Tau mediates the impact of amyloid and vascular disease burden on the trajectory of clinical symptoms.

INTRODUCTION: Amyloid (A) and vascular (V) pathologies often co-occur and progress over decades. We leveraged chronicity, defined as the years above a biomarker-positivity threshold, to examine how the timing of A and V relates to cognitive decline. METHODS: We modeled Clinical Dementia Rating-Sum of Boxes (CDR-SB) trajectories in n = 558 participants with [C-11] Pittsburgh compound B positron emission tomography (PET), magnetic resonance imaging-derived white matter hyperintensities (WMHs), and longitudinal CDR assessments. In n = 500 with MK6240 PET, we tested whether tau mediates A-V associations with CDR-SB in a moderated mediation framework. RESULTS: Whether biomarker "burden" was modeled as chronicity (A+years, V+years), or estimated amyloid and WMH at CDR visits, significant interactions showed a synergistic effect of WMHs and amyloid on accelerated CDR-SB trajectories. Tau significantly mediated these associations. DISCUSSION: Operationalizing chronicity clarifies how long individuals have exceeded A and V thresholds and improves clinical interpretability. WMH accumulation exacerbates amyloid-related cognitive decline. Longitudinal tau imaging could further inform staging and intervention timing. HIGHLIGHTS: Longer amyloid (A) and vascular disease (V) chronicity were associated with faster cognitive decline, emphasizing the importance of considering chronic exposure to these pathologies. Individuals with higher V burden experienced a steeper decline in cognition in the presence of A pathology, highlighting the interaction between V and neurodegenerative processes. Progression from early to mild dementia was faster with greater white matter hyperintensity chronicity, even when A duration was held constant, supporting the idea that V pathology amplifies the clinical impact of amyloid in Alzheimer's disease. Tau accumulation played a significant mediating role in linking A and V burden to cognitive decline, suggesting that tau pathology is a critical downstream factor in symptom progression. Person-level chronicity estimates of A and V provide a more precise understanding of cognitive decline trajectories, offering insights for early intervention strategies.