Locus coeruleus integrity predicts tau accumulation and memory dysfunction in autosomal dominant Alzheimer's disease.

Abstract

Developments in neuroimaging have demonstrated that the structural integrity of the locus coeruleus (LC) changes around age 50-55, which correlates with cognitive performance, and - consistent with postmortem studies - correlates with accumulation of cortical tau pathology. It remains unknown whether the LC is similarly affected in individuals with autosomal dominant Alzheimer's disease due to a PSEN-E280A mutation, as brain pathology is evident as early as age 28, an average of 16 years before estimated clinical onset. Here, we aimed to investigate associations between LC integrity, age, cortical tau and amyloid deposition and cognition in carriers and non-carriers. 27 mutation carriers (19 cognitively unimpaired and 8 impaired) and 27 non-carriers from the Colombian-kindred underwent PiB-PET, Flortaucipir-PET, 3T-MRI and memory testing. Of these, 10 carriers underwent a follow-up imaging and testing session. Using previously reported methods, we extracted LC intensity (or integrity) from the MRI-images (referenced to pontine tegmentum). Group differences were tested with the Wilcoxon rank test, and correlations were tested using Spearman rank correlations. Longitudinal associations between LC integrity and tau accumulation were evaluated with mixed effects models and repeated measures correlation for change-on-change models. The direction of the age-associations and LC integrity differed between carriers and non-carriers, with a negative association in carriers (peak at 31.5 years). LC integrity was lower in impaired carriers as compared to unimpaired carriers and non-carriers (Figure 1). LC integrity was associated with widespread tau accumulation in carriers, while in non-carriers only with the entorhinal cortex. The longitudinal analyses showed that baseline LC integrity as well as declines in LC integrity predicted precuneus tau accrual in the unimpaired carriers and across all carriers (Figure 2). LC integrity correlated positively with word list learning and delayed recall in all carriers. The positive LC integrity - delayed recall association was mediated by medial parietal tau deposition in carriers (Figure 3). LC integrity is associated with the initial pathologic and clinical phenotypes of autosomal dominant Alzheimer's disease. These relationships are observed earlier in life than in sporadic AD, suggesting that LC integrity is not merely age-related but can be an early indicator of disease progression.