Vascular Risk and β-Amyloid Are Synergistically Associated with Cortical Tau

Abstract

Objective: Neuropathological studies have demonstrated that cerebrovascular disease and Alzheimer disease (AD) pathology frequently co-occur in older adults. The extent to which cerebrovascular disease influences the progression of AD pathology remains unclear. Leveraging newly available positron emission tomography (PET) imaging, we examined whether a well-validated measure of systemic vascular risk and β-amyloid (Aβ) burden have an interactive association with regional tau burden.

Methods: Vascular risk was quantified at baseline in 152 clinically normal older adults (mean age = 73.5 ± 6.1 years) with the office-based Framingham Heart Study cardiovascular disease risk algorithm (FHS-CVD). We acquired Aβ (¹¹ C-Pittsburgh compound B) and tau (¹⁸ F-flortaucipir) PET imaging on the same participants. Aβ PET was performed at baseline; tau PET was acquired on average 2.98 ± 1.1 years later. Tau was measured in the entorhinal cortex (EC), an early site of tau deposition, and in the inferior temporal cortex (ITC), an early site of neocortical tau accumulation associated with AD. Linear regression models examined FHS-CVD and Aβ as interactive predictors of tau deposition, adjusting for age, sex, APOE ε4 status, and the time interval between baseline and the tau PET scan.

Results: We observed a significant interaction between FHS-CVD and Aβ burden on subsequently measured ITC tau (p < 0.001), whereby combined higher FHS-CVD and elevated Aβ burden was associated with increased tau. The interaction was not significant for EC tau (p = 0.16).

Interpretation: Elevated vascular risk may influence tau burden when coupled with high Aβ burden. These results suggest a potential link between vascular risk and tau pathology in preclinical AD. Ann Neurol 2019; 1-8 ANN NEUROL 2019;85:272-279.

Figure 1.. Plots demonstrating the interaction between the Framingham Heart Study cardiovascular disease risk score (FHS-CVD) and Aβ burden in relation to tau burden.

Plots illustrate the predicted trajectories from the full regression model adjusted for age, sex, APOE ε4 status, and the time interval between baseline and the tau PET scan. For visualization purposes, low and high levels of Aβ burden are represented based on distribution volume ratio (DVR) values at the 25^th percentile and 75^th percentiles, respectively. PET data were partial volume corrected. The interaction was significant for tau in the inferior temporal cortex (left panel), such that combined higher FHS-CVD and elevated Aβ burden was associated with higher tau burden in this region. The effect was not significant for tau in the entorhinal cortex (right panel). Shaded regions represent the 95% confidence interval for the regression line.

Figure 2.. Exploratory regional analyses depicting the interaction between the Framingham Heart Study cardiovascular disease risk score (FHS-CVD) and Aβ burden on tau burden.

FreeSurfer-defined regions in which the interaction of FHS-CVD and Aβ correlated significantly with regional tau deposition. Regions were averaged across left and right hemispheres. In all regions shown, combined higher FHS-CVD and elevated Aβ was associated higher tau burden. Color bars indicate the t-statistic for the association, adjusting for age, sex, APOE ε4 status, and the time interval between baseline and the tau PET scan. Regions shown are p < 0.05 corrected for multiple comparisons (FWE).