Lower Incidence of Dementia Following Cancer Diagnoses: Evidence from a Large Cohort and Mendelian Randomization Study

D. T. Bassil, B. Zheng, B. Su, D. Kafetsouli, C. Udeh-Momoh, I. Tzoulaki, S. Ahmadi-Abhari, D. C. Muller, Elio Riboli, L. T. Middleton
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Abstract

Background

The reported inverse association between cancer and subsequent Alzheimer’s disease and related dementias (ADRD) remains uncertain.

Objectives

To investigate the association between these common conditions of old age and explore possible causal factors.

Design, Setting, Participants and Measurements

We conducted a large population-based cohort analysis using data from 3,021,508 individuals aged 60 and over in the UK Clinical Practice Research Datalink (CPRD), over a period up to 30 years (1988–2018). Cox proportional hazards models were fitted to estimate hazard ratios (HR) for risk of dementia associated with previous cancer diagnosis. Competing risk models were employed to account for competing risk of death. Two-sample Mendelian Randomization analysis based on meta-analysis data from large-scale GWAS studies was also conducted.

Results

In the CPRD cohort, 412,903 participants had cancer diagnosis and 230,558 were subsequently diagnosed with dementia over a median follow-up period of 7.9 years. Cancer survivors had a 25% lower risk of developing dementia (HR=0.75, 95% CI:0.74–0.76) after adjustment for potential confounders. Accounting for competing risk of death provided a sub-distribution HR of 0.56 (95% CI:0.55–0.56). Results were consistent for prevalent and incident cancer and different common cancer types. Two-sample Mendelian Randomization analysis, using 357 cancer-related instrumental single-nucleotide polymorphisms (SNPs) revealed evidence of vertical pleiotropy between genetically predicted cancer and reduced risk of Alzheimer’s disease (OR=0.97,95% CI:0.95–0.99).

Conclusion

Our results provide strong epidemiological evidence of the inverse association between cancer and risk of ADRD and support the potential causal nature of this association via genetic instruments. Further investigations into the precise underlying biological mechanisms may reveal valuable information for new therapeutic approaches.

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癌症诊断后痴呆症发病率降低:来自大型队列和孟德尔随机研究的证据
背景据报道,癌症与阿尔茨海默病及相关痴呆症(ADRD)之间的反比关系仍不确定。目的研究这些常见老年疾病之间的关系,并探讨可能的致病因素。设计、设置、参与者和测量我们利用英国临床实践研究数据链接(CPRD)中 3,021,508 名 60 岁及以上的人的数据进行了一项大型人群队列分析,分析时间跨度长达 30 年(1988-2018 年)。采用 Cox 比例危险模型估算与既往癌症诊断相关的痴呆症风险的危险比 (HR)。采用竞争风险模型来考虑死亡的竞争风险。结果在 CPRD 队列中,有 412,903 人曾被诊断患有癌症,230,558 人随后被诊断患有痴呆症,随访时间中位数为 7.9 年。在对潜在的混杂因素进行调整后,癌症幸存者患痴呆症的风险降低了25%(HR=0.75,95% CI:0.74-0.76)。考虑到死亡的竞争风险,亚分布HR为0.56(95% CI:0.55-0.56)。流行性癌症和偶发性癌症以及不同常见癌症类型的结果是一致的。使用 357 个与癌症相关的工具性单核苷酸多态性(SNPs)进行的双样本孟德尔随机分析表明,在遗传预测的癌症与阿尔茨海默病风险降低之间存在垂直多效性(OR=0.97,95% CI:0.95-0.99)。进一步研究其确切的生物学机制可能会为新的治疗方法提供有价值的信息。
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来源期刊
The Journal of Prevention of Alzheimer's Disease
The Journal of Prevention of Alzheimer's Disease Medicine-Psychiatry and Mental Health
CiteScore
9.20
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期刊介绍: The JPAD Journal of Prevention of Alzheimer’Disease will publish reviews, original research articles and short reports to improve our knowledge in the field of Alzheimer prevention including: neurosciences, biomarkers, imaging, epidemiology, public health, physical cognitive exercise, nutrition, risk and protective factors, drug development, trials design, and heath economic outcomes.JPAD will publish also the meeting abstracts from Clinical Trial on Alzheimer Disease (CTAD) and will be distributed both in paper and online version worldwide.We hope that JPAD with your contribution will play a role in the development of Alzheimer prevention.
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