EFFECTIVE CONNECTIVITY WITHIN THE LEFT AND RIGHT EXECUTIVE CONTROL NETWORKS IN MCI AND AD

Abstract

Background: APOE ε4 has been linked to accelerated amyloid deposition and tau-tangle formation. We hypothesized that cognitively normal AD biomarker-negative individuals would exhibit synaptic dysfunction and subsequent resting-state functional connectivity (rs-fc) network disruptions related to the presence of APOE ε4. Methods: Using cross-sectional analyses, we examined rs-fc from 120 cognitively-normal adults (CDR 0) with negative CSFAb42, CSF ptau/Ab42, and PET (PiB-SUVR) according to established criteria (Hansson et al 2018). The cohort had a mean age of 76.4 years 67.59 years, 15% were APOE e4 carriers and 65% were female. All participants had cerebrospinal fluid (CSF) and positron emission tomography (PET) evaluations. Rs-fc were aggregated into canonical cortical networks based on defined criteria (Power et al 2011). A 298x298 connectivity matrix was generated and was then masked to examine only intra-hemispheric (i.e. lateralized) and inter-hemispheric (i.e. callosal) connections between APOE ε4 carriers/non-carriers, with particular focus on the default-mode, memory, and salience (i.e. DMS) networks. Results: Qualitative rs-fc differences observed in the group difference matrix (Fig. 1A) were quantified by averaging, with differences observed between (p1⁄4 0.03), not within (p1⁄4 0.08), the DMS cluster (Fig. 1B). Observed rs-fc differences were primarily due to a significant strengthening of lateralized versus callosal connections both within (p 1⁄4 0.02) and between (p 1⁄4 0.02) the DMS networks (Fig. 1C, Fig. 1D). We next modeled this dysfunction as a function of imaging and CSF biomarkers. First, participants were categorized using the amyloid, tau, neurodegeneration (A/T/N) CSF and imaging criteria (Jack et al, 2016), with subthreshold levels noted across all biomarkers (Fig. 2A). Next, a linear regression model of the rs-fc dysfunction revealed significant weighting for CSF ptau (p 1⁄4 0.05) and t-tau (p 1⁄4 0.05) but not for CSF Ab42 or PETPiB (Fig. 2B). Conclusions: Early changes in key rs-fc networks in cognitively-normal, AD biomarker-negative APOE ε4 carriers are driven by changes in local lateralized connections relative to long-range callosal connections. Linear modeling results are suggestive of an early role of tau in early network dysfunction in elderly asymptomatic APOE ε4 carriers without biomarker evidence of AD.