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NETWORK-BASED TAU DEPOSITION PATTERNS ARE RELATED TO FUNCTIONAL NETWORK FAILURE LARGELY VIA BETA-AMYLOID ACROSS THE ALZHEIMER’S SPECTRUM

      Background

      The cascading network failure model of Alzheimer’s disease (AD) pathophysiology hypothesizes that synaptic activity related to shifts in large-scale functional network organization is causally related to observed beta-amyloid accumulation via alteration in amyloid precursor protein processing. Once the large-scale network reorganization interacts with vulnerable brain systems, a tau-related neurodegenerative process initiates within that system. To test these predications we investigated the relationship between Tau-PET, task-free fMRI, and beta amyloid-PET in a cross-sectional sample spanning the Alzheimer’s disease spectrum.

      Methods

      Tau-PET (AV-1451), beta amyloid-PET (PiB), and TF-fMRI were obtained in a cohort of subjects across the AD spectrum (n = 218). All subjects who were clinically impaired (MCI = 12, dementia = 29) had PiB SUVR > 1.5. Tau-PET scans were intensity normalized to the cerebellar gray matter, spatially normalized to standard space, and smoothed. An independent component analysis was performed, with biologically relevant components being identified via a strong amyloid effect (Bonferroni corrected p < 0.01). A goodness-of-fit (GOF) analysis of these components with a functional connectivity atlas was then performed. Tau-PET memory system component scores were included in a mediation analyses with PiB-PET and a marker of functional network failure we term the network failure quotient (NFQ).

      Results

      Five biologically relevant tau-PET components were identified. These components had high GOF scores with visual, executive, and memory-related networks likely reflecting phenotypic heterogeneity in the AD cohort given the visual and executive components were associated with age-of-onset, but the memory component was elevated in cases independent of age-of -onset (Figure). The memory-related Tau-PET component was associated with PiB-PET (beta=0.59, p<0.001) and NFQ (beta = 0.30, p<0.001). A mediation analysis showed a strong mediation effect by PiB-PET (mediation effect [95% CI] = 0.85 [0.23, 1.41], p<0.001) on the relationship between NFQ and tau-PET (direct effect [95% CI] = 0.30 [-0.01, 0.57], p = 0.08).

      Conclusions

      Tau deposits in visual, executive, and memory-related networks which may reflect phenotypic heterogeneity in AD. Consistent with the CNF model of AD, direct examination of tau-PET and functional connectivity in the same subjects demonstrates a strong association of network failure with tau that is largely mediated by beta-amyloid.
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      FigureThe spatial extent of the five biologically relevant Tau-PET independent components are overlaid on orthogonal slices of a template brain (color bar encodes z-score from -5 to 5). The cognitive associations of the functional connectivity atlas components associated with each Tau-PET pattern are listed above. Inset, the component scores are plotted vs. age-of-onset for the dementia cases. Note that the memory Tau-PET component is elevated across age-of-onset.