Cerebrospinal fluid NPTX2 and [18F]FDG PET track serotonergic vulnerability to neurodegeneration in prodromal Alzheimer’s disease

In Alzheimer’s disease (AD) the progressive accumulation of misfolded proteins, notably amyloid-β and hyperphosphorylated tau, initiates a cascade of metabolic and synaptic dysfunction, and ultimately neurodegeneration. These early molecular alterations interact with diffuse neurotrasmitter projection systems, contributing to cognitive and behavioural manifestations. This study assessed baseline [18F]FDG-PET metabolism and its relationship with neurotransmitter receptor/transporter maps and cerebrospinal fluid (CSF) markers of AD neuropathology (Aβ42/Aβ40, pTau181, t-Tau), neuroaxonal (NFL), and synaptic damage (NPTX2, neurogranin) in 49 Mild Cognitive Impairment (MCI)-AD patients. Relative hypometabolism was derived by comparing [¹⁸F]FDG-PET scans of patients and 40 healthy controls. Spatial correlation coefficients between hypometabolism maps and normative cortical maps of neurotransmitter receptor/transporter density were computed and included in linear models with CSF biomarkers, adjusting for demographic and cognitive variables. Patients exhibited significant hypometabolism in bilateral temporo-parietal regions. Negative correlations emerged between hypometabolism and receptor distributions for 5-HT1A (r = − 0.36, p < 0.001), D1 (r = − 0.15, p = 0.03), and mGluR5 (r = − 0.14, p = 0.02), which indicates that reduced glucose uptake in MCI-AD was mostly found in areas with normally high receptor densities. Noteworthy, CSF NPTX2 levels correlated with the co-localization of hypometabolism and 5-HT1A receptor distribution (β = 0.003, p = 0.038) with no significant associations for other CSF markers. According to our findings, correlations between reduced glucose metabolism and specific neurotransmitter receptor densities suggest early involvement and vulnerability of these systems in MCI-AD. Moreover, the association between CSF NPTX2 and 5-HT1A receptor vulnerability indicates that synaptic dysfunction in AD may parallel serotonergic involvement, and supports CSF NPTX2 as a potential biomarker for disease staging.