Lower novelty‐related locus coeruleus function is associated with entorhinal tau‐mediated memory decline in older individuals.

Abstract

AbstractBackgroundThe locus coeruleus (LC) is considered one of the earliest regions accumulating hyperphosphorylated tau before this pathology emerges in the entorhinal cortex (EC). Recent animal work suggested that LC phasic activity, which can be induced with exposure to novelty, can protect the cognitive downstream effects of tauopathy. Here we investigate whether activity of the LC during novelty is associated with memory decline and whether this association is mediated by EC‐tau deposition.Method92 participants (51 F, mean age at imaging (baseline) = 69.55±10.17 years) from the Harvard Aging Brain Study underwent both longitudinal memory testing (mean follow‐up = 4.8±1.9 years) and PiB(Aβ)‐, FTP(tau)‐PET, and 3T task‐fMRI scans performed within 1 year of each other (mean time difference = 0.29±0.24 years). The fMRI‐task consisted of novel and repeated face‐name pairs that the participants were instructed to remember. Voxel‐wise mixed‐effects analyses were performed to detect regions exhibiting significant novelty‐related activation. Vertex‐wise linear regression analyses were used to detect significant associations between LC activity and cortical tau deposition. Both analyses were adjusted for age, sex and multiple comparisons (pcl<0.05). The association between LC activity and memory decline (composite, Fig. 3 caption) was evaluated using linear regression adjusted for age, sex and education. Mediation analyses were performed using a quasi‐Bayesian bootstrap (n = 1000) approach to investigate whether EC‐tau mediates the association and whether this mediation effect is moderated by Aβ status.ResultWe observed greater novelty‐related activation within the bilateral LC, amygdala, hippocampus, and fusiform and insular cortices (Fig. 1). LC activation was associated with tau in the EC, inferior‐temporal and fusiform cortices (confirmed by EC‐ROI analyses‐Fig. 2). Lower LC activation was associated with steeper memory decline (p<0.05‐Fig. 3a), and this association was found to be mediated by EC‐tau (p<0.05‐Fig. 3b). This mediation effect was significantly stronger for the Aβ+ compared to the Aβ– group (p<0.05‐Fig. 3c).ConclusionThis work demonstrates that lower LC activity is associated with tau deposition in the medial‐ and inferior‐temporal lobe, consistent with the spatial patterns of tau observed in preclinical Alzheimer’s disease. Moreover, our observation that EC‐tau mediates the relationship between LC activity and memory decline suggests that lower LC function may indicate risk associated with Alzheimer’s‐related processes.