Re-thinking Alzheimer\u27s disease therapeutic targets using gene-based tests

Background: Alzheimer\u27s disease (AD) is a devastating condition with no known effective drug treatments. Existing drugs only alleviate symptoms. Given repeated expensive drug failures, we assessed systematically whether approved and investigational AD drugs are targeting products of genes strongly associated with AD and whether these genes are targeted by existing drugs for other indications which could be re-purposed. Methods: We identified genes strongly associated with late-onset AD fromthe loci of genetic variants associated with AD at genome-wide-significance and from a gene-based test applied to the most extensively genotyped late-onset AD case (n=17,008)-control (n=37,154) study, the International Genomics of Alzheimer\u27s Project. We used three gene-to-drug cross-references, Kyoto Encyclopedia of Genes and Genomes, Drugbank and Drug Repurposing Hub, to identify genetically validated targets of AD drugs and any existing drugs or nutraceuticals targeting products of the genes strongly associated with late-onset AD. Findings: A total of 67 autosomal genes (forming 9 gene clusters) were identified as strongly associated with lateonset AD, 28 from the loci of single genetic variants, 51 from the gene-based test and 12 by both methods. Existing approved or investigational AD drugs did not target products of any of these 67 genes. Drugs for other indications targeted 11 of these genes, including immunosuppressive disease-modifying anti-rheumatic drugs targeting PTK2B gene products. Interpretation: Approved and investigational AD drugs are not targeting products of genes strongly associated with late-onset AD. However, other drugs targeting products of these genes exist and could perhaps be repurposing to combat late-onset AD after further scrutiny

Habitual coffee consumption and risk of type 2 diabetes, ischemic heart disease, depression and Alzheimer’s disease: a Mendelian randomization study

Observationally, coffee is inversely associated with type 2 diabetes mellitus (T2DM), depression and Alzheimer’s disease, but not ischemic heart disease (IHD). Coffee features as possibly protective in the 2015 Dietary Guidelines for Americans. Short-term trials suggest coffee has neutral effect on most glycemic traits, but raises lipids and adiponectin. To clarify we compared T2DM, depression, Alzheimer’s disease, and IHD and its risk factors by genetically predicted coffee consumption using two-sample Mendelian randomization applied to large extensively genotyped case-control and cross-sectional studies. Childhood cognition was used as a negative control outcome. Genetically predicted coffee consumption was not associated with T2DM (odds ratio (OR) 1.02, 95% confidence interval (CI) 0.76 to 1.36), depression (0.89, 95% CI 0.66 to 1.21), Alzheimer’s disease (1.17, 95% CI 0.96 to 1.43), IHD (0.96, 95% CI 0.80 to 1.14), lipids, glycemic traits, adiposity or adiponectin. Coffee was unrelated to childhood cognition. Consistent with observational studies, coffee was unrelated to IHD, and, as expected, childhood cognition. However, contrary to observational findings, coffee may not have beneficial effects on T2DM, depression or Alzheimer’s disease. These findings clarify the role of coffee with relevance to dietary guidelines and suggest interventions to prevent these complex chronic diseases should be sought elsewhere

Changes in Cardiovascular Disease Burden in China after Release of the 2011 Chinese Guidelines for Cardiovascular Disease Prevention: A Bayesian Causal Impact Analysis

Objective: This study aimed to investigate the effects of the 2011 Chinese Society of Cardiology guidelines (2011 CSC guidelines) on the overall and subtype specific cardiovascular disease (CVD) burden in China. Methods: We conducted a Bayesian causal impact analysis to investigate changes in the burden of CVD overall and 13 subcategories, before and after release of the 2011 CSC guidelines, by using publicly available data during 1990–2019. Results: The 2011 CSC guidelines were associated with moderate declines in CVD mortality (5.7%; equivalent to 161 per 100,000) and DALYs (2.9%; 1429 per 100,000), but small increases in incidence and prevalence, with an approximately 1-year lagged effect. Similar impact patterns were observed for ischemic stroke, cardiomyopathy and myocarditis, and aortic aneurysm. Release of the 2011 CSC guidelines increased intracerebral hemorrhage incidence, but sharply decreased rheumatic, ischemic, and non-rheumatic valvular heart disease mortality and DALY rates. The burden of other CVD subcategories was unchanged. Health worker numbers, population size, disposable income, hospital admission rates, and crude death rates were critical contributors to CVD burden beyond the 2011 CSC guidelines. Conclusion: The 2011 CSC guidelines decreased the burden of CVD and several subcategories. However, efforts to enhance health promotion and strengthen healthcare remain urgently needed in China

