Abstract
BACKGROUND: The noradrenergic locus coeruleus (LC) accumulates pathology early in Alzheimer's disease (AD), with LC dysfunction contributing to symptoms and disease progression. We investigated LC and substantia nigra (SN) integrity in healthy controls and AD participants. METHODS: Ninety-three AD participants and 29 controls underwent neuromelanin magnetic resonance imaging. LC and SN contrast, reflecting nucleus integrity, related to cognitive and neuropsychiatric symptoms, as well as cognitive decline and atrophy rates. RESULTS: LC - but not SN - integrity was reduced in AD versus controls (b = -0.39, p = 0.001) and within AD was associated with global cognition (b = 8.53, p = 0.04) and neuropsychiatric symptoms, accounting for SN. An AD subgroup with reduced SN integrity had worse cognition. LC integrity predicted plasma phosphorylated tau protein 217 (b = -0.30, p = 0.03). Lower LC and SN integrities were both related to faster cognitive decline (LC: b = -4.74, p = 0.048; SN: b = -2.27, p = 0.03), accounting for one another. DISCUSSION: Catecholaminergic nucleus integrity plays an important role in AD. Both systems are relevant to cognitive performance and decline. LC, in particular, relates closely to symptoms, pathology, and rate of progression. HIGHLIGHTS: In symptomatic AD, LC integrity reflects cortical AD pathology, measured by pTau217. LC integrity predicts cognitive function in AD, independent of cortical atrophy. LC and SN integrity independently relate to attentional performance. Symptoms of anxiety, depression, and apathy are associated with lower LC integrity. LC and SN relate to cognitive decline rate and left LC predicts atrophy rate.