AbstractINTRODUCTIONThe locus coeruleus (LC), the brain's primary source of noradrenaline (NA), undergoes early neurodegeneration in Parkinson's disease (PD), Alzheimer's diseases (AD), and Down syndrome (DS); however, differences have not been examined in parallel.METHODSPost mortem brains (n = 67) from individuals with AD, DS‐AD, and PD without and with dementia (PD‐D) and controls were analyzed for amyloid beta (Aβ), phosphorylated tau (pTau), α‐synuclein, endo‐lysosomal alterations, biogenic amines, and selective biomarkers.RESULTSLC degeneration correlated with age, peaking in AD and PD‐D, while NA and dopaminergic metabolites were significantly reduced only in PD‐D. DS‐AD, the youngest group, showed the highest Aβ and pTau levels but the least noradrenergic neuron loss. We demonstrated for the first time that endosomal alterations were present in AD, lysosomal changes were present in PD‐D/DS‐AD, and DYRK1A, a key protein from chromosome 21, was elevated only in DS‐AD.DISCUSSIONLoss of noradrenergic neurons may occur independently of amyloid and tau pathologies.Highlights We provide the first analysis of neuropathological and biochemical features including biogenic amines of the LC in AD, DS, and PD. Loss of noradrenergic neurons was most severe in AD and PD. Only in DS, levels of DYRK1A – a kinase encoded on chromosome 21 and implicated in neurodegenerative processes – were elevated and negatively correlated to biogenic amine levels. Although individuals with DS having AD were the youngest group, they had the highest levels of amyloid and tau pathologies, but less noradrenergic neurons loss compared to other disease groups.