Investigating the link between cancer and neurodegenerative disease

描述(由申请人提供)： 阿尔茨海默病(AD)是当今影响老年退伍军人的最具破坏性的疾病之一，尽管进行了数十年的紧张研究，但仍然没有有效的治疗方法。令人信服的流行病学证据表明，癌症幸存者患AD的风险较低，AD患者患癌症的风险较低。在这项建议中，我们继续提出这样的假设，即这种反向关联可能是预防和治疗AD的新方法的关键。我们在全国退伍军人队列中的试点数据显示，许多癌症类型的幸存者患AD的风险降低，这与癌症治疗无关，接受化疗的人风险甚至更低。化疗的保护作用似乎不能用癌症患者较早死亡或较少被诊断为其他疾病来解释。抗癌治疗可以降低AD的风险是很有可能的，因为一些常见的药物已知通过稳定微管和溶解缠结等多种机制改善AD小鼠模型的预后。其他抗癌药物在细胞周期的早期阶段中断细胞周期，从而可能防止神经细胞死亡。此外，癌症和阿尔茨海默病有许多重要的病理生理特征，包括氧化应激、代谢失调、DNA损伤和炎症。抑制这些途径的药物可能被用于这两种疾病的化学预防。一个例子是糖尿病药物二甲双胍，有新的证据表明它具有抗肿瘤和神经保护作用。在这份提案中，我们的多学科研究团队将进一步探索 利用马萨诸塞州退伍军人流行病学研究和信息中心和哈佛大学公共卫生学院统计遗传学系的丰富资源，研究AD和癌症之间的流行病学和生物学联系。在目标1中，我们将在超过350万退伍军人的全国数据集中调查20种不同癌症类型与阿尔茨海默病的相关性。我们将通过验证更准确的AD定义、通过退伍军人管理局癌症注册中心确认癌症诊断以及请求相关的医疗保险数据来完善我们的试点分析。在目标2中，我们将在国家VA数据集和我们更详细的药物流行病学数据库中检查特定类别的抗肿瘤治疗与AD风险之间的关系。我们还将确定经常服用二甲双胍的患者患AD的风险是否较低。在目标3中，我们将对已发表的关于癌症和阿尔茨海默病的研究进行全基因组荟萃分析，以确定这两种疾病的共同遗传变异。我们将使用新技术，如基因集浓缩、途径和网络分析，深入了解常见的生物途径。这些研究的成功完成将产生关于可以重新定位为AD治疗或化学预防的药物的重要假设，并导致将直接使美国退伍军人受益的临床试验。表征癌症和AD之间的生物学重叠可能会产生新的病理生理学见解，并可能确定新的治疗靶点。

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is among the most devastating conditions that affect older Veterans today, and despite decades of intense research, there is still no effective treatment. Convincing epidemiologic evidence suggests that cancer survivors have a lower risk of AD, and that people with AD have a lower risk of cancer. In this proposal, we pursue the hypothesis that this inverse association may hold the key to new approaches to prevention and treatment of AD. Our pilot data in a national cohort of Veterans shows that survivors of many cancer types have a decreased risk of AD that is independent of cancer treatment, and that those who receive chemotherapy have an even lower risk. The protective effect of chemotherapy did not seem to be explained by earlier death or less frequent diagnosis of other conditions among cancer patients. It is quite plausible that anti-cancer treatments could decrease AD risk, since some common drugs are known to improve outcomes in mouse models of AD through multiple mechanisms including stabilization of microtubules and dissolution of tangles. Other cancer drugs interrupt the cell cycle in its early stages, and may thus prevent neuronal cell death. Furthermore, cancer and AD share many key pathophysiologic features, including oxidative stress, metabolic dysregulation, DNA damage, and inflammation. Agents that suppress these pathways might be used as chemoprevention for both diseases. One example is the diabetes drug metformin, for which there is emerging evidence of both anti-neoplastic and neuroprotective effects. In this proposal, our multidisciplinary research team will further explore the epidemiologic and biological link between AD and cancer using the rich resources of the Massachusetts Veterans Epidemiology Research and Information Center and the Department of Statistical Genetics at the Harvard School of Public Health. In Aim 1 we will investigate the association between 20 different cancer types and AD in our national dataset of over 3.5 million Veterans. We will refine our pilot analyses by validating a more accurate definition of AD, confirming the cancer diagnosis through the VA Cancer Registry, and requesting linked Medicare data. In Aim 2, we will examine the relationship between particular classes of anti-neoplastic therapy and the risk of AD in both the national VA dataset and our more detailed pharmaco-epidemiology database. We will also determine whether regular users of metformin have a lower risk of AD. In Aim 3, we will perform genome-wide meta- analyses of published studies on cancer and AD to identify shared genetic variants of both diseases. We will gain insight into common biological pathways using novel techniques such as gene-set enrichment, pathway and network analysis. Successful completion of these studies will generate important hypotheses about drugs that could be repositioned as treatment or chemoprevention for AD, and lead to clinical trials that would directly benefit US Veterans. Characterization of the biological overlap between cancer and AD will likely yield new pathophysiologic insights and could identify new targets for therapy.