The inverse association between cancer and Alzheimers disease: comparing spurious and causal explanations to illuminate the causes of Alzheimers disease

癌症与阿尔茨海默病之间的负相关：比较虚假解释和因果解释以阐明阿尔茨海默病的原因

• 批准号: 10465775
• 负责人: Medellena Maria Glymour
• 金额: $ 39.99万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10465775
• 关键词: Accounting; Alzheimer' s Disease; Alzheimer' s disease risk; Apoptosis; Biological; Cancer Patient; Cancer Survivor; Cell Cycle; Cell division; Cell physiology; DNA Repair; Data; Diagnosis; Diagnostic; Elderly; Environmental Risk Factor; Enzymes; Epidemiology; Etiology; Event; Functional disorder; Genetic; Health and Retirement Study; Immune response; Impaired cognition; Incidence; Individual; Learning; Link; Longitudinal Studies; Malignant Neoplasms; Measures; Meta-Analysis; Metabolism; Methods; Natural Immunity; Nerve Degeneration; Onset of illness; Pattern; Physiological; Physiological Processes; Physiology; Preventive; Process; Quasi-experiment; Recording of previous events; Regulation; Reporting; Research; Research Design; Risk; Risk Factors; Sampling Biases; Sampling Studies; Side; Smoking; Source; Testing; Therapeutic; Therapeutic Intervention; Time; To specify; Variant; base; biobank; cancer diagnosis; cancer risk; cancer survival; cancer therapy; cancer type; cell growth; cognitive change; cohort; comorbidity; follow-up; genetic risk factor; genetic variant; genome-wide; improved; innovation; insight; lifetime risk; longitudinal analysis; middle age; models and simulation; mortality; neoplastic cell; neuron loss; non-smoking; novel; novel strategies; overexpression; prevent; preventive intervention; simulation; theories; treatment response

Abstract/Summary Several studies report an inverse comorbidity between cancer and Alzheimer’s Disease (AD). Incidence rates of AD are about 30% lower among cancer survivors than individuals with no history of cancer. Recent findings indicate that differential survival after cancer cannot fully explain this inverse association, and biological explanations are hypothesized. Neoplastic cell growth underlying cancer may be the flip side of the cellular process that contributes to neuronal death in AD; for example regulation of apoptosis, immune response, or DNA repair may account for the inverse comorbidity of cancer and AD. If the inverse association between cancer and AD arises from a common physiologic process, explaining this association could reveal novel insights into the pathophysiology of AD and highlight targets for preventive or therapeutic interventions. We propose to evaluate competing explanations for the inverse cancer-AD association : (1) diagnostic bias: individuals with a history of cancer are less likely to be diagnosed with AD; (2) competing risks: both conditions increase mortality, so occurrence of either reduces lifetime risk of the other; (3) survival bias: factors that improve survival of cancer patients are associated with lower AD risk, so cancer survivors are a biased sample of all cancer patients; (4) inverse common causes: cancer incidence is reduced by genetic or environmental factors which increase AD risk; (5) causality: physiologic or treatment responses to cancer reduce risk of AD. We will systematically evaluate these 5 alternative explanations for the inverse comorbidity of cancer and AD, with the aim of improving understanding of the biological events that initiate or maintain the Alzheimer’s cascade. We use longitudinal analyses of two large cohorts (the Health and Retirement Study [HRS] and the UK Biobank [UKB]), genetic quasi-experiments, and simulation models to evaluate the plausibility of competing explanations. In AIM 1, we evaluate the link between cancer and longitudinal rate of cognitive change in HRS and UKB. Only one prior study evaluated cancer and longitudinal cognitive change. We hypothesize that cognitive decline will be slower both before and after cancer diagnosis, even for non-life-threatening cancers, compared to people with no cancer diagnosis. In AIM 2, we test whether cancer shares genetic risk factors with AD or cognitive change. We construct polygenic cancer risk scores both using genome-wide data and using specific variants previously confirmed to influence cancer risk. We then assess whether these polygenic cancer risk scores predict lower risk of AD. We also examine the reverse, whether polygenic AD risk scores predict lower cancer risk. In AIM 3, we combine multiple sources of evidence on cancer type specific mortality rates, genetic correlations, and associations with AD to specify simulation models. In combination, these observations will demonstrate the most likely explanation for the inverse cancer-AD link. We leverage the apparently paradoxical inverse comorbidity of cancer and AD to gain new insights into the biological mechanisms underlying AD and point the way towards novel preventive and therapeutic strategies. Page |1

