ChAT, AChE, and Cholinergic Neurons in Aging and AD

ChAT、AChE 和胆碱能神经元在衰老和 AD 中的作用

• 批准号: 7841710
• 负责人: STEVEN G YOUNKIN
• 金额: $ 58.52万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7841710
• 关键词: APP717; Ache; Affect; Age; Aging; Alleles; Alzheimer' s Disease; Alzheimer' s disease risk; Amino Acids; Amyloid; Amyloid Fibrils; Biochemical Markers; Biological Markers; Brain; Brain-Derived Neurotrophic Factor; CCL2 gene; CSF2 gene; Cells; Cholesterol; Chromosomes, Human, Pair 21; Collaborations; Conditioned Culture Media; Consensus; Cultured Cells; Data; Deposition; Diagnostic; Disease; Event; Fostering; Funding; Grant; Heart Diseases; Human; Immunotherapy; Incidence; Individual; Investigation; Laboratories; Link; Maps; Molecular; Mutation; Pathogenesis; Patients; Peptides; Pharmacologic Substance; Phase; Plasma; Presenile Alzheimer Dementia; Preventive; Process; Protein Precursors; Reporting; Risk; Senile Plaques; Series; Transgenic Organisms; adiponectin; angiogenin; apolipoprotein E-4; cerebral atrophy; cholinergic neuron; early onset; familial Alzheimer disease; hippocampal atrophy; interest; mild neurocognitive impairment; neuropathology; platelet-derived growth factor BB; pre-clinical; presenilin-1; presenilin-2; prevent; programs; protein B; protein aggregate; protein aggregation; therapeutic target; tool; working group

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.

描述（由申请人提供）：越来越多的人一致认为，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，开发与 AD 相关的生物标志物非常重要，这些生物标志物可用于识别高危个体，就像利用胆固醇水平来识别有动脉粥样硬化性心脏病风险的人一样。因此，我们在上一个周期中建议确定血浆 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 比率是一个极好的生物标志物，可用于识别三到五年内出现轻度认知障碍或 AD 的人。调整年龄和 ApoE4 后，AB42/AB40 比率位于最低四分位的受试者与比率位于最高四分位的受试者相比，AD/MCI 的累积发生率显着更高。具有 ApoE4 等位基因且 AB42/40 比率较低（低于中值）的受试者在 2-3 岁时开始出现 AD/MCI，到 5 年时，该组中超过 20% 的受试者受到影响。相比之下，AB42/AB40 比率较高（高于中值）的 ApoE 4 携带者中，只有 3% 在五年内患上 AD。结合年龄和 AB42/AB40 比率也能非常有效地将患病受试者与未患病受试者区分开来。 AB42/40 比率较低（低于中位数）的老年受试者（年龄 > 80 岁）在 2-3 岁时开始出现 AD/MCI，到 5 年，该组中超过 20% 的受试者受到影响。相比之下，不到 4% 的其他受试者在五年内患上 AD。如果这些发现得到证实，血浆 AB42/AB40 比率似乎可以成为开发和实施 AD 治疗预防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 比率是识别三到五年内将患 MCI 或 AD 的人的有用生物标志物，以及 (2) 确定 AB（AB40 和/或 AB42）升高是否有助于识别五到十五年内将患 MCI 或 AD 的人。将在分析血浆 AB 的同一纵向系列中评估几种其他生物标志物。 Wyss-Coray 博士将分析 BDNF、AcrpSO（又名脂联素）、血管生成素、PDGF-BB 和 MCP-1。 Jack 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。这些附加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。