Purpose <p>To characterize the spatiotemporal progression of tau pathology and neurodegeneration across medial temporal lobe (MTL) subregions—critical hubs for memory and early Braak-stage pathology—in Alzheimer’s disease (AD), using tau-PET with the second-generation tracer and MRI.</p> Methods <p>114 participants underwent [¹⁸F]florbetapir, [¹⁸F]MK-6240 PET and structural MRI, then classified into four groups (32 AD Aβ+, 20 MCI Aβ+, 21 CU Aβ+, 41 CU Aβ−). Tau uptake and brain volumetry were measured in MTL subregions: anterior hippocampus (aHIP), Brodmann areas 35/36 (BA35/36), entorhinal cortex (ERC), parahippocampal cortex (PHC), and posterior hippocampus (pHIP), then compared among groups. Correlations between tau deposition and volumetry, also with cognitive scores (MMSE, AVLT, BNT) were analyzed.</p> Results <p>Tau deposition and brain atrophy followed an anteroposterior gradient throughout MTL subregions. Tau pathology initially emerged in anterior MTL regions (ERC, BA35, and aHIP) during preclinical stages (CU Aβ+), then progressively spread to posterior MTL subregions (PHC and pHIP) as cognitive decline advances to MCI and AD. Correlations between tau deposition and neurodegeneration progressively strengthened with disease progression, peaking in AD Aβ + group (<i>p</i> &lt; 0.001). Elevated tau deposition across MTL subregions inversely correlated with cognitive performance, with reduced volumes in specific subregions conferring additional predictive value.</p> Conclusion <p>Tau pathology progresses from anterior to posterior MTL subregions, co-occurring with neurodegeneration and memory deficits. These spatiotemporal patterns captured by [¹⁸F]MK-6240 PET may provide detailed understanding of AD continuum, especially help to guide early therapies.</p>