Resting-State Network Alterations Differ between Alzheimer's Disease Atrophy Subtypes

Abstract

Several Alzheimer's disease (AD) atrophy subtypes were identified, but their brain network properties are unclear. We analyzed data from two independent datasets, including 166 participants (103 AD/63 controls) from the DZNE-longitudinal cognitive impairment and dementia study and 151 participants (121 AD/30 controls) from the AD neuroimaging initiative cohorts, aiming to identify differences between AD atrophy subtypes in resting-state functional magnetic resonance imaging intra-network connectivity (INC) and global and nodal network properties. Using a data-driven clustering approach, we identified four AD atrophy subtypes with differences in functional connectivity, accompanied by clinical and biomarker alterations, including a medio-temporal-predominant (S-MT), a limbic-predominant (S-L), a diffuse (S-D), and a mild-atrophy (S-MA) subtype. S-MT and S-D showed INC reduction in the default mode, dorsal attention, visual and limbic network, and a pronounced reduction of "global efficiency" and decrease of the "clustering coefficient" in parietal and temporal lobes. Despite severe atrophy in limbic areas, the S-L exhibited only marginal global network but substantial nodal network failure. S-MA, in contrast, showed limited impairment in clinical and cognitive scores but pronounced global network failure. Our results contribute toward a better understanding of heterogeneity in AD with the detection of distinct differences in functional connectivity networks accompanied by CSF biomarker and cognitive differences in AD subtypes.

Keywords: Alzheimer’s disease; brain structure; graph theory; independent component analysis; resting-state connectivity.

Figure 1

Atrophy regions in Alzheimer’s disease subtypes versus healthy control subjects across atrophy subtypes in the ADNI (A) and DELCODE (B) dataset. ^*Uncorrected P < 0.05; ^**FWE-corrected P < 0.05.

Figure 2

(A) Boxplots of the mean cognitive composite and cerebrospinal fluid biomarker normalized scores ±95% confidence interval (in z-scores). Significant post-hoc comparisons are shown with a line, top: sig. comparisons among the subtypes, bottom: sig. comparisons between HC and subtypes. (B) Spider plot of the estimated mean z-scores of INC in the resting-state networks. Z-scores of the HC are shown for comparison. Abbreviations: Aβ42, amyloid-β42; tTau, total tau; pTau, phosphorylated tau; INC, intrinsic network connectivity; SMN, sensorimotor network; ^*P (overall) < 0.05; Sig., significantly differing subgroups in post-hoc tests when FDR-corrected two-tailed P  (overall) < 0.05.

Figure 3

Differences between subtypes in degree and clustering coefficient in Brainnetome atlas derived regions of interest. Permutation based FDR-corrected two-tailed P < 0.05 are shown.