Phases of Hyperconnectivity and Hypoconnectivity in the Default Mode and Salience Networks Track with Amyloid and Tau in Clinically Normal Individuals

Abstract

Alzheimer's disease (AD) is characterized by two hallmark molecular pathologies: amyloid aβ_1-42 and Tau neurofibrillary tangles. To date, studies of functional connectivity MRI (fcMRI) in individuals with preclinical AD have relied on associations with in vivo measures of amyloid pathology. With the recent advent of in vivo Tau-PET tracers it is now possible to extend investigations on fcMRI in a sample of cognitively normal elderly humans to regional measures of Tau. We modeled fcMRI measures across four major cortical association networks [default-mode network (DMN), salience network (SAL), dorsal attention network, and frontoparietal control network] as a function of global cortical amyloid [Pittsburgh Compound B (PiB)-PET] and regional Tau (AV1451-PET) in entorhinal, inferior temporal (IT), and inferior parietal cortex. Results showed that the interaction term between PiB and IT AV1451 was significantly associated with connectivity in the DMN and salience. The interaction revealed that amyloid-positive (aβ⁺) individuals show increased connectivity in the DMN and salience when neocortical Tau levels are low, whereas aβ⁺ individuals demonstrate decreased connectivity in these networks as a function of elevated Tau-PET signal. This pattern suggests a hyperconnectivity phase followed by a hypoconnectivity phase in the course of preclinical AD.SIGNIFICANCE STATEMENT This article offers a first look at the relationship between Tau-PET imaging with F¹⁸-AV1451 and functional connectivity MRI (fcMRI) in the context of amyloid-PET imaging. The results suggest a nonlinear relationship between fcMRI and both Tau-PET and amyloid-PET imaging. The pattern supports recent conjecture that the AD fcMRI trajectory is characterized by periods of both hyperconnectivity and hypoconnectivity. Furthermore, this nonlinear pattern can account for the sometimes conflicting reports of associations between amyloid and fcMRI in individuals with preclinical Alzheimer's disease.

Keywords: AV1451; DMN; PiB; Tau; amyloid; fcMRI.

Figure 1.

Visualization of the PiB × IT AV1451 interaction term vs DMN connectivity (left) and salience (SAL) connectivity (right). Both networks show a significant quadratic pattern that can be described as a positive relationship with amyloid when the IT AV1451 signal is low and as a negative association with the IT AV1451 signal when the PiB signal is high. The significant interaction is driven in large part by the relatively elevated connectivity seen in high-PiB low-IT AV1451 participants (triangular points near the middle of the x-axis).

Figure 2.

The top two panels show the relationship between inferior temporal (IT) AV1451 signal in the high PiB group (top) with DMN connectivity (left) and salience (SAL) connectivity (right). Within the context of high amyloid level, increased levels of IT AV1451 are associated with decreased connectivity in the DMN and SAL networks. The bottom two panels show the association between amyloid burden in the low-IT AV1451 signal subjects (median split) with DMN connectivity (left), and SAL (right). These two effects, the positive effect of amyloid when the IT AV1451 signal is low and the negative effect of IT AV1451 signal when amyloid level is high, account for the observed interaction effect and the absence of main effects.

Figure 3.

Node-level analysis of the IT AV1451 × PiB interaction term on connectivity between each pair of nodes. Lines on the outside of the figure correspond to within network connections. Lines on the inside correspond with between network connections. Purple colors represent decreased connectivity (movement toward 0); yellow colors represent increased connectivity (movement away from 0). Only connections with an effect of p < 0.01 are shown. The patterns of significant nodes correspond well to the whole-network analysis and demonstrate that the sensitivity to AV1451 and PiB is largely focused within and between the DMN and salience (SAL).