Purpose <p>Neurodegeneration is a hallmark of Alzheimer’s disease (AD), measurable in-vivo with [¹⁸F]FDG PET or MRI. However, the relative sensitivities of these modalities at different stages of AD remain poorly understood. Here, we directly compared associations of hypometabolism and gray matter (GM) atrophy with tau pathology staging at autopsy.</p> Methods <p> Eighty-eight individuals from the ADNI autopsy cohort with Braak tau staging and ante-mortem [¹⁸F]FDG PET and T1-weighted MRI scans were analyzed. Spearman correlations assessed associations between Braak stage and hypometabolism or GM atrophy across 52 regions of interest. Regions showing significant correlations were further assessed for differences between early/intermediate (II-IV; n=24) and advanced (V/VI, n=56) Braak stages compared to controls (0/I, <i>n</i>=8). To address the limited size of the pathological control group, analyses were replicated using a larger sample of age-matched cognitively unimpaired individuals with no evidence of amyloid or tau pathology on PET imaging (<i>n</i>=45).</p> Results <p> Higher Braak stages were associated with [¹⁸F]FDG PET hypometabolism in temporo-parietal regions, with large effects detectable even at early/intermediate stages and further reductions in advanced stages. Concomitant MRI-derived GM atrophy showed similar but smaller effects, significant only for advanced stages. Direct cross-modality comparisons confirmed more pronounced hypometabolism than GM atrophy across most affected regions. Replication analyses using the larger cognitively unimpaired control sample yielded highly similar findings.</p> Conclusion <p> [¹⁸F]FDG PET hypometabolism is a sensitive and early marker of AD-related neurodegeneration, preceding MRI-detectable GM atrophy and more closely reflecting underlying tau pathology across disease stages.</p>