Bowirrat Abdalla, Pinhasov Albert, Bowirrat Aia, Badgaiyan Rajendra
Adelson School of Medicine, Department of Molecular Biology, Ariel University, Ariel 40700, Israel.
Department of Psychiatry, Texas Tech University Health Science Center, Midland, TX 79430, USA.
Int J Mol Sci. 2025 Aug 26;26(17):8253. doi: 10.3390/ijms26178253.
One hundred and eighteen years have passed since Alzheimer's disease (AD) was first diagnosed by Alois Alzheimer as a multifactorial and complex neurodegenerative disorder with psychiatric components. It is inaugurated by a cascade of events initiating from amnesic-type memory impairment leading to the gradual loss of cognitive and executive capacities. Pathologically, there is overwhelming evidence that clumps of misfolded amyloid-β (Aβ) and hyperphosphorylated tau protein aggregate in the brain. These pathological processes lead to neuronal loss, brain atrophy, and gliosis culminating in neurodegeneration and fueling AD. Thus, at a basic level, abnormality in the brain's protein function is observed, causing disruption in the brain network and loss of neural connectivity. Nevertheless, AD is an aging disorder caused by a combination of age-related changes and genetic and environmental factors that affect the brain over time. Its mysterious pathology seems not to be limited to senile plaques (Aβ) and neurofibrillary tangles (tau), but to a plethora of substantial and biological processes, which have also emerged in its pathogenesis, such as a breakdown of the blood-brain barrier (BBB), patients carrying the gene variant APOE4, and the immuno-senescence of the immune system. Furthermore, type 2 diabetes (T2DM) and metabolic syndrome (MS) have also been observed to be early markers that may provoke pathogenic pathways that lead to or aggravate AD progression and pathology. There are numerous substantial AD features that require more understanding, such as chronic neuroinflammation, decreased glucose utilization and energy metabolism, as well as brain insulin resistance (IR). Herein, we aim to broaden our understanding and to connect the dots of the multiple comorbidities and their cumulative synergistic effects on BBB dysfunction and AD pathology. We shed light on the path-physiological modifications in the cerebral vasculature that may contribute to AD pathology and cognitive decline prior to clinically detectable changes in amyloid-beta (Aβ) and tau pathology, diagnostic biomarkers of AD, neuroimmune involvement, and the role of APOE4 allele and AD-IR pathogenic link-the shared genetics and metabolomic biomarkers between AD and IR disorders. Investment in future research brings us closer to knowing the pathogenesis of AD and paves the way to building prevention and treatment strategies.
自阿洛伊斯·阿尔茨海默首次将阿尔茨海默病（AD）诊断为一种具有精神症状的多因素复杂神经退行性疾病以来，已经过去了118年。它始于一系列事件，从失忆型记忆障碍开始，导致认知和执行能力逐渐丧失。在病理上，有大量证据表明，错误折叠的淀粉样β蛋白（Aβ）团块和过度磷酸化的tau蛋白在大脑中聚集。这些病理过程导致神经元丢失、脑萎缩和胶质增生，最终导致神经退行性变并加剧AD。因此，在基本层面上，可以观察到大脑蛋白质功能异常，导致脑网络破坏和神经连接丧失。然而，AD是一种由年龄相关变化以及随着时间影响大脑的遗传和环境因素共同导致的衰老性疾病。其神秘的病理学似乎不仅限于老年斑（Aβ）和神经原纤维缠结（tau），还涉及大量实质性的生物学过程，这些过程也出现在其发病机制中，如血脑屏障（BBB）的破坏、携带APOE4基因变体的患者以及免疫系统的免疫衰老。此外，2型糖尿病（T2DM）和代谢综合征（MS）也被观察到是早期标志物，可能引发导致或加剧AD进展和病理的致病途径。有许多重要的AD特征需要更多的了解，如慢性神经炎症、葡萄糖利用和能量代谢降低以及脑胰岛素抵抗（IR）。在此，我们旨在拓宽我们的理解，并将多种合并症及其对BBB功能障碍和AD病理的累积协同作用联系起来。我们阐明了脑血管系统中的病理生理改变，这些改变可能在临床上可检测到的淀粉样β蛋白（Aβ）和tau病理变化、AD的诊断生物标志物、神经免疫参与之前，就对AD病理和认知衰退产生影响，以及APOE4等位基因的作用和AD-IR致病联系——AD与IR疾病之间共享的遗传学和代谢组学生物标志物。对未来研究的投入使我们更接近了解AD的发病机制，并为制定预防和治疗策略铺平道路。