摘要/总结 多项研究报告癌症和阿尔茨海默病 (AD) 的发病率呈负相关。 癌症幸存者中 AD 的发病率比没有癌症病史的人低约 30%。 表明癌症后的生存差异不能完全解释这种负相关性，并且生物学 癌症背后的肿瘤细胞生长可能是细胞的另一面。 导致 AD 中神经死亡的过程；例如细胞凋亡、免疫反应的调节，或 DNA 修复可能解释了癌症和 AD 之间的负相关性。 癌症和 AD 源于共同的生理过程，解释这种关联可以揭示新的 深入了解 AD 的病理生理学并突出预防或治疗干预的目标。 提议评估癌症-AD 反向关联的竞争性解释：(1) 诊断偏倚： (2)竞争风险：两种情况 (3) 生存偏差：影响因素 提高癌症患者的生存率与降低 AD 风险相关，因此癌症幸存者是一个有偏差的样本 所有癌症患者中；（4）逆常见原因：遗传或环境降低癌症发病率 增加 AD 风险的因素；(5) 因果关系：对癌症的生理或治疗反应可降低 AD 风险。 我们将系统地评估这 5 种对癌症和 AD 反向共病的替代解释， 目的是增进对引发或维持阿尔茨海默病的生物事件的理解 我们使用两个大型队列的纵向分析（健康与退休研究 [HRS] 和 英国生物银行[UKB]）、遗传准实验和模拟模型来评估竞争的合理性 在 AIM 1 中，我们评估了癌症与 HRS 认知变化纵向率之间的联系。 我们之前只有一项研究评估了癌症和纵向认知变化。 在癌症诊断之前和之后，认知能力下降都会减慢，即使对于不危及生命的癌症， 在 AIM 2 中，我们测试癌症是否具有相同的遗传风险因素。 我们使用全基因组数据和认知变化构建多基因癌症风险评分。 然后我们使用先前证实会影响癌症风险的特定变异来评估这些多基因是否存在。 癌症风险评分可预测 AD 风险较低，我们还研究了相反的情况，即多基因 AD 风险评分是否存在。 在 AIM 3 中，我们结合了有关癌症类型特定死亡率的多种证据来源。 率、遗传相关性以及与 AD 的关联来指定模拟模型。 观察结果将证明癌症与 AD 反向联系的最可能的解释。 我们利用癌症和 AD 之间明显矛盾的逆并存关系来获得对这一问题的新见解。 AD 的生物学机制，并为新的预防和治疗策略指明了道路。 页 |1

项目成果

Alzheimer's and Parkinson's Diseases and the Risk of Cancer: A Cohort Study.

阿尔茨海默病和帕金森病以及癌症风险：一项队列研究。

• 发表时间: 2019
• 作者: Ording, Anne G;Veres, Katalin;Horváth;Glymour, M Maria;Rørth, Mikael;Henderson, Victor W;Sørensen, Henrik T
• 通讯作者: Sørensen, Henrik T

Association between cancer and dementia risk in the UK Biobank: evidence of diagnostic bias.

英国生物银行癌症与痴呆风险之间的关联：诊断偏倚的证据。

• 发表时间: 2023-10
• 影响因子: 13.6
• 作者: Wang, Jingxuan;Buto, Peter;Ackley, Sarah F;Kobayashi, Lindsay C;Graff, Rebecca E;Zimmerman, Scott C;Hayes;Mayeda, Elizabeth Rose;Asiimwe, Stephen B;Calmasini, Camilla;Glymour, M Maria
• 通讯作者: Glymour, M Maria

Rate of Memory Change Before and After Cancer Diagnosis.

癌症诊断前后的记忆变化率。

• 发表时间: 2019-06-05
• 影响因子: 13.8
• 作者: Ospina;Abdiwahab, Ekland;Kobayashi, Lindsay;Filshtein, Teresa;Brenowitz, Willa D;Mayeda, Elizabeth R;Glymour, M Maria
• 通讯作者: Glymour, M Maria

Association Between Alzheimer Disease and Cancer With Evaluation of Study Biases: A Systematic Review and Meta-analysis.

阿尔茨海默病和癌症之间的关联与研究偏差的评估：系统评价和荟萃分析。

• 发表时间: 2020
• 影响因子: 13.8
• 作者: Ospina;Glymour, M Maria;Hayes;Mayeda, Elizabeth Rose;Graff, Rebecca E;Brenowitz, Willa D;Ackley, Sarah F;Witte, John S;Kobayashi, Lindsay C
• 通讯作者: Kobayashi, Lindsay C

The Role of Dementia Diagnostic Delay in the Inverse Cancer-Dementia Association.

痴呆诊断延迟在癌症-痴呆反向关联中的作用。

• 发表时间: 2022
• 作者: Hayes;Shaw, Crystal;Ackley, Sarah F;Zimmerman, Scott C;Glymour, M Maria;Graff, Rebecca E;Witte, John S;Kobayashi, Lindsay C;Mayeda, Elizabeth Rose
• 通讯作者: Mayeda, Elizabeth Rose