Background Synaptic loss is an important factor in Alzheimer disease (AD); however, blood assays that conveniently and rapidly reflect changes in synaptic density are lacking. Purpose To correlate multiple potential synaptic blood markers with synaptic density measured using ¹⁸F-SynVesT-1, a fluorine 18 (¹⁸F)-labeled radiotracer, brain PET and to explore the independent associations between these markers and synaptic density. Materials and Methods This prospective study included 50 cognitively unimpaired (mean age, 65.0 years ± 8.3 [SD]; 37 female) participants and 70 participants with cognitive impairment (mean age, 69.5 years ± 7.9; 43 female) from the Memory Clinic of Shanghai Jiao Tong University Affiliated Ruijin Hospital and communities in Shanghai. Amyloid-β (Aβ) and tau were assessed using ¹⁸F-florbetapir and ¹⁸F-MK6240 PET/CT. Synaptic density was evaluated with ¹⁸F-SynVesT-1 PET/MRI. Pearson correlation analysis was used to investigate relationships of plasma (Aβ42/40 ratio, phosphorylated tau 181 [p-tau-181], glial fibrillary acid protein [GFAP], neurofilament light) and serum (C-reactive protein, tumor necrosis factor-α, α-synuclein, neurogranin, active plasminogen activator inhibitor-1, tissue plasminogen activator) biomarkers with synaptic density. Linear regression models and mediation analysis were used to explore effects of other AD-related pathologies on these relationships. Results Correlations were observed between increased p-tau-181 and GFAP and decreased synaptic density in global cortex (r_p-tau-181 = -0.352, r_GFAP = -0.386; both P < .001) and hippocampus (r_p-tau-181 = -0.361, r_GFAP = -0.369; both P < .001) at ¹⁸F-SynVesT-1 PET/MRI. The relationships between p-tau-181 and GFAP with ¹⁸F-SynVesT-1 PET/MRI persisted after controlling for plasma Aβ42/40 ratio, Aβ PET, or cortical thickness (P value range, <.001-.01). This association disappeared after controlling for tau PET (P value range, .08-.83). Conclusion Plasma p-tau-181 and GFAP are closely associated with synaptic density measured using ¹⁸F-SynVesT-1 PET/MRI, with the relationship primarily influenced by tau accumulation rather than Aβ deposition or cortical thickness. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Giannakopoulos in this issue.

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