomarker IIV may offer research and clinical utility beyond evaluating absolute biomarker load or thresholds.