Structural tract alterations predict downstream tau accumulation in amyloid-positive older individuals

Abstract

Animal models of Alzheimer's disease have suggested that tau pathology propagation, facilitated by amyloid pathology, may occur along connected pathways. To investigate these ideas in humans, we combined amyloid scans with longitudinal data on white matter connectivity, hippocampal volume, tau positron emission tomography and memory performance in 256 cognitively healthy older individuals. Lower baseline hippocampal volume was associated with increased mean diffusivity of the connecting hippocampal cingulum bundle (HCB). HCB diffusivity predicted tau accumulation in the downstream-connected posterior cingulate cortex in amyloid-positive but not in amyloid-negative individuals. Furthermore, HCB diffusivity predicted memory decline in amyloid-positive individuals with high posterior cingulate cortex tau binding. Our results provide in vivo evidence that higher amyloid pathology strengthens the association between HCB diffusivity and tau accumulation in the downstream posterior cingulate cortex and facilitates memory decline. This confirms amyloid's crucial role in potentiating neural vulnerability and memory decline marking the onset of preclinical Alzheimer's disease.

Figure 1. The hypothesized model motivating our design and analyses

The relationships that were specifically analyzed in the current manuscript are within the blue box. The green boxes hypothesize that hippocampal volume loss is resulting from neuronal damage, partially due to early tau pathology in the medial temporal lobe. As tau PET was acquired later in the study and thus this information was not available at baseline, we could not examine the green boxes. The relationship between hippocampal volume and diffusivity of the hippocampal cingulum bundle was analyzed using both baseline measures of hippocampal volume and change in hippocampal volume over time. Abbreviations: MTL = medial temporal lobe, PCC = posterior cingulate cortex.

Figure 2. Associations between hippocampal volume and change in mean diffusivity in the HCB and UF

The orange boxes depict part of the model that is being investigated: we hypothesized that hippocampal volume predicts annual change in white matter diffusivity of the HCB (n= 256 unique participants) and not of the UF (n=253 unique participants). Figures below the models show the anatomical localization of the hippocampus (green), the HCB (red) and the UF (yellow) and the investigated link (arrow). The line plots (top row = left, bottom row = right hemisphere) show that right hippocampal volume predicted increased MD of the right HCB over time (left, bottom corner). No significant associations were found between hippocampal volume and changes in MD of the UF. In all line plots, estimated marginal means of the moderation by hippocampal volume are plotted at the mean and ± 1 standard deviation, but analyses were done continuously using linear mixed effects models. Shaded areas around the fit lines show the 95% confidence interval. All p-values are two-sided and unadjusted for multiple comparisons.

Figure 3. Associations between tract diffusivity and tau accumulation in the PCC or inferior temporal

The orange/pink boxes depict part of the model that is being investigated as depicted in Figure 1 (tract diffusivity predicting annual change in tau binding). The first column depicts first the anatomical localization of the HCB (red), the PCC (blue) and the investigated link (arrow). The line plots (top = left, bottom = right hemisphere) show that higher levels of MD in the right HCB predicted increased PCC tau accumulation (bottom left, in the black box, n=141 unique participants). The middle column shows the associations between the control tract, UF (yellow) and the PCC (blue). No significant associations were found for left or right, consistent with our hypothesis (n=139 unique participants). The right column shows the associations between the HCB (red) and the control tau region (IT cortex). No significant associations were found for left or right (n=141 unique participants). The zoomed in section at the bottom shows the link between amyloid pathology, tract diffusivity and annual change in PCC tau accumulation (model depicted in the boxes). The line plots show that the association between right HCB diffusivity and right PCC tau change is only found in amyloid positive individuals (right, n=36 unique participants) and not amyloid negative individuals (left, n=103 unique participants). In all line plots, time was defined at the time since the baseline MRI measurement and MD of the tracts is depicted in mean ± 1 standard deviation, but analyses were done continuously using linear mixed effects models. Shaded areas around the fit lines show the 95% confidence interval. All p-values are two-sided and unadjusted for multiple comparisons. Abbreviations: HCB = Hippocampal cingulum bundle, UF = uncinate fasciculus, PCC = Posterior cingulate cortex

Figure 4. Associations between tract diffusivity, tau accumulation in the PCC, amyloid pathology and memory performance

The colored boxes depict part of the investigated model in Figure 1. The line plots show the breakdown of the estimates from linear mixed models examining changes memory performance predicted by hippocampal cingulum tract diffusivity in low tau (left a, n=93 unique participants) and high tau (right a,n=48 unique participants) individuals. Panel b investigated the associations between right hippocampal cingulum diffusivity and memory performance in individuals with high PCC tau who either were amyloid negative (n=30 unique participants) or positive (n=18 unique participants). The plots show a significant change in memory in individuals with high PCC tau and high amyloid levels (n=18, right b). In all line plots, HCB MD is depicted in mean ± 1 standard deviation, but analyses were done continuously using linear mixed effects models. Shaded areas around the fit lines show the 95% confidence interval. All p-values are two-sided and unadjusted for multiple comparisons. Abbreviations: HCB = Hippocampal cingulum bundle, PCC = Posterior cingulate cortex, SUVr = Standardized uptake value ratio.