Zhang Luyue, Franceschi Ana M, Crary John F, Provenzano Frank A
Department of Biomedical Engineering, Columbia University New York, NY, USA.
Neuroradiology Division, Department of Radiology, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Lenox Hill Hospital, New York, NY, USA.
bioRxiv. 2025 Sep 4:2025.09.02.670249. doi: 10.1101/2025.09.02.670249.
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; =47). Based on this neuroanatomical contact coefficient (NCC), participants were heuristically stratified into high (=24) and low (=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 =0.009, tau PET in EC =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.
阿尔茨海默病（AD）是一个日益严重的公共卫生危机。该疾病在神经病理学上的定义是，大脑中由异常tau蛋白组成的淀粉样β斑块和神经原纤维缠结（NFTs）的积累。内嗅皮质（EC）早期的神经原纤维变性是AD的一个标志，也是分级病理解剖进展中的一个关键起始事件。然而，触发EC中初始tau沉积的因素仍不清楚。我们提出了一种新的生物力学级联假说，假定EC独特的解剖学下内侧定位，包括靠近小脑幕切迹（TI）和其他颅底结构，使其易受非常轻微但持续的与年龄相关的机械应力影响，类似于重复性轻度创伤性脑损伤的影响，从而触发tau病理学。为了验证这一假说，我们开发了一种量化内嗅-小脑幕（EC-TI）接近度的方法，并将其应用于来自阿尔茨海默病神经影像倡议（ADNI；n = 47）的多模态成像数据。基于这种神经解剖接触系数（NCC），参与者被启发式地分为高接触组（n = 24）和低接触组（n = 23）。在控制其他风险因素时，EC中的tau PET信号仅在高接触组中预测了从轻度认知障碍向AD的转化（似然比 = 0.009，EC中的tau PET = 0.036）。这些发现确定EC-TI接近度是AD进展风险的一种新的、基于解剖学的生物标志物。更广泛地说，它们表明了对衰老和散发性AD中tau病理学起始的一种先前未被认识的生物力学贡献，为早期检测、风险分层和机制靶向预防策略开辟了新途径。
