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

## TL;DR

The study shows that both amyloid and vascular disease burdens contribute to faster cognitive decline, with tau pathology acting as a key mediator in Alzheimer's disease progression.

## Contribution

The novel contribution is demonstrating that tau mediates the combined effect of amyloid and vascular disease on cognitive decline trajectories.

## Key findings

- Longer amyloid and vascular disease chronicity are linked to faster cognitive decline.
- Tau accumulation mediates the relationship between amyloid and vascular burden and cognitive decline.
- White matter hyperintensity chronicity accelerates dementia progression even when amyloid duration is constant.

## Abstract

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.

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.

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.

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.

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.

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.