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Abstract

Introduction:
Our main source of noradrenaline in the cortex is the locus coeruleus, a brainstem nucleus which is amongst the brain structures affected earliest by Alzheimer's disease-related tau pathology (Braak et al., 2011). Since intact noradrenergic modulation has been linked to cognitive reserve in ageing (Wilson et al., 2013), interindividual differences in the integrity of cortical noradrenaline-projection regions could be an important neural resource for cognitive reserve in ageing. The aim of this study was to determine whether volumes of brain areas known to be rich in noradrenergic receptors and transporters are relatively preserved in individuals with lower levels of Alzheimer's disease pathology.
Methods:
Based on prior work on NA receptor and transporter distribution (Palomero-Gallagher et al., 2015), we distinguished between 'areas high in noradrenaline' and 'areas low in noradrenaline' and compared differential associations of atrophy in those areas with CSF amyloid-ß 42/40, CSF phosphorylated tau protein, and memory function across healthy controls (n = 122), subjects with subjective cognitive decline (n = 156) and patients with mild cognitive impairment or mild Alzheimer's disease dementia (n = 126). Analyses were carried out with structural equation modeling which allows to assess the interrelations between multiple variables while testing for group differences in these interrelations.
Results:
Our analyses confirmed that regional brain volumes in 'areas high in NA' vs. 'areas low in NA' are differentially related to AD pathology markers. Only 'areas high in noradrenaline' were related to disease markers. Across all groups, atrophy in 'areas high in noradrenaline' were linked to worse memory. Moreover, groups differed in their links between atrophy in 'areas high in noradrenaline' and amyloid levels or memory capacity. In subjects with subjective cognitive decline, higher amyloid pathology predicted atrophy in 'areas high in noradrenaline' (ß = 0.343), while in patients with mild cognitive impairment and Alzheimer's disease, higher amyloid pathology was associated with memory impairment (ß = 0.295). The study also found that CSF amyloid and tau biomarkers were less correlated in the subjective cognitive decline (ß = -0.366) as compared to the mild cognitive impairment/Alzheimer's disease groups (ß = -0.424), suggesting distinguishable interrelatedness of amyloid and tau after early disease onset.