Local amyloid-b toxicity on large intrinsic brain networks in cognitively healthy elderly


      Considerable in vitro and animal data suggests that Aβ, even in the absence of tau tangles, has adverse effects on neuronal dysfunction, supporting the hypothesis that neuronal dysfunction is due in part to direct Aβ toxicity that is not completely mediated by tau. Although previous studies demonstrated the effects of global Aβ burden on the default mode network in cognitively normal elderly individuals, effects of local network Aβ burden on the other large-scale intrinsic connectivity networks (ICNs) are not yet clear in asymptomatic individuals. In this study, we aimed to investigate the effects of both global and local Aβ deposition on various cortical ICNs in older adults with normal cognition.


      Fifty-three elderly subjects with normal cognition were included. We characterized the association of Aβ burden with intrinsic connectivity changes in a wide range of functional networks, including working memory, attention, motor and perceptual timing, and visual detection networks, as well as resting-state default mode network. Aβ deposition was quantified both globally, and also within ICN-specific cortical regions.


      We found that even in the absence of any cognitive or structural changes, global cortical Aβ burden was associated with functional connectivity in the DMN as well as cortical networks involved in executive control, motor and perceptual timing, and visual detection but not salience processing, attention, and working memory. We also found that there were significant effects of local network Aβ burden (i.e., ICN Aβ burden) on the network functional connectivity for all ICNs considered in this study; and the effects were associated more closely to local network Aβ burden than global Aβ burden.


      The relationship between local network Aβ burden and disrupted intrinsic connectivity in various brain networks, in the absence of cognitive deficit and brain atrophy (and presumably absence of cortical tau tangles and neurodegeneration based on previous pathology reports), suggests that neuronal dysfunction may be due to local toxicity of Aβ independent of the presence of tau. Furthermore, the results suggest that local toxicity of Aβ may represent an early change in preclinical AD.
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      Figure 1Spatial maps of the ICNs of interest identified by seed-to-voxel based analysis of Aβ– and ApoE ε4 non-carrier subjects.
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      Figure 2Voxel-based maps of latent variables inferred by partial least squares regression analyses of functional connectivity and global Aβ burden associations.
      TableCoefficients of determination (R2) of the endogenous latent variables inferred by partial least squares regression analyses to assess the amount of variance in functional connectivity explained by global Aβ burden and ICN Aβ burden.
      Global Aβ burden
      ICN Aβ burden
       Default mode network (DMN)
       Dorsal attention network (dAN)
       Episodic memory network (EMN)
       Executive control network (ECN)
       Salience processing network (SPN)
       Sensory motor network (SMN)
       Supplementary motor area network (SMA)
       Visual network (VN)