Tau Pathology in Alzheimer's Disease Uniquely Affects Sulcal Depths

OBJECTIVE: Though it is widely known that tau deposition affects brain structure, the precise localization of these effects is poorly understood, especially in relation to gyral and sulcal anatomy. We investigated whether tau pathology in Alzheimer's disease (AD) preferentially affects sulci, and particularly sulcal depths. METHODS: We analyzed 675 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) with magnetic resonance imaging (MRI) and positron emission tomography (PET) data to investigate relationships between neocortical tau PET signal and cortical thickness. We then examined an advanced AD case with postmortem MRI and coregistered whole-brain phospho-tau staining for evidence of sulcal tau distribution in AD. Finally, in a sample of 187 cognitively unimpaired young and older adults with resting-state functional MRI, we examined connectivity strength between tau-vulnerable regions and the hippocampus across adulthood, prior to disease-related cognitive decline. RESULTS: Our findings revealed that tau-related cortical thinning predominantly occurs in sulcal regions, especially the deepest parts. Postmortem histology confirmed preferential tau accumulation in sulcal depths. Additionally, connectivity analyses revealed that, across adulthood, these primarily sulcal regions most susceptible to tau-related thinning also have stronger connectivity to the hippocampus, suggesting a role for network connectivity in the vulnerability of sulci to the effects of tau pathology later in life. INTERPRETATION: These findings support the hypothesis that sulci, and particularly their depths, represent structurally and functionally vulnerable regions for tau deposition in AD. Understanding the mechanisms underlying this sulcal vulnerability provides insight into general principles driving regional susceptibility to pathology, and sheds light on the detrimental functional and cognitive effects of tau pathology. ANN NEUROL 2026;99:1343-1353.