Associations between Vascular Function and Tau PET Are Associated with Global Cognition and Amyloid

Abstract

Tau pathology and vascular dysfunction are important contributors to Alzheimer's disease (AD), but vascular-tau associations and their effects on cognition are poorly understood. We investigated these associations in male and female humans by conducting voxelwise comparisons between cerebral blood flow (CBF) and tau positron emission tomography (PET) images in independent discovery [cognitively normal (CN), 19; mild cognitive impairment (MCI) risk, 43; MCI, 6] and replication (CN,73; MCI, 45; AD, 20) cohorts. In a subgroup, we assessed relationships between tau and soluble platelet-derived growth factor β (sPDGFRβ), a CSF marker of pericyte injury. We tested whether CBF/sPDGFRβ-tau relationships differed based on Montreal Cognitive Assessment (MoCA) global cognition performance, or based on amyloid burden. Mediation analyses assessed relationships among CBF/sPDGFRβ, tau, and cognition. Negative CBF-tau correlations were observed predominantly in temporal-parietal regions. In the replication cohort, early negative CBF-tau correlations increased in spatial extent and in strength of correlation with increased disease severity. Stronger CBF-tau and sPDGFRβ-tau correlations were observed in participants with greater amyloid burden and lower MoCA scores. Importantly, when stratifying by amyloid status, stronger CBF-tau relationships in individuals with lower MoCA scores were driven by amyloid⁺ participants. Tau PET was a significant mediator CBF/sPDGFRβ-MoCA relationships in numerous regions. Our results demonstrate vascular-tau associations across the AD spectrum and suggest that early vascular-tau associations are exacerbated in the presence of amyloid, consistent with a two-hit model of AD on cognition. Combination treatments targeting vascular health, as well as amyloid-β and tau levels, may preserve cognitive function more effectively than single-target therapies.SIGNIFICANCE STATEMENT Emerging evidence demonstrates a role for vascular dysfunction as a significant contributor to Alzheimer's pathophysiology. However, associations between vascular dysfunction and tau pathology, and their effects on cognition remain poorly understood. Multimodal neuroimaging data from two independent cohorts were analyzed to provide novel in vivo evidence of associations between cerebral blood flow (CBF), an MRI measure of vascular health, and tau pathology using PET. CBF-tau associations were related to cognition and driven in part by amyloid burden. Soluble platelet-derived growth factor β, an independent CSF vascular biomarker, confirmed vascular-tau associations in a subgroup analysis. These results suggest that combination treatments targeting vascular health, amyloid-β, and tau levels may more effectively preserve cognitive function than single-target therapies.

Keywords: PET imaging; amyloid; cerebral blood flow; cognition; pericyte; tau.

Figure 1.

CBF and tau are negatively correlated in discovery and replication analyses. A, Clusters shown in blue color scale depict significant negative correlations between CBF (normalized by global gray matter CBF) and FTP SUVR in the discovery cohort (n = 68). B, Blue clusters show significant CBF–tau correlations in the ADNI replication cohort (n = 138), masked with significant results from the discovery analysis (A). All analyses were covaried for age, sex, diagnosis, and amyloid CL. CL calibration is shown in Extended Data Figures 1-1 and 1-2. For visualization purposes, average values from selected significant clusters were extracted, adjusted for covariates, and plotted below each analysis. Coordinates and statistics for all significant clusters are listed in Extended Data Figure 1-3. Note: because the voxelwise statistical threshold was set at p < 0.001, the p value for each of the plots is <0.001.

Figure 2.

CBF and tau are negatively correlated in secondary gray matter-masked ADNI analyses. A, Clusters shown in blue color scale depict significant negative correlations between CBF (normalized by global gray matter CBF) and FTP SUVR across the whole group (n = 138). B, Blue clusters show significant CBF–tau correlations in the ADNI AD-MCI subgroup (n = 65). C, Significant negative CBF–tau correlations in the ADNI CN subgroup (n = 73). All analyses were covaried for age, sex, and amyloid CL (and diagnosis in A and B). For visualization purposes, average CBF and FTP SUVRs from selected significant clusters in the voxelwise analysis were extracted, adjusted for covariates, and plotted below voxelwise results. Coordinates and statistics for all significant clusters are listed in Extended Data Figure 2-1. Note: because the voxelwise statistical threshold was set at p < 0.001, the p value for each of the plots is <0.001. EC – entorhinal cortex; IPL/SPL – inferior/superior parietal lobe; SMG – supramarginal gyrus; mPFC – medial prefrontal cortex.

Figure 3.

