<p>An early, biomarker-based diagnosis of Alzheimer’s Disease (AD) is crucial, especially with the emerging availability of novel therapeutic options. However, the role of ¹⁸F-FDG-PET and its relationship to other PET and CSF biomarkers remains unclear. Therefore, the aim of this study was the evaluation of the role of ¹⁸F-FDG-PET in AD diagnosis and its relationship to other commonly used fluid and PET biomarkers and their individual and multimodal accuracy in AD diagnosis. We included <i>n</i> = 157 AD patients, <i>n</i> = 603 MCI patients, and <i>n</i> = 380 cognitively normal participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) that underwent PET imaging with ¹⁸F-FDG or ¹⁸F-Florbetapir. Clinical and imaging data including patient characteristics, CSF biomarkers, cognition tests, ¹⁸F-FDG-PET, ¹⁸F-Florbetapir-PET, and ¹⁸F-Flortaucipir-PET were retrospectively analyzed. PET images were quantified in several brain regions. The uptake of ¹⁸F-FDG was inversely correlated with ¹⁸F-Florbetapir and positively correlated with CSF Aβ42 in several brain regions commonly affected by AD. Additionally, ¹⁸F-FDG uptake showed an inverse correlation with both forms of CSF tau, t-tau and p-tau, in various brain regions, but did not correlate with ¹⁸F-Flortaucipir uptake. Moreover, regional ¹⁸F-FDG uptake was positively correlated with cognitive function. Diagnostic accuracies were similarly high for ¹⁸F-FDG uptake in the PCC/Precuneus region, ¹⁸F-Florbetapir uptake, CSF Aβ42, CSF p-tau, and ¹⁸F-Flortaucipir uptake in differentiating AD from cognitively normal individuals. ¹⁸F-FDG-PET and its combination with CSF p-tau/ Aβ42 ratio showed the highest predictive power for disease severity. The study underscores the potential of integrating ¹⁸F-FDG-PET with CSF biomarkers to enhance the diagnosis, prognosis, and monitoring of AD, highlighting the complexity and regional specificity of biomarker interactions in neurodegeneration.</p>