Spatiotemporal Assessment of Locus Coeruleus Integrity Predicting Cortical Tau and Cognition

Abstract

AbstractBackgroundMisfolded tau protein, an Alzheimer’s Disease (AD) hallmark, accumulates decades before the emergence of cognitive decline. Autopsy and neuroimaging studies support the locus coeruleus (LC) as an early site of tau and its contribution to disease progression. However, whether tau in LC precedes cortical tau deposition remains unclear. Understanding the topography of tau progression and the biological factors making specific neuronal systems prone to AD‐related pathology is essential to target interventions appropriately. We examined the spatiotemporal relationships between LC integrity and cortical tau accumulation and its relevance to cognition.,MethodsWe combined longitudinal LC‐integrity (T1‐TSE‐imaging) and tau pathology (18F‐FTP‐PET) data from 77 adults (Fig1A). We used whole‐brain voxel‐wise GLM analysis to investigate the relationship between baseline LC‐integrity (inverted signal) and longitudinal tau accumulation and compared the correlation distributions in both directions. Robust regression analysis was used to examine whether the observed tau spreading pathway predicts PACC5 performance at follow‐up. We used neuropathological measures from 160 cognitively unimpaired or MCI/AD adults (Fig1B) to support the in‐vivo neuroimaging data. Spearman‐rank partial correlations were used to relate LC tangle density to tangles in temporal cortex areas. Using AHBA, the biological backgrounds underlying the connectomic‐genetic relationships related to LC were explored using a whole‐brain region‐wise transcriptomic similarity analysis.,ResultsCorrelations between baseline LC‐integrity and follow‐up tau were stronger than the inverse correlations, indicative of lower LC‐integrity preceding tau accumulation in MTL (Fig1C‐D). LC tangle density was strongly related to tangles in MTL structures (Fig1E). Longitudinal tau accumulation in the LC‐MTL axis is associated with lower cognitive performance (Fig2). Common neurogenetic profiles exist between LC and MTL/limbic regions, supporting a shared connectomic‐transcriptomic substrate. The genetic profile displays specific biological functions in protein transport regulation and lipid biosynthetic processes (Fig3).,ConclusionOur results suggest that changes in LC‐integrity may occur before tau spreads into the MTL, which jointly contributes to lower cognitive performance. The neurogenetic profiles can provide a biological framework for identifying individuals more likely to be at risk for AD disease progression. Future developments could examine the intersection between amyloid and LC‐related tau progression in the context of AD.