ChAT, AChE, and Cholinergic Neurons in Aging and AD

描述（由申请人提供）：越来越多的人认为控制阿尔茨海默病（AD）的最佳方法是通过预防性治疗。为了促进预防性治疗，重要的是开发ad相关的生物标志物，这些生物标志物可用于识别高危人群，就像胆固醇水平用于识别动脉粥样硬化性心脏病的高危人群一样。因此，我们在上一个周期中提出确定血浆AB40和/或AB42是否可能是识别高危个体的有用生物标志物。在我们纵向跟踪的563名正常受试者中，血浆AB42/40比率是识别3至5年内发生轻度认知障碍或AD的优秀生物标志物。在调整年龄和ApoE4后，AB42/AB40比值在最低四分位数的受试者与比值在最高四分位数的受试者相比，AD/MCI的累积发病率显著更高。ApoE4等位基因和低（低于中位数）AB42/40比率的受试者在2-3岁时开始发展为AD/MCI，到5岁时，该组中超过20%的受试者受到影响。相比之下，AB42/AB40比率高（高于中位数）的apoe4携带者中，只有3%在5年内发展为AD。结合年龄和AB42/AB40比值也非常有效地区分了发病和未发病的受试者。AB42/40比值较低（低于中位数）的老年受试者（bb0 ~ 80岁）在2 ~ 3岁时开始发展为AD/MCI，到5岁时，该组中超过20%的受试者受到影响。相比之下，在所有其他受试者中，不到4%的人在5年内患上了AD。如果这些发现能够得到证实，那么血浆AB42/AB40比值可能会成为开发和实施AD治疗预防性方法的重要生物标志物。我们的具体目标是：(1)确认血浆AB42/AB40比值是识别3 - 5年内将发展为MCI或AD的人的有用生物标志物；(2)确定AB （AB40和/或AB42）升高是否有助于识别5 - 15年内将发展为MCI或AD的人。在分析血浆AB的纵向序列中，还将评估其他几种生物标志物。Wyss-Coray博士将分析BDNF、AcrpSO（又名脂联素）、血管生成素、PDGF-BB和MCP-1。杰克博士将使用边界移位积分（BSI）方法分析海马萎缩和全脑萎缩。这些额外的生物标志物的效用将单独与血浆Aft进行比较，并与血浆AB联合进行评估。

DESCRIPTION (provided by applicant): There is a growing consensus that the best way to manage Alzheimer's Disease (AD) will be through preventive therapy. To facilitate preventive therapy, it is important to develop AD-related biomarkers that can be used to identify at risk individuals in the same way that cholesterol levels are used to identify those at risk for atherosclerotic heart disease. For this reason, we proposed in the last cycle to determine if plasma AB40 and/or AB42 might be useful biomarkers for identifying at risk individuals. In 563 normal subjects that we followed longitudinally, the plasma AB42/40 ratio was an excellent biomarker for identifying those who developed Mild Cognitive Impairment or AD in three to five years. The cumulative incidence of AD/MCI was significantly greater in subjects with an AB42/AB40 ratio in the lowest quartile as compared to those with a ratio in the highest quartile after adjusting for age and ApoE4. Subjects with an ApoE4 allele and a low (below median) AB42/40 ratio, began to develop AD/MCI at 2-3 years and, by 5 years, over 20% of the subjects in this group were affected. In contrast, only 3% of the ApoE 4 carriers with a high (above median) AB42/AB40 ratio developed AD in five years. Combining age and the AB42/AB40 ratio was also highly effective in separating subjects who developed disease from those who did not. Older subjects (age > 80 years) with a low (below median) AB42/40 ratio began to develop AD/MCI at 2-3 years and, by 5 years, over 20% of the subjects in this group were affected. In contrast, less than 4% of all other subjects developed AD within five years. If these findings can be confirmed, it seems likely that the plasma AB42/AB40 ratio can become an important biomarker for developing and implementing a preventive approach to AD therapy. Our specific aims are to (1) confirm that the plasma AB42/AB40 ratio is a useful biomarker for identifying those who will develop MCI or AD in three to five years, and (2) determine if elevated AB (AB40 and/or AB42) is useful for identifying those who will develop MCI or AD in five to fifteen years. Several additional biomarkers will be evaluated in the same longitudinal series where plasma AB is analyzed. Dr. Wyss-Coray will analyze BDNF, AcrpSO (aka adiponectin), angiogenin, PDGF-BB, and MCP-1. Dr. Jack will analyze hippocampal atrophy as well as whole brain atrophy using the Boundary Shift Integral (BSI) approach. The utility of these additional biomarkers will be evaluated singly as compared to plasma Aft and jointly with plasma AB.