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/概要 几项研究报告了癌症和阿尔茨海默病（AD）之间的逆共病。发生率 癌症幸存者的AD比没有癌症史的人低约30%。最近的调查结果 表明癌症后不同存活率不能完全解释这种反向关联， 解释是假设的。肿瘤细胞的生长可能是细胞增殖的另一面， 导致AD中神经元死亡的过程;例如调节细胞凋亡、免疫应答或 DNA修复可以解释癌症和AD的逆共病。如果两个变量之间的反向关联 癌症和AD源于一个共同的生理过程，解释这种关联可以揭示新的 深入了解AD的病理生理学，并强调预防或治疗干预的目标。我们 建议评估癌症-AD反向关联的竞争性解释：（1）诊断偏倚： 有癌症史的人不太可能被诊断为AD;（2）竞争风险：两种情况 增加死亡率，因此任何一种的发生都会降低另一种的终生风险;（3）生存偏倚： 癌症患者生存率的提高与AD风险的降低有关，因此癌症幸存者是一个有偏见的样本 所有癌症患者;（4）反向共同原因：癌症发病率因遗传或环境因素而降低 增加AD风险的因素;（5）因果关系：对癌症的生理或治疗反应降低AD风险。 我们将系统地评估这5种癌症和AD反向共病的替代解释， 目的是提高对引发或维持阿尔茨海默氏症的生物学事件的理解， 级联。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，以评估竞争的可行性， 解释。在AIM 1中，我们评估了癌症与HRS中认知变化纵向速率之间的联系 和UKB。只有一项先前的研究评估了癌症和纵向认知变化。我们假设 在癌症诊断之前和之后，认知能力下降的速度都会变慢，即使是非危及生命的癌症， 与没有癌症诊断的人相比。在AIM 2中，我们测试癌症是否具有遗传风险因素 AD或认知改变。我们使用全基因组数据构建多基因癌症风险评分， 使用先前证实会影响癌症风险的特定变异。然后我们评估这些多基因的 癌症风险分数预测AD的风险较低。我们还研究了相反的情况，多基因AD风险评分 预测较低的癌症风险。在AIM 3中，我们结合了联合收割机多种癌症类型特异性死亡率的证据来源 率，遗传相关性，并与AD的关联，以指定模拟模型。结合起来，这些 观察结果将证明癌症-AD反向联系的最可能的解释。 我们利用癌症和AD的明显矛盾的逆共病性来获得对AD的新见解。 生物学机制的基础上，AD和指向新的预防和治疗策略的方式。 页面|1

项目成果

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。

• DOI: 10.1007/s10654-023-01036-x
• 发表时间: 2023
• 期刊: European journal of epidemiology
• 影响因子: 13.6
• 作者: Wang,Jingxuan;Buto,Peter;Ackley,SarahF;Kobayashi,LindsayC;Graff,RebeccaE;Zimmerman,ScottC;Hayes-Larson,Eleanor;Mayeda,ElizabethRose;Asiimwe,StephenB;Calmasini,Camilla;Glymour,MMaria
• 通讯作者: Glymour,MMaria

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

• DOI: 10.1001/jamanetworkopen.2020.25515
• 发表时间: 2020-11-02
• 期刊: JAMA network open
• 影响因子: 13.8
• 作者: Ospina-Romero M;Glymour MM;Hayes-Larson E;Mayeda ER;Graff RE;Brenowitz WD;Ackley SF;Witte JS;Kobayashi LC
• 通讯作者: Kobayashi LC

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。

• DOI: 10.1093/gerona/glab341
• 发表时间: 2022
• 期刊: The journals of gerontology. Series A, Biological sciences and medical sciences
• 作者: Hayes-Larson,Eleanor;Shaw,Crystal;Ackley,SarahF;Zimmerman,ScottC;Glymour,MMaria;Graff,RebeccaE;Witte,JohnS;Kobayashi,LindsayC;Mayeda,ElizabethRose
• 通讯作者: Mayeda,ElizabethRose

Education, incident cancer, and rate of memory decline in a national sample of US adults in mid-to-later-life.

美国中年成年人全国样本的教育程度、癌症发生率和记忆力下降率。

• DOI: 10.1016/j.jgo.2023.101530
• 发表时间: 2023
• 期刊: Journal of geriatric oncology
• 影响因子: 3
• 作者: Ospina-Romero,Monica;Brenowitz,WillaD;Glymour,MMaria;Westrick,Ashly;Graff,RebeccaE;Hayes-Larson,Eleanor;Mayeda,ElizabethRose;Ackley,SarahF;Kobayashi,LindsayC
• 通讯作者: Kobayashi,LindsayC