Connectomics and neurotransmitter receptor profile explain regional tau pathology in Alzheimer’s disease

Alzheimer's disease tau pathology spreads through neuronal pathways and synaptic connections. Alteration in synaptic activity facilitates tau spreading. Multiple neurotransmitter systems are shown to be implicated in Alzheimer's disease, but their influence on the trans-synaptic spread of tau is not well understood. I aimed to combine resting-state functional magnetic resonance imaging connectomics, neurotransmitter receptor profiles, and tau-PET data to explain the regional susceptibility to tau accumulation. The tau-PET imaging data of 161 amyloid-beta-negative cognitively unimpaired participants as control and 259 amyloid-beta-positive subjects were recruited from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Linear regression analysis revealed that a higher tau-PET z-score is associated with a lower density of nine receptors in the serotonin, dopamine, gamma-aminobutyric acid (GABA), acetylcholine, and glutamate systems. Furthermore, adding four neurotransmitter receptor density z-scores significantly increased the proportion of explained variance by 3% to 7% compared to the epicenter-connectivity distance model in the group-level analysis. Also, adding nine neurotransmitter receptor density z-scores to the epicenter-connectivity distance model increased the explanatory power of variability in individual levels of tau-PET z-score by 3% to 8%. The current study demonstrated the additive value of atlas-based neurotransmitter receptor mapping and individual-level amyloid-beta-PET scans to enhance the connectivity-based explanation of tau accumulation.