Gawor Klara, Verrept Sam, Arekatla Geethika, Wouters David, Ronisz Alicja, Hecht Moritz, Laureyssen Celeste, Donck Helena Ver, Lahaije Bas, Ospitalieri Simona, Vandenbulcke Mathieu, Otto Markus, von Arnim Christine A F, Ghebremedhin Estifanos, Hanseeuw Bernard, Vandenberghe Rik, Blaschko Matthew, Sifrim Alejandro, Sleegers Kristel, Thal Dietmar Rudolf, Tomé Sandra O
Department of Imaging and Pathology, Laboratory of Neuropathology, KU Leuven, Leuven, Belgium.
Department of Neuroscience, Laboratory of Neurobiology, KU Leuven, Leuven, Belgium.
Alzheimers Dement. 2025 Jul;21(7):e70483. doi: 10.1002/alz.70483.
In neurodegenerative dementias, the co-occurrence and interaction of amyloid β peptide (Aβ), tau pathology, and other pathological lesions confound their individual contributions to neurodegeneration and their modulation by risk factors.
We analyzed 480 post mortem human brains (ages 50-99) using regression and structural equation models to assess the relationships among Aβ, tau, limbic-predominant age-related TDP-43 encephalopathy neuropathological changes (LATE-NC), α-synuclein, other age-related lesions, and apolipoprotein E (APOE) ε4, as well as their effects on CA1 neuronal density, brain weight, and cognitive status.
Aβ, tau, LATE-NC, and amygdala-predominant α-synuclein pathology were mutually interdependent. Tau was the strongest predictor of global neurodegeneration, while LATE-NC primarily, but not exclusively, affected hippocampal neuron loss. Small vessel disease correlated with both LATE-NC and α-synuclein, while APOE ε4 was mainly associated with extracellular parenchymal and capillary Aβ pathology.
Although Alzheimer's disease pathology plays a central role in brain degeneration, coexisting pathologies can both exacerbate and independently contribute to it. These factors should be considered in patient stratification.
In aging individuals, amyloid β peptide (Aβ), tau pathology, limbic-predominant age-related TDP-43 encephalopathy neuropathological changes (LATE-NC), and amygdala-predominant α-synuclein pathology were interrelated but contributed independently to neurodegeneration. LATE-NC was the strongest driver of CA1 neuronal loss, while tau burden was the strongest predictor of global brain degeneration. Apolipoprotein E ε4 was associated with both extracellular and capillary Aβ deposits, but not with tau burden. Temporal lobe small vessel disease was associated with both LATE-NC and amygdala-predominant α-synuclein pathology. Neural network models can reliably identify hippocampal pyramidal neurons on hematoxylin-stained histological slides.
在神经退行性痴呆中，淀粉样β肽（Aβ）、tau病理变化及其他病理损害的共同出现和相互作用，混淆了它们对神经退行性变的各自影响以及危险因素对它们的调控作用。
我们使用回归模型和结构方程模型分析了480例死后人体大脑（年龄50 - 99岁），以评估Aβ、tau、边缘叶为主的年龄相关性TDP - 43脑病神经病理变化（LATE - NC）、α - 突触核蛋白、其他年龄相关性病变及载脂蛋白E（APOE）ε4之间的关系，以及它们对CA1神经元密度、脑重量和认知状态的影响。
Aβ、tau、LATE - NC和杏仁核为主的α - 突触核蛋白病理变化相互依存。tau是全球神经退行性变最强的预测因子；而LATE - NC主要但并非唯一地影响海马神经元丢失；小血管疾病与LATE - NC和α - 突触核蛋白均相关；APOE ε4主要与细胞外实质和毛细血管Aβ病理变化相关联。
尽管阿尔茨海默病病理变化在脑退变中起核心作用，但共存的病理变化既能加剧退变，也能独立导致退变。在患者分层时应考虑这些因素。
在老年个体中，淀粉样β肽（Aβ）、tau病理变化、边缘叶为主年龄相关性TDP - 43脑病神经病理变化（LATE - NC）以及杏仁核为主的α - 突触核蛋白病理变化相互关联，但对神经退行性变有独立影响。LATE - NC是CA1神经元丢失的最强驱动因素，而tau负荷是全脑退变的最强预测因子。载脂蛋白E ε与细胞外及毛细血管Aβ沉积相关，但与tau负荷无关。颞叶小血管疾病与LATE - NC和杏仁核为主的α - 突触核蛋白病理变化均相关。神经网络模型能够在苏木精染色的组织学切片上可靠地识别海马锥体细胞。
