# Blood-brain barrier water exchange in relation to amyloid, cognition and cerebrovascular burden

## TL;DR

This study shows that changes in blood-brain barrier water exchange happen early in cognitive decline and are linked to vascular issues, not amyloid buildup.

## Contribution

Introduces BBB water exchange time as an early, non-invasive biomarker for cognitive decline and cerebrovascular burden.

## Key findings

- Tex decreases in subjective cognitive decline and mild cognitive impairment before changes in cerebral blood flow.
- Tex changes correlate with moderate white matter hyperintensities but not amyloid status.
- Tex alterations precede traditional perfusion markers and reflect early vascular dysfunction.

## Abstract

•BBB water exchange time (Tex) is reduced in early cognitive impairment.•Tex decreases with moderate white matter hyperintensities burden.•Tex changes precede hemodynamic changes in cognitive and cerebrovascular decline.•These Tex changes are independent of amyloid status after age and sex adjustment.

BBB water exchange time (Tex) is reduced in early cognitive impairment.

Tex decreases with moderate white matter hyperintensities burden.

Tex changes precede hemodynamic changes in cognitive and cerebrovascular decline.

These Tex changes are independent of amyloid status after age and sex adjustment.

Blood-brain barrier (BBB) water exchange may serve as a sensitive early biomarker for Alzheimer’s disease and age-related cognitive decline. This study applied a non-invasive multi-echo arterial spin labeling (ASL) technique to measure BBB water exchange time (Tex), cerebral blood flow (CBF), and arterial transit time (ATT) in 160 adults aged 50 years and older. Participants were classified as cognitively normal (CN), having subjective cognitive decline (SCD), or mild cognitive impairment (MCI). They were assessed for amyloid status and cerebrovascular burden. Compared to CN participants, Tex was significantly lower in both SCD (−9.5 %) and MCI (−14.5 %) groups, suggesting that reductions in BBB water exchange emerge early in the course of cognitive decline. In contrast, CBF was reduced only in MCI participants (−20.8 % compared to CN), and ATT was significantly increased only in individuals with severe cerebrovascular burden (Fazekas score 3). Notably, Tex showed a stepwise decrease with increasing Fazekas scores (1–2), supporting its sensitivity to moderate small vessel disease. No associations were found between Tex and amyloid positivity after adjusting for age and sex. These findings indicate that Tex alterations may precede changes in traditional perfusion markers and are more closely related to vascular and early cognitive changes than to amyloid pathology. BBB water exchange mapping may therefore provide a promising, non-invasive tool to detect early neurovascular dysfunction that contributes to cognitive decline in aging populations, potentially offering a useful biomarker for early intervention trials targeting vascular contributions to dementia.