CSF biomarkers are differentially linked to brain areas high and low in noradrenaline, dopamine and serotonin across the Alzheimer’s disease spectrum
Authors: Haag Lena , Lancini Elisa , Yakupov Renat , Ziegler Gabriel , Yi Yeo-Jin , Lüsebrink Falk , Glanz Wenzel , Peters Oliver , Spruth Eike Jakob , Altenstein Slawek , Priller Josef , Schneider Luisa Sophie , Wang Xiao , Preis Lukas , Brosseron Frederic , Roy-Kluth Nina , Fliessbach Klaus , Wagner Michael , Wolfsgruber Steffen , Kleineidam Luca , Ramirez Alfredo , Spottke Annika , Jessen Frank , Wiltfang Jens , Schneider Anja , Hansen Niels , Rostamzadeh Ayda , Buerger Katharina , Ewers Michael , Perneczky Robert , Janowitz Daniel , Rauchmann Boris-Stephan , Teipel Stefan , Kilimann Ingo , Goerss Doreen , Laske Christoph , Munk Matthias H , Heneka Michael , Dechent Peter , Hetzer Stefan , Scheffler Klaus , Düzel Emrah , Betts Matthew J , Hämmerer Dorothea 
Published: January 2025

Abstract
Neurotransmitter systems of noradrenaline, dopamine, serotonin and acetylcholine are implicated in cognitive functions such as memory, learning and attention and are known to be altered in neurodegenerative diseases like Alzheimer’s disease. Specific brain structures involved in these systems, e.g. the locus coeruleus, the main source of noradrenaline in the cortex, are in fact affected earliest by Alzheimer’s disease tau pathology. Preserved volumetric neurotransmitter specific brain areas could therefore be an important neural resource for cognitive reserve in aging. The aim of this study was to determine whether volumes of brain areas known to be high in neurotransmitter receptors are relatively preserved in individuals with lower levels of Alzheimer’s disease pathology. Based on the Human Protein Atlas for neurotransmitter receptor distribution, we distinguished between ‘areas high and low’ in noradrenaline, dopamine, serotonin and acetylcholine and assessed associations of atrophy in those areas with CSF amyloid-ß 42/40, CSF phosphorylated tau protein and cognitive function across healthy controls (n = 122), individuals with subjective cognitive decline (n = 156), mild cognitive impairment or mild Alzheimer’s disease dementia (n = 126) using structural equation modelling. CSF pathology markers were inversely correlated and showed a stronger association with disease severity, suggesting distinguishable interrelatedness of these biomarkers depending on the stage of Alzheimer’s disease dementia. Across groups, amyloid pathology was linked to atrophy in areas high as well as low in neurotransmitter receptor densities, while tau pathology did not show any significant link to brain area volumes for any of the neurotransmitters. Within disease severity groups, individuals with more amyloid pathology showed more atrophy only in ‘areas high in noradrenaline’, whereas for dopamine tau pathology was linked to higher volumes in areas low in receptor density possibly indicating compensatory mechanisms. Furthermore, individuals with more tau pathology showed a selective decrease in memory function while amyloid pathology was related to a decline in executive function and language capacity as well as memory function. In summary, our analyses highlight the benefits of investigating disease-relevant factors in Alzheimer’s disease using a multivariate multigroup approach. Assessing multivariate dependencies in different disease stages and across individuals revealed selective links of pathologies, cognitive decline and atrophy in particular for areas modulated by noradrenaline, dopamine and serotonin.