Abstract
Alzheimer's disease (AD) is a growing public health crisis. The disease is defined neuropathologically by accumulation of amyloid-β plaques and neurofibrillary tangles (NFTs) composed of abnormal tau protein in the brain. Early neurofibrillary degeneration in the entorhinal cortex (EC) is a hallmark of AD and a critical initiating event in the hierarchical pathoanatomical progression. However, the factors triggering initial tau deposition in the EC remain unclear. We propose a novel biomechanical cascade hypothesis, positing that the unique anatomical inferomedial positioning of the EC, including proximity to the tentorial incisura (TI) and other skull base structures, renders it susceptible to very mild yet persistent age-related mechanical stress, analogous to the effects of repetitive mild traumatic brain injury, triggering tau pathology. To test this hypothesis, we developed a method to quantify Entorhinal-Tentorial (EC-TI) proximity and applied it to multimodal imaging data from the Alzheimer's Disease Neuroimaging Initiative (ADNI; n=47). Based on this neuroanatomical contact coefficient (NCC), participants were heuristically stratified into high (n=24) and low (n=23) adjacency groups. When controlling for other risk factors, tau PET signal in the EC predicted conversion from mild cognitive impairment to AD only in the high-adjacency group (LLR p=0.009, tau PET in EC p=0.036). These findings identify EC-TI proximity as a novel and anatomically grounded biomarker of AD progression risk. More broadly, they suggest a previously unrecognized biomechanical contribution to the initiation of tau pathology in aging and sporadic AD, opening new avenues for early detection, risk stratification, and mechanistically targeted prevention strategies.