A longitudinal investigation of locus coeruleus norepinephrine system integrity and cognitive performance across the Alzheimer’s spectrum

Abstract

Loss of locus coeruleus (LC) integrity, a debilitating feature of Alzheimer’s disease (AD), can be visualized in vivo with MRI. Longitudinal investigation across the AD spectrum can elucidate the timing of LC damage and its behavioral correlates. Cognitively normal adults (n = 153), individuals with mild cognitive impairment (n = 73), and with AD (n = 43) underwent MR imaging to assess LC integrity, PET imaging to assess tau and Aβ ([¹⁸F]MK6240 and [¹⁸F]AZD4694, respectively) and completed a battery of cognitive tests. For a subset of participants, these assessments were repeated annually for up to 4 years. Linear mixed effects analysis examined the association of time and cognitive performance with LC signal. Reduction in LC integrity over time was significant for patients early in the course of AD (t₉₅ = −3.72, p = 0.0003) but not in later AD phases or healthy aging. In AD participants, several cognitive measures correlated with LC integrity including logical memory (t₆₄ = 2.57, p = 0.013) and object recognition (t₆₄ = 3.41, p = 0.001). LC imaging reveals degeneration of the LC-norepinephrine system within subjects over time in early AD phases. LC damage correlates to cognitive impairment and the strong relationship observed of LC signal to object recognition could suggest an important role of this system in novelty detection in AD.