Participants with low global cognition show stronger relationships between CBF and sPDGFRβ. A–D, MoCA * CBF interaction effects on FTP SUVR in discovery (A), replication (B), and secondary GM-masked ADNI (C) analyses. MoCA * sPDGFRβ interaction effects on FTP SUVR from discovery analysis ROIs (D). Average CBF and FTP from significant clusters in the voxelwise analysis, or CSF sPDGFRβ, were entered into GLMs. The predicted FTP SUVRs from the models are plotted against regional CBF (normalized by global gray matter CBF) or sPDGFRβ (D). All analyses were covaried for age, sex, diagnosis, gray matter volume, and amyloid CL. MoCA was entered as a continuous variable in the model, but for visualization purposes a median split was used to group participants into a low-MoCA score group (shown in purple) and a high-MoCA score group (shown in green). Detailed statistics for all MoCA * CBF/sPDGFRβ interaction terms are listed in Extended Data Figure 3-1. Plots for AD-MCI and CN subgroups of the ADNI replication cohort are displayed in Extended Data Figure 3-2. Note: the p values shown on the scatterplots is for display purposes only and is not a statistical result from the primary GLM analyses including MoCA as a continuous variable.

Figure 4.

Participants with high amyloid burden show stronger relationships between CBF and sPDGFRβ. A–C, Amyloid * CBF interaction effects on FTP SUVR in discovery (A), replication (B), and secondary GM-masked ADNI (C) analyses. D, Amyloid * sPDGFRβ interaction effects on FTP SUVR from discovery analysis ROIs. Average CBF and FTP SUVR from significant clusters in the voxelwise analysis, or CSF sPDGFRβ, were entered into GLMs. Predicted FTP SUVR from the models is plotted against regional CBF (normalized by global gray matter CBF) or sPDGFRβ (D). All analyses were covaried for age, sex, diagnosis, gray matter volume, and amyloid CL. Amyloid CL was entered as a continuous variable in the model, but for visualization purposes a median split was used to group participants into a low-amyloid group (shown in blue) and a high-amyloid group (shown in red). Detailed statistics for all amyloid * CBF/sPDGFRβ interaction terms are listed in Extended Data Figure 4-1. Plots for AD-MCI and CN subgroups of the ADNI replication cohort are displayed in Extended Data Figure 4-2. Note: the p values shown on the scatterplots is for display purposes only and is not a statistical result from the primary GLM analyses including amyloid CL as a continuous variable.

Figure 5.

Interactions between MoCA and CBF are stronger in amyloid⁺ individuals. Amyloid * CBF interaction effects on FTP SUVR in replication (A), and secondary GM-masked ADNI (B) analyses, split by amyloid status (amyloid⁺ on the left, amyloid^– on the right). Average CBF and FTP SUVR from significant clusters in the voxelwise analysis were entered into GLMs. Predicted FTP SUVR from the models is plotted against regional CBF (normalized by global gray matter CBF). All analyses were covaried for age, sex, diagnosis, gray matter volume, and amyloid CL. MoCA was entered as a continuous variable in the model, but for visualization purposes a median split was used to group participants into a low-MoCA group (shown in orange) and a high-MoCA group (shown in green). Detailed statistics for all MoCA * CBF/sPDGFRβ interaction terms for amyloid⁺ and amyloid^– groups are listed in Extended Data Figure 5-1. Plots for the AD-MCI subgroup of the ADNI replication cohort are displayed in Extended Data Figure 5-2. Note: the p values shown on the scatterplots is for display purposes only and is not a statistical result from the primary GLM analyses including MoCA as a continuous variable.

Figure 6.

In amyloid⁺ individuals, tau SUVR mediates the relationship between CBF/sPDGFRβ and MoCA. A, B, Mediation models assessing the relationship among CSF/sPDGFRβ, FTP SUVR, and MoCA in the whole USC (n = 68) or ADNI (n = 138) cohorts (A), and within the cohorts split by amyloid status (B). The a, b, and c′ path values are shown for one representative region, the temporal-parietal cortex, identified by the white stars on the surface projections below. Each region exhibiting a significant mediating effect is shown in red-yellow color scale on the surface projections. Mediation effects for the pathway displayed here (CBF/sPDGFRβ → tau PET → MoCA) were substantially stronger than for the alternative pathway (tau PET → CBF/sPDGFRβ → MoCA). Detailed results from the mediation analyses for model 1 and model 2, and model 1 split by amyloid status are listed in Extended Data Figures 6-1, 6-2, and 6-3.

Figure 7.

CBF and amyloid-β are negatively correlated. A–D, Clusters shown in blue colorscale depict significant negative correlations between CBF (normalized by global gray matter CBF) and FBB SUVR in the USC cohort (A; n = 68), in the entire ADNI cohort (B; n = 60), and in ADNI AD-MCI (C; n = 36) and CN (D; n = 24) subgroups. All analyses were covaried for age, sex, Braak stage 1-2 FTP SUVR, and diagnosis (A–C only). For visualization purposes, average values from selected significant clusters were extracted, adjusted for covariates, and plotted below each analysis. Note: because the voxelwise statistical threshold was set at p < 0.001, the p value for each of the plots is <0.001. S1/M1, primary somatosensory/motor cortex.