Neurotransmitter landscape and neurodegeneration patterns in Alzheimer's Disease

Alterations of neurotransmitter systems in Alzheimer's Disease (AD) remain partially understood, mainly due to the complexity of simultaneously and directly assessing these systems in vivo. To address this knowledge gap, recent approaches have been proposed correlating normative multi-tracer neurotransmitter data with established disease biomarkers, including [¹⁸F]FDG-PET. We retrospectively enrolled 90 AD patients (72.8 ± 7 years, Mini Mental State Examination - MMSE 24 ± 4.1) and 42 Healthy Controls (HC, 70 ± 8.5 years, MMSE 29 ± 0.8), all with a brain [¹⁸F]FDG-PET scan and MMSE collected at baseline. All AD diagnoses were confirmed by a positive amyloid marker (CSF or Amyloid PET). We performed a voxel-based analysis between AD and HC to explore brain relative hypometabolism and then, using the established JuSpace toolbox, we explored the spatial correlation between brain hypometabolism and PET-maps targeting glutamate (mGluR5), GABA (GABA-a), dopamine (D1, D2, FDOPA), serotonin (SERT, 5HT1a, 5HT1b, 5HT2a, 5HT4), noradrenaline (NAT) and choline (VAChT) systems. The significant results obtained were then correlated with MMSE and cortical amyloid burden, measured with Amyloid PET. The distribution of brain relative hypometabolism of AD patients was spatially associated with maps of 5HT2a and mGluR5 distribution (both p = 0.02, r = -0.11). Both 5HT2a and mGluR5 regional relative distribution correlated with a lower MMSE, 5HT2a was also associated with a greater cerebral amyloid burden. These findings are consistent with recent multimodal imaging studies and suggest that serotonergic and glutamatergic receptor-dense regions may show preferential metabolic vulnerability in AD, with relevance for cognitive impairment.