JAMA Neurol. 2013 Sep 1;70(9):1167-72. doi: 10.1001/jamaneurol.2013.284.
Peripheral glucose homeostasis has been implicated in the pathogenesis of Alzheimer disease (AD). The relationship among diabetes mellitus, insulin, and AD is an important area of investigation. However, whether cognitive impairment seen in those with diabetes is mediated by excess pathological features of AD or other related abnormalities, such as vascular disease, remains unclear.
To investigate the association between serial measures of glucose intolerance and insulin resistance and in vivo brain β-amyloid burden, measured with carbon 11–labeled Pittsburgh Compound B (11C-PiB), and AD pathology at autopsy.
Scores calculated from the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) and Braak criteria were correlated with measures of hyperglycemia, hyperinsulinemia, glucose intolerance, and insulin resistance in 197 participants who underwent autopsy after death and who had undergone 2 or more oral glucose tolerance tests (OGTT) using grouped analyses and a continuous mixed-models analysis. The same measures of glucose intolerance and insulin resistance were also correlated with brain 11C-PiB retention in an additional 53 living subjects from the Baltimore Longitudinal Study of Aging neuroimaging study.
Prospective, serially assessed cohort of community-dwelling subjects.
Cohort 1 consisted of 197 participants enrolled in the Baltimore Longitudinal Study of Aging who had 2 or more OGTTs during life and a complete brain autopsy after death. Cohort 2 consisted of 53 living subjects who had 2 or more OGTTs and underwent brain 11C-PiB positron emission tomography.
Autopsy and 11C-PiB positron emission tomography.
The correlation of brain markers of AD, including CERAD score, Braak score, and 11C-PiB retention, with serum markers of glucose homeostasis using grouped and continuous mixed-models analyses.
We found no significant correlations between measures of brain AD pathology or 11C-PiB β-amyloid load and glucose intolerance or insulin resistance in subjects who had a mean (SD) of 6.4 (3.2) OGTTs during 22.1 (8.0) years of follow-up. Thirty subjects with frank diabetes mellitus who received medications also had AD pathology scores that were similar to those of the cohort as a whole.
In this prospective cohort with multiple assessments of glucose intolerance and insulin resistance, measures of glucose and insulin homeostasis are not associated with AD pathology and likely play little role in AD pathogenesis. Long-term therapeutic trials are important to elucidate this issue.
外周葡萄糖稳态与阿尔茨海默病（AD）的发病机制有关。糖尿病、胰岛素与 AD 之间的关系是一个重要的研究领域。然而，糖尿病患者认知功能障碍是否是由 AD 的过度病理性特征或其他相关异常（如血管疾病）引起的，目前仍不清楚。
本研究旨在通过使用碳 11-标记的匹兹堡化合物 B（11C-PiB），检测体内脑β-淀粉样蛋白负荷，并结合尸检 AD 病理学，探讨多次测量的葡萄糖耐量和胰岛素抵抗与 AD 之间的相关性。
采用队列研究，对 197 名接受尸检的参与者进行分组分析和连续混合模型分析，将使用 Consorcium to Establish a Registry for Alzheimer’s Disease（CERAD）和 Braak 标准计算的分数与高血糖、高胰岛素血症、葡萄糖耐量受损和胰岛素抵抗的测量值相关联。在巴尔的摩纵向研究衰老神经影像学研究中，另外 53 名生活受试者也进行了相同的葡萄糖耐量和胰岛素抵抗测量，并与脑 11C-PiB 保留率相关联。
社区居住受试者的前瞻性、连续评估队列。
队列 1 由 197 名参加巴尔的摩纵向研究衰老的参与者组成，这些参与者在生前进行了 2 次或以上口服葡萄糖耐量试验（OGTT），死后进行了完整的大脑尸检。队列 2 由 53 名生活受试者组成，他们进行了 2 次或以上 OGTT，并进行了脑 11C-PiB 正电子发射断层扫描。
尸检和 11C-PiB 正电子发射断层扫描。
使用分组和连续混合模型分析，将 AD 脑标志物（包括 CERAD 评分、Braak 评分和 11C-PiB 保留率）与葡萄糖稳态的血清标志物进行相关性分析。
在平均（标准差）进行了 6.4（3.2）次 OGTT 的 22.1（8.0）年随访中，我们未发现脑 AD 病理学或 11C-PiBβ-淀粉样蛋白负荷与葡萄糖耐量或胰岛素抵抗之间有显著相关性。30 名患有明显糖尿病且接受药物治疗的受试者的 AD 病理学评分与整个队列相似。
在这项具有多次葡萄糖耐量和胰岛素抵抗评估的前瞻性队列研究中，葡萄糖和胰岛素稳态的测量值与 AD 病理学无关，并且可能在 AD 发病机制中作用不大。长期治疗试验对于阐明这一问题很重要。
