Abstract
Young adult APOE-ε4 carriers show increased activity in posterior regions of the default mode network (pDMN), but how this is related to structural connectivity is unknown. Thirty young adults (one half of whom were APOE-ε4 carriers; mean age 20 years) were scanned using both diffusion and functional magnetic resonance imaging. The parahippocampal cingulum bundle (PHCB)—which links the pDMN and the medial temporal lobe—was manually delineated in individual participants using deterministic tractography. Measures of tract microstructure (mean diffusivity and fractional anisotropy) were then extracted from these tract delineations. APOE-ε4 carriers had lower mean diffusivity and higher fractional anisotropy relative to noncarriers in PHCB, but not in a control tract (the inferior longitudinal fasciculus). Furthermore, PHCB microstructure was selectively associated with pDMN (and medial temporal lobe) activity during a scene discrimination task known to be sensitive to Alzheimer's disease. These findings are consistent with a lifespan view of Alzheimer's disease risk, where early-life, connectivity-related changes in specific, vulnerable “hubs” (e.g., pDMN) lead to increased neural activity. Critically, such changes may reflect reduced network efficiency/flexibility in APOE-ε4 carriers, which in itself may portend a faster decline in connectivity over the lifespan and ultimately trigger early amyloid-β deposition in later life.
Highlights
The default mode network (DMN) is a large-scale brain system displaying continuously high levels of coordinated activity in the resting state (Raichle, 2015)
Based on the view that posterior DMN (pDMN) vulnerability to Ab arises from its role as a large-scale connectivity hub (Buckner et al, 2009; de Haan et al, 2012), we asked whether young adults at heightened genetic risk for Alzheimer’s disease (AD) would show increased pDMN structural connectivity (Greicius et al, 2009). Supporting this hypothesis, we found that APOE-ε4 carriers, relative to noncarriers, had microstructural differences in the PHCBda white matter tract linking the pDMN with the medial temporal lobe (MTL), parahippocampal regions (Heilbronner and Haber, 2014)
Interindividual variation in parahippocampal cingulum bundle (PHCB) microstructure was selectively associated with pDMN activity during a scene discrimination task that is sensitive to early AD (Lee et al, 2006)
Summary
The default mode network (DMN) is a large-scale brain system displaying continuously high levels of coordinated activity in the resting state (Raichle, 2015). Based on its extensive connectivity with the medial temporal lobe (MTL) (Greicius et al, 2009; Heilbronner and Haber, 2014), it has been proposed that the pDMN anchors a posteromedial system involved in forming mental scenes, or “situation models” (Murray et al, 2016; Ranganath and Ritchey, 2012) Such models may underpin a range of cognitive processes that are affected in early AD, including episodic past/future thinking (Addis et al, 2009; Irish et al, 2015), spatial navigation (Lester et al, 2017), and complex scene discrimination (Lee et al, 2006)
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