Associations between Potentially Modifiable Risk Factors and Alzheimer Disease: A Mendelian Randomization Study

Abstract Dementia and cognitive impairment can be attributed to both genetic and modifiable risk factors. Recently, considerable evidence emerged and urgently require standardized evaluation. To address it, we conducted an umbrella review of prospective studies regarding the associations of dementia and cognitive impairment with modifiable factors to evaluate the strength and validity of the existing evidence. We searched PubMed, Embase, CINAHL and Cochrane Database of Systematic Reviews to identify relevant systematic reviews and meta-analyses of prospective studies. Mendelian randomization studies were reviewed to assess the causality for these associations. For each association, we analyzed the summary effect size, 95% confidence interval, 95% prediction interval, heterogeneity, small study effect and excess significance bias. Based on these estimates, the evidence was graded into levels of convincing, highly suggestive, suggestive, or weak. In total, 12015 articles were identified, of which 118 eligible studies yielded 243 unique associations. Convincing evidence was found for associations of dementia and cognitive impairment with early-life education, midlife to late-life plasma glucose, body mass index, atrial fibrillation, benzodiazepine use, and gait speed. Suggestive to highly suggestive evidence was found for associations of dementia and cognitive impairment with midlife to late-life blood pressure, homocysteine, cerebrovascular diseases, hearing impairment, respiratory illness, anemia, smoking, alcohol consumption, diet, sleep, physical activity and social engagement. Among convincing evidence, Mendelian randomization studies verified genetic predicted causal relationships for education and plasma glucose with Alzheimer's disease. Modifiable factors identified in this study, especially those with high-level evidence, should be considered in dementia prevention. Trial registration: PROSPERO CRD42020195729.

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Evaluating causal associations between previously reported risk factors and epithelial ovarian cancer: a Mendelian randomization analysis

10.1101/472696 ◽

2018 ◽

Cited By ~ 1

Author(s):

James Yarmolinsky ◽

Caroline L Relton ◽

Artitaya Lophatananon ◽

Kenneth Muir ◽

Usha Menon ◽

...

Keyword(s):

Risk Factors ◽

Ovarian Cancer ◽

Cancer Risk ◽

Epithelial Ovarian Cancer ◽

Genetic Variants ◽

Mendelian Randomization ◽

Modifiable Risk Factors ◽

Ovarian Cancer Risk ◽

Genetic Liability ◽

Suggestive Evidence

AbstractBackgroundVarious modifiable risk factors have been associated with epithelial ovarian cancer risk in observational epidemiological studies. However, the causal nature of the risk factors reported, and thus their suitability as effective intervention targets, is unclear given the susceptibility of conventional observational designs to residual confounding and reverse causation. Mendelian randomization uses genetic variants as proxies for modifiable risk factors to strengthen causal inference in observational studies. We used Mendelian randomization to evaluate the causal role of 13 previously reported risk factors (reproductive, anthropometric, clinical, lifestyle, and molecular factors) in overall and histotype-specific epithelial ovarian cancer in up to 25,509 case subjects and 40,941 controls in the Ovarian Cancer Association Consortium.Methods and FindingsGenetic instruments to proxy 13 risk factors were constructed by identifying single nucleotide polymorphisms (SNPs) robustly (P<5×10−8) and independently associated with each respective risk factor in previously reported genome-wide association studies. SNPs were combined into multi-allelic inverse-variance weighted fixed or random-effects models to generate causal estimates. Three complementary sensitivity analyses were performed to examine violations of Mendelian randomization assumptions: MR-Egger regression and weighted median and mode estimators. A Bonferroni-corrected P-value threshold was used to establish “strong evidence” (P<0.0038) and “suggestive evidence” (0.0038<P<0.05) for associations.In Mendelian randomization analyses, there was strong or suggestive evidence that 9 of 13 risk factors had a causal effect on overall or histotype-specific epithelial ovarian cancer. There was strong evidence that genetic liability to endometriosis increased risk of epithelial ovarian cancer (OR per log odds higher liability:1.27, 95% CI: 1.16-1.40; P=6.94×10−7) and suggestive evidence that lifetime smoking exposure increased risk of epithelial ovarian cancer (OR per unit increase in smoking score:1.36, 95% CI: 1.04-1.78; P=0.02). In histotype-stratified analyses, the strongest associations found were between: height and clear cell carcinoma (OR per SD increase:1.36, 95% CI: 1.15-1.61; P=0.0003); age at natural menopause and endometrioid carcinoma (OR per year later onset:1.09, 95% CI: 1.02-1.16; P=0.007); and genetic liability to polycystic ovary syndrome and endometrioid carcinoma (OR per log odds higher liability:0.74, 95% CI:0.62-0.90; P=0.002). There was little evidence for an effect of genetic liability to type 2 diabetes, parity, or circulating levels of 25-hydroxyvitamin D and sex hormone-binding globulin on ovarian cancer or its subtypes. The primary limitations of this analysis include: modest statistical power for analyses of risk factors in relation to some less common ovarian cancer histotypes (low grade serous, mucinous, and clear cell carcinomas), the inability to directly examine the causal effects of some ovarian cancer risk factors that did not have robust genetic variants available to serve as proxies (e.g., oral contraceptives, hormone replacement therapy), and the assumption of linear relationships between risk factors and ovarian cancer risk.ConclusionsOur comprehensive examination of possible etiological drivers of ovarian carcinogenesis using germline genetic variants to proxy risk factors supports a causal role for few of these factors in epithelial ovarian cancer and suggests distinct etiologies across histotypes. The identification of novel modifiable risk factors remains an important priority for the control of epithelial ovarian cancer.

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Antidiabetic therapies and Alzheimer disease

Dialogues in Clinical Neuroscience ◽

10.31887/dcns.2019.21.1/bbendlin ◽

2019 ◽

Vol 21 (1) ◽

pp. 83-91 ◽

Cited By ~ 3

Keyword(s):

Physical Activity ◽

Risk Factors ◽

Alzheimer Disease ◽

Modifiable Risk Factors ◽

Cardiovascular Risks ◽

Increased Risk ◽

Modifiable Factors ◽

Diet And Physical Activity ◽

Substantial Interest

Given current lack of therapies for dementia, there is substantial interest in identifying potentially modifiable risk factors. Clarifying the potential of these factors to mitigate risk as well as determining the mechanisms that link these factors to dementia is expected to lead to new approaches for both preventing and treating neurodegenerative diseases such as Alzheimer disease. Modifiable factors include cardiovascular risks as well as related lifestyle-centric factors such as diet and physical activity (reviewed in this issue). Given reports that type 2 diabetes and associated features increase the risk for developing dementia, there has been tremendous interest in exploring whether use of antidiabetic medications may impact the risk of dementia, as well as whether antidiabetic medications could be used to prevent or treat dementia, particularly Alzheimer disease. This review will briefly cover the known links between diabetes and risk for dementia, the state of evidence linking antidiabetic treatments with either protection against dementia or possibly increased risk for cognitive dysfunction, and provide a brief overview of what has been learned from clinical trials testing antidiabetic treatments in Alzheimer disease.

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