Tau accumulation and degeneration differ across functional networks in atypical Alzheimer's disease phenotypes

Abstract

AbstractBackgroundRecent models of Alzheimer's disease (AD) posit that pathogenic tau propagates through interconnected structural networks, suggesting amnestic and non‐amnestic AD (aAD & naAD) phenotypes could reflect differential involvement of functional networks. We tested this hypothesis by contrasting longitudinal grey matter (GM) atrophy and tau accumulation across AD clinical phenotypes in 7 canonical functional networks.MethodsWe analyzed longitudinal 3‐Tesla T1‐weighted MRI from 122 patients [aAD=49; logopenic primary progressive aphasia (lvPPA)=31; posterior cortical atrophy (PCA)=23; behavioral/dysexecutive AD (bvAD)=6; corticobasal syndrome (CBS)=6; mixed naAD=4] with autopsy or CSF evidence of AD pathology and 91 cognitively normal controls (Table 1). Thirty‐one patients (aAD=9; lvPPA=7; PCA=9; bvAD=2; CBS=3; naAD=1) had longitudinal flortaucipir PET (FTP‐PET) data. We computed baseline values and annualized change for GM volume and FTP‐PET standardized uptake value ratios (SUVRs) in the 100‐label, 7‐network parcellation of Schaefer et al. (2018). Linear mixed effects models (α=0.05, corrected) adjusting for MMSE assessed group differences in atrophy and tau accumulation.ResultsAll groups exhibited significant baseline and longitudinal atrophy vs. controls in multiple networks (Figs. 1‐2). Differences in longitudinal atrophy rate (Fig. 2) were observed in the dorsal attention network [PCA>lvPPA, t(371)=3.1, p<0.04], salience network [PCA>aAD, t(371)=3.1, p<0.04], and limbic network [CBS>aAD, t(371)=3.3, p<0.02; CBS>bvAD, t(371)=3.7, p<0.006]. PCA patients exhibited FTP‐PET SUVR increases in all networks (all p<0.02), while aAD patients displayed increases in all networks except visual and limbic (all others p<0.0001). LvPPA patients exhibited net SUVR increases only in the somatomotor network [t(97)=3.5, p<0.001]. At baseline, lvPPA patients had left > right atrophy in all networks [all t>3.7, p<0.0002]; right > left atrophy was observed in the visual network for PCA and CBS; the salience network for PCA and bvAD; and in the dorsal attention, frontoparietal control, and default mode networks for bvAD [all t>3.0, p<0.03]. In longitudinal analyses, no hemispheric differences were found in rates of GM volume loss or FTP‐PET change.ConclusionAD clinical variants exhibited GM atrophy and tau accumulation in partially overlapping networks. Investigating early‐stage disease will be crucial for assessing whether disease spread through canonical functional networks can explain anatomic differences in aAD and naAD phenotypes.