Volumetric postmortem MRI of the medial temporal lobe in Alzheimer’s disease and related disorders: methodological advances and implications for in vivo biomarker development

Magnetic resonance imaging (MRI) is central to the study and diagnosis of neurodegenerative diseases. Yet, no MRI biomarker is currently specific to a given neurodegenerative disease. This may result from the limited resolution of conventional MRI, which restricts detailed investigation of medial temporal lobe (MTL) subregions, a crucial hub for many neuropathologies. Moreover, in vivo MRI cannot be directly compared with neuropathological data, the gold standard for disease definition. Even when antemortem MRI and postmortem analyses are combined, the time gap between imaging and neuropathological examination allows pathogenic processes to progress, reducing the accuracy of these correlations. Over the past two decades, postmortem MRI has gained increasing interest because it enables long, motion-free acquisitions and the use of specialized coils and preclinical scanners, providing ultra-high spatial resolution. Additionally, it allows direct correspondence between imaging and neuropathological measures. Consequently, volumetric postmortem MRI, particularly investigations of the MTL, has become an increasingly common approach in Alzheimer's disease and related disorders (ADRD). This narrative review specifically focuses on volumetric postmortem MRI of the MTL and summarizes the main methodologies for anatomical postmortem MTL imaging in ADRD and recent advances in the characterization of neurodegenerative changes, from brain preparation to MRI acquisition. It also highlights the translational potential of volumetric postmortem MRI for developing in vivo biomarkers, optimizing imaging protocols and segmentation methods, and assessing the impact of proteinopathies. Finally, it outlines current limitations, technical challenges, and perspectives for future research.