Locus coeruleus in the pathogenesis of Alzheimer's disease: A systematic review

The locus coeruleus (LC) is a nucleus in the brain stem producing noradrenaline. While cognitive decline in Alzheimer's disease (AD) has primarily been related to cholinergic depletion, evidence indicates extensive LC degeneration as its earliest pathological marker. The current study aimed to systematically evaluate current evidence investigating the role of the LC in the pathogenesis of AD. A systematic search of the literature was performed on electronic databases including PubMed and Web of Science. Twelve animal, human post mortem, and human imaging studies were included in this review. Screening, data extraction, and quality assessment were undertaken following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines for preferred reporting of systematic reviews. Significant associations were identified between LC changes and cognitive decline. Significant reductions in fiber density, neuronal number, and LC volume were seen to correlate with other pathological degenerative markers. Current evidence indicates an important role of the LC in pathogenesis of AD and suggests its potential in both diagnosis and treatment of AD. This systematic review advances our understanding of the role of the LC in AD by synthesizing available evidence, identifying research gaps, highlighting methodological challenges, and making recommendations for future work.