Differential gray matter connectivity correlates of CSF biomarkers: Results from the EPAD Cohort

Abstract

AbstractBackgroundGray matter network (GMN) disruptions correlate with amyloid burden in the earliest stages of Alzheimer’s Disease (AD) pathology in cognitively unimpaired individuals. However, it remains unknown if and how hyperphosphorylated tau (p‐tau) influences GMNs. Here, we investigated the relation between GMNs and cerebrospinal fluid (CSF) p‐tau181 levels in non‐demented individuals from the European Prevention of Alzheimer Dementia (EPAD) cohort and evaluated whether this relationship is mediated by amyloid and Clinical Dementia Rating (CDR) status.MethodWe included 1198 participants from the EPAD v1500.0 release, who had both CSF biomarkers and structural MRI available. The cut‐off for amyloid‐β positivity (A+) was defined at <1000 pg/mL. Single‐subject network properties were extracted from 3D‐T1w MRI (Figure 1). Regional values were computed for 117 AAL atlas regions. Linear models were used to investigate main effects and interactions between amyloid status and p‐tau181 levels on global GMN measures. A three‐way interaction with CDR was modeled. Age, sex, site, total intracranial volume, and network size were included as covariates. Analyses were repeated for local network properties across AAL regions and FDR‐adjusted.ResultSample characteristics are provided in Table 1. A+ individuals had lower degree, clustering, gamma, and small world coefficients, and higher betweenness centrality (Figure 2). Higher p‐tau181 levels were associated with lower values of degree, betweenness centrality, lambda, and path length (Figure 3). Lambda, path length, and clustering showed an interaction effect of amyloid status and CDR on their relationship with p‐tau181 levels: A‐ individuals with CDR 0 had lower path length and lambda in association with tau, while A+ CDR 0.5 individuals with lower clustering coefficient values showed higher p‐tau181 (Figure 4). No associations were found for other GMN measures. Regional analysis showed a relationship of p‐tau181 with local path length in the precuneus (Figure 5).ConclusionGMN alterations show distinct associations with p‐tau181 levels, partially affected by amyloid and CDR status. Non‐amyloid related alterations of path length might be linked to axonal tau‐related changes. Clustering alterations seem instead to be linked to amyloid deposition and resulting local synaptic disconnectivity.