Interplay between the catecholaminergic enzymatic axis and neurodegeneration/neuroinflammation processes in the Alzheimer's disease continuum

Background and Purpose: The locus coeruleus (LC) provides dopamine/noradrena- line (DA/NA) innervation throughout the brain and undergoes early degeneration in Alzheimer's disease (AD). We evaluated catecholaminergic enzyme levels in the cerebro- spinal fluid (CSF) of a group of patients biologically defined as within the AD continuum (ADc) and explored their relationship with AD biomarkers and cytokine/growth factor levels to investigate their interplay with neurodegenerative and neuroinflammatory processes.Methods: The CSF concentration of DA transporter (DAT), tyrosine-hydroxylase (TH), DOPA-decarboxylase (DDC), and dopamine-beta- hydroxylase (D beta H), as well as cytokine/growth factor levels, were analyzed in 41 ADc patients stratified according to CSF beta-amyloid (A beta)1-42 (A) and p -tau (T) in AD pathological changes (A+ T-) and AD (A+ T+) subgroups, as well as in 15 control subjects (A- T-).Results: The ADc group had lower CSF levels of DAT and TH but increased D beta H levels to compensate for NA synthesis. DDC levels were higher in the A+ T+ subgroup but com- parable with controls in the A+ T- subgroup, probably because the DA system is resilient to the degeneration of LC neurons in the absence of tau pathology. Adjusting for age, sex, APOE genotype, and cognitive status, a significant association was found between TH and A beta 1-42 (R2 = 0.25) and between DDC and p -tau (R2 = 0.33). Finally, TH correlated with interleukin (IL) -10 levels (p = 0.0008) and D beta H with IL- 1 beta (p = 0.03), IL -4 (p = 0.02), granulocyte colony-stimulating factor (p = 0.007), and IL -17 (p = 0.01).Conclusions: Taken together, these findings suggest that catecholaminergic enzymes, functional markers of the catecholaminergic system, are closely linked to the neurode- generative and neuroinflammatory processes in AD pathology.