Changes in neurotransmitter-related functional connectivity along the Alzheimer’s disease continuum

Abstract Alzheimer’s disease may be associated with early dopamine dysfunction. However, its effects on neurofunctional alterations in the neurotransmission pathways remain elusive. In this study, positron emission tomography atlases and functional MRI data for 86 older adults with mild cognitive impairment Alzheimer's disease (MCI), 58 with mild Alzheimer's disease-dementia and 76 cognitively unimpaired were combined to investigate connectivity alterations associated with the dopaminergic and cholinergic systems. A cross-sectional design was used to compare neurotransmitter-related functional connectivity across groups and associations between functional connectivity and cognitive performance. The findings show that the Alzheimer's disease dementia group showed a decline in mesocorticolimbic dopamine-related connectivity in the precuneus but heightened connectivity in the thalamus, whereas the Alzheimer's disease-MCI group showed a decline in nigrostriatal connectivity in the left temporal areas. Acetylcholine-related connectivity decline was observed in both Alzheimer's disease-MCI and Alzheimer's disease-dementia primarily in the temporo-parietal areas. Episodic memory scores correlated positively with acetylcholine- and dopamine-related connectivity in the temporo-parietal cortex and negatively with dopamine-related functional connectivity in the fronto-thalamic areas. This study shows that connectivity alterations in acetylcholine and dopamine functional pathways parallel cognitive decline in Alzheimer's disease and might be a clinically relevant marker in early Alzheimer's disease.