Cerebral blood flow is associated with plasma and PET biomarkers of tau pathology in middle age

Abstract

Cerebrovascular dysfunction is associated with risk and progression of Alzheimer's disease, but the extent to which it promotes Alzheimer's pathophysiology is unclear. Understanding the relationship between cerebrovascular dysfunction and Alzheimer's disease markers in midlife is critical to inform our understanding of the earliest manifestations of the disease and prevention strategies. We examined the association of cerebral blood flow with two biomarkers of tau pathophysiology, plasma phosphorylated tau 181 (p-tau181) concentrations and tau PET MK6240 standard uptake value ratio. This was a cross-sectional study of participants in the Offspring Study in upper Manhattan. Analyses included arterial spin labelling MRI, plasma p-tau181 concentration and 18F-MK-6240 tau PET data in the entorhinal cortex. Four hundred and fifty-nine participants (54.8 ± 10.8 years old, 63.3% women) had available MRI and plasma p-tau181 data, and 98 (60.4 ± 5.8 years old, 61.2% women) had additional tau PET data. Lower cerebral blood flow was associated with both higher plasma p-tau181 concentration and entorhinal cortex tau standard uptake value ratio. Higher plasma p-tau181 levels were associated with small clusters of lower regional cerebral blood flow, primarily in regions that correspond to sites of early Alzheimer's disease pathology. Higher tau PET levels were associated with lower cerebral blood flow throughout the brain. These findings suggest that there is relationship between cerebral blood flow and indicators of tau pathophysiology in middle age that is likely bidirectional.

Keywords: Alzheimer’s disease; biomarkers; blood flow; neuroimaging; tau.

Graphical Abstract

Figure 1

Surface-based correlation analyses and effect size. This figure illustrates the results of surface-based correlation analyses and their corresponding effect sizes. (A) Clusters of significant negative correlation between CBF and plasma p-tau181. (B) Effect size of the CBF and plasma p-tau181 correlation shown in A. (C) Clusters of negative correlation between CBF and tau SUVR in the entorhinal cortex. (D) Effect size of the CBF and tau SUVR correlation shown in C. The colour scale for effect size ranges from purple to orange, representing the magnitude of correlations in both directions. Darker colours indicate stronger correlations, while lighter colours represent weaker correlations. Grey areas in the template colour represent regions with zero or near-zero correlations. Sample sizes: plasma p-tau181 group (A and B): n = 459; tau PET SUVR group (C and D): n = 98.

Figure 2

Pairwise correlations between regional CBF and plasma p-tau181 concentration. Bar plot (left) illustrating the pairwise Pearson correlations between CBF and plasma p-tau181 across brain regions (n = 459). The colour scheme indicates the directionality and strength of the correlations: blue represents negative correlations and red represents positive correlations, and the colour intensity corresponds to the strength of the correlation. Asterisks (*) denote statistically significant correlations (P < 0.05). Scatter plots (right) show individual data points for the statistically significant correlations.

Figure 3

Pairwise correlations between regional CBF and entorhinal cortex tau SUVR. Bar plot (left) illustrating the pairwise Pearson correlations between CBF and entorhinal cortex tau SUVR across brain regions (n = 98). The x-axis represents the Pearson correlation coefficient values, while the y-axis displays the brain regions. The colour scheme indicates the directionality and strength of the correlations: blue represents negative correlations and red represents positive correlations, and the colour intensity corresponds to the strength of the correlation. Asterisks (*) denote statistically significant correlations (P < 0.05). Scatter plots (right) show individual data points for the statistically significant correlations.