Association Between Alzheimer Disease and Cancer With Evaluation of Study Biases: A Systematic Review and Meta-analysis - PubMed (original) (raw)

Meta-Analysis

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

Monica Ospina-Romero et al. JAMA Netw Open. 2020.

Abstract

Importance: Observational studies consistently report inverse associations between cancer and Alzheimer disease (AD). Shared inverse etiological mechanisms might explain this phenomenon, but a systematic evaluation of methodological biases in existing studies is needed.

Objectives: To systematically review and meta-analyze evidence on the association between cancer and subsequent AD, systematically identify potential methodological biases in studies, and estimate the influence of these biases on the estimated pooled association between cancer and AD.

Data sources: All-language publications were identified from PubMed, Embase, and PsycINFO databases through September 2, 2020.

Study selection: Longitudinal cohort studies and case-control studies on the risk of AD in older adults with a history of any cancer type, prostate cancer, breast cancer, colorectal cancer, or nonmelanoma skin cancer, relative to those with no cancer history.

Data extraction and synthesis: Two reviewers independently abstracted the data and evaluated study biases related to confounding, diagnostic bias, competing risks, or survival bias. Random-effects meta-analysis was used to provide pooled estimates of the association between cancer and AD. Metaregressions were used to evaluate whether the observed pooled estimate could be attributable to each bias. The study was designed and conducted according to the Preferring Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline.

Main outcomes and measures: Incidence, hazard, or odds ratios for AD comparing older adults with vs without a previous cancer diagnosis.

Results: In total, 19 cohort studies and 3 case-control studies of the associations between any cancer type (n = 13), prostate cancer (n = 5), breast cancer (n = 1), and nonmelanoma skin cancer (n = 3) with AD were identified, representing 9 630 435 individuals. In all studies combined, cancer was associated with decreased AD incidence (cohort studies: random-effects hazard ratio, 0.89; 95% CI, 0.79-1.00; case-control studies: random-effects odds ratio, 0.75; 95% CI, 0.61-0.93). Studies with insufficient or inappropriate confounder control or greater likelihood of AD diagnostic bias had mean hazard ratios closer to the null value, indicating that these biases could not explain the observed inverse association. Competing risks bias was rare. Studies with greater likelihood of survival bias had mean hazard ratios farther from the null value.

Conclusions and relevance: The weak inverse association between cancer and AD may reflect shared inverse etiological mechanisms or survival bias but is not likely attributable to diagnostic bias, competing risks bias, or insufficient or inappropriate control for potential confounding factors.

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Conflict of interest statement

Conflict of Interest Disclosures: None reported.

Figures

Figure 1.. Directed Acyclic Graphs Depicting Alternative Explanations for the Observed Cancer–Alzheimer Disease (AD) Association

The panel headings A through G correspond to the scenarios depicted in each panel. The directed acyclic graphs presented in panels A through G represent assumed data structures that could lead to spurious observed associations between cancer and AD. A, The direct arrow from cancer to AD indicates a causal association between cancer and subsequent AD risk. B, The direct arrows from unknown confounders U to cancer and to AD indicate that these conditions share a common cause. C-G, Alternative (noncausal) explanations for the cancer-AD association with no meaningful contribution of cancer to the etiology of neurodegeneration. C, The missing box around “Known confounders” indicates lack of statistical control for known confounders of the cancer-AD association. D, Adjustment for downstream variables, such as cancer treatment and comorbidities after cancer, is always inappropriate because it can introduce bias. E, A history of cancer diagnosis may influence the probability of receiving a diagnosis of AD. F, Cancer reduces life expectancy, and death is a competing risk to AD diagnosis. G, An unmeasured factor U promotes survival after cancer and reduces risk of AD. (The box around “Survival after cancer” indicates the restriction of the study population to those who survived cancer.)

Figure 2.. Forest Plot of Random-Effects Models for the Pooled Cancer–Alzheimer Disease (AD) Risk Estimatesa

Random-effects meta-analyses were stratified by cancer type and study design. HR indicates hazard ratio; OR, odds ratio. Solid squares represent individual study estimates. The diamonds represent pooled estimates from the random-effects models. aThe random-effects meta-analysis for cohort studies (16 studies) includes only the main study results to avoid double counting study participants when cancer type-specific subgroup analyses were performed.

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Association Between Alzheimer Disease and Cancer With Evaluation of Study Biases: A Systematic Review and Meta-analysis - PubMed (original) (raw)