Vulnerability of anterior medial temporal lobe subregions to early tau-related neurodegeneration in Alzheimer's disease: Converging evidence from tau-PET and plasma p-tau217.

INTRODUCTION: The anterior medial temporal lobe (MTL), including the entorhinal cortex (ERC) and Brodmann area 35 (BA35), is among the earliest cortical sites of tau pathology in Alzheimer's disease (AD), yet conventional image segmentation methods poorly capture these regions.

METHODS: We applied an automated segmentation approach using an extended Automatic Segmentation of Hippocampal Subfields (ASHS) atlas, including anterior MTL subregions, in 448 Pennsylvania Alzheimer's Disease Research Center participants with magnetic resonance imaging, tau positron emission tomography (PET) (n = 199), and/or plasma phosphorylated tau 217 (p-tau217) (n = 377). Amyloid beta (Aβ) positivity was defined using PET or plasma.

RESULTS: Tau-PET showed an anterior-posterior gradient, with highest uptake in BA35, ERC, and anterior hippocampus. Increased MTL tau-PET uptake and plasma p-tau217 were associated with cortical thinning localized to BA35 and ERC, even in cognitively unimpaired Aβ-positive individuals.

CONCLUSIONS: Anterior MTL subregions, especially BA35, show early vulnerability to tau-related neurodegeneration. Extended anterior MTL parcellation improves localization of early tau-associated structural changes and may facilitate biological staging in preclinical AD.