Uncovering distinct spatiotemporal trajectories of T‐N mismatch subtypes with likely co‐pathology in Alzheimer's disease using event‐based modeling

INTRODUCTION: In Alzheimer's disease (AD), tau-neurodegeneration (T-N) mismatch has been proposed to reflect non-AD processes such as transactive response DNA binding protein 43 kDa and vascular disease. We aimed to characterize the spatiotemporal trajectories of T-N mismatch that may reflect non-AD progression. METHODS: We performed T-N regression on 710 Alzheimer's Disease Neuroimaging Initiative participants using cortical thickness and 18F-flortaucipir uptake across 20 cortical regions. SuStaIn, a data-driven phenotype discovery and staging algorithm, was applied to standardized T-N residuals in canonical (N∼T) and vulnerable (N > T) cases. RESULTS: SuStaIn identified three vulnerable subtypes with distinct N > T progression patterns. The posterior and anterior subtypes displayed different, but progressively diffuse mismatch patterns, while the limbic subtype exhibited temporal-limbic progression. Subtypes and SuStaIn stages were associated with distinct clinical features. Their longitudinal trajectories aligned with SuStaIn inferred progression. DISCUSSION: Findings support that T-N mismatch progression captures specific co-pathological processes.