Bradley David
Diabetes and Metabolism Research Center, Division of Endocrinology, Diabetes & Metabolism, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
Biomark Insights. 2020 Oct 12;15:1177271920964108. doi: 10.1177/1177271920964108. eCollection 2020.
Over 35% of the adult US population is obese. In turn, excess adiposity increases the risk of multiple complications including type 2 diabetes (T2D), insulin resistance, and cardiovascular disease; yet, obesity also independently heightens risk of Alzheimer's Disease (AD), even after adjusting for other important confounding risk factors including blood pressure, sociodemographics, cholesterol levels, smoking status, and Apolipoprotein E (ApoE) genotype. Among patients over the age of 65 with dementia, 37% have coexisting diabetes, and an estimated 7.3% of cases of AD are directly attributable to midlife obesity. Clusterin, also known as apolipoprotein J (ApoJ), is a multifunctional glycoprotein that acts as a molecular chaperone, assisting folding of secreted proteins. Clusterin has been implicated in several physiological and pathological states, including AD, metabolic disease, and cardiovascular disease. Despite long-standing interest in elucidating clusterin's relationship with amyloid beta (Aβ) aggregation/clearance and toxicity, significant knowledge gaps still exist. Altered clusterin expression and protein levels have been linked with cognitive and memory function, disrupted central nervous system lipid flux, as well as pathogenic brain structure; and its role in cardiometabolic disease suggests that it may be a link between insulin resistance, dyslipidemia, and AD. Here, we briefly highlight clusterin's relevance to AD by presenting existing evidence linking clusterin to AD and cardiometabolic disease, and discussing its potential utility as a biomarker for AD in the presence of obesity-related metabolic disease.
超过35%的美国成年人口患有肥胖症。肥胖反过来又会增加包括2型糖尿病（T2D）、胰岛素抵抗和心血管疾病在内的多种并发症的风险；然而，肥胖还会独立增加患阿尔茨海默病（AD）的风险，即使在调整了包括血压、社会人口统计学、胆固醇水平、吸烟状况和载脂蛋白E（ApoE）基因型等其他重要的混杂风险因素之后也是如此。在65岁以上患有痴呆症的患者中，37%同时患有糖尿病，估计7.3%的AD病例直接归因于中年肥胖。聚集素，也称为载脂蛋白J（ApoJ），是一种多功能糖蛋白，作为分子伴侣，协助分泌蛋白的折叠。聚集素与多种生理和病理状态有关，包括AD、代谢疾病和心血管疾病。尽管长期以来人们一直关注阐明聚集素与淀粉样β蛋白（Aβ）聚集/清除及毒性之间的关系，但仍存在重大的知识空白。聚集素表达和蛋白水平的改变与认知和记忆功能、中枢神经系统脂质通量紊乱以及致病性脑结构有关；并且其在心脏代谢疾病中的作用表明它可能是胰岛素抵抗、血脂异常和AD之间的一个联系。在此，我们通过展示将聚集素与AD和心脏代谢疾病联系起来的现有证据，并讨论其在存在肥胖相关代谢疾病时作为AD生物标志物的潜在效用，简要强调聚集素与AD的相关性。