The Role of Dairy Products and Milk in Adolescent Obesity: Evidence from Hong Kong’s ‘‘Children of 1997’’ Birth Cohort

Background Observational studies, mainly from Western populations, suggest dairy consumption is inversely associated with adiposity. However, in these populations the intake range is limited and both diet and obesity may share social patterning. Evidence from non-Western developed settings with different social patterning, is valuable in distinguishing whether observed associations are biologically mediated or socially confounded. Objective To examine the associations of milk or other dairy product consumption with adolescent obesity. Methods We used multivariable linear regression models to examine the associations of milk or other dairy product consumption, obtained from a food frequency questionnaire, at 11 years with body mass index (BMI) z-scores at 13 years and waist hip ratio (WHR) at 11 years, in 5,968 adolescents from a Chinese birth cohort, comprising 88% of births in April and May 1997. We used multiple imputation for missing exposures and confounders. Results Only 65.7% regularly consumed milk and 72.4% other dairy products. Milk and other dairy product consumption was positively associated with socio-economic position but not with BMI z-score or WHR, with or without adjustment for sex, mother’s birthplace, parental education, physical activity and other food consumption. Conclusions The lack of association of milk and other dairy product consumption with adiposity in a non-Western setting was not consistent with the majority of evidence from Western settings. Observed anti-obesigenic effects in Western settings may be due to socially patterned confounding

Short and medium term health outcomes of infant lifestyle

published_or_final_versionCommunity MedicineDoctoralDoctor of Philosoph

Unraveling Potential Sex‐Specific Effects of Cardiovascular Medications on Longevity Using Mendelian Randomization

Background Establishing the sex‐specific efficacy of cardiovascular medications is pivotal to evidence‐based clinical practice, potentially closing the gender gap in longevity. Trials large enough to establish sex differences are unavailable. This study evaluated sex‐specific effects of commonly prescribed cardiovascular medications on lifespan. Methods and Results In a two‐sample Mendelian randomization study, established genetic variants mimicking effects of lipid‐lowering drugs, antihypertensives, and diabetes drugs were applied to genetic associations with lifespan proxied by UK Biobank maternal (n=412 937) and paternal (n=415 311) attained age. Estimates were obtained using inverse variance weighting, with sensitivity analyses where possible. For lipid‐lowering drugs, genetically mimicked PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors were associated with longer lifespan, particularly in men (2.39 years per SD low‐density lipoprotein cholesterol reduction [95% CI, 0.42–4.36], P for interaction=0.14). Genetically mimicked treatments targeting APOC3, LPL, or possibly LDLR were associated with longer lifespan in both sexes. For antihypertensives, genetically mimicked β‐blockers and calcium channel blockers were associated with longer lifespan, particularly in men (P for interaction=0.17 for β‐blockers and 0.31 for calcium channel blockers). For diabetes drugs, genetically mimicked metformin was associated with longer lifespan in both sexes. No associations were found for genetically mimicked statins, ezetimibe, or angiotensin‐converting enzyme inhibitors. Conclusions PCSK9 inhibitors, β‐blockers, and calcium channel blockers may prolong lifespan in the general population, particularly men. Treatments targeting APOC3, LPL, or LDLR and metformin may be relevant to both sexes. Whether other null findings are attributable to lack of efficacy requires investigation. Further investigation of repurposing should be conducted

Breastfeeding and adolescent blood pressure: evidence from Hong Kong's "Children of 1997" Birth Cohort.

Observationally, breastfeeding is associated with lower blood pressure in Western developed settings, whereas little association exists in developing settings. However, postnatal characteristics (e.g., breast milk substitutes, infection rates, underweight, and pubertal timing) differ between these settings. We examined the association of breastfeeding with blood pressure at ∼13 years, using multivariable linear regression, in 5,247 term births in 1997 from a population-representative Hong Kong Chinese birth cohort where socioeconomic patterning of breastfeeding differs from that of Western and developing settings but standard of living, social infrastructure, and postnatal characteristics are similar to those of Western settings. Higher education is associated with short-term breastfeeding but recent migration with longer-term breastfeeding. Compared with never breastfeeding, exclusive breastfeeding for ≥3 months was not associated with blood pressure (systolic mean difference = 0.82 mm Hg, 95% confidence interval (CI): -0.46, 2.11 and diastolic mean difference = 0.49 mm Hg, 95% CI: -0.22, 1.21), nor was partial breastfeeding for any length of time or exclusive breastfeeding for <3 months (systolic mean difference = 0.01 mm Hg, 95% CI: -0.64, 0.66 and diastolic mean difference = 0.16 mm Hg, 95% CI: -0.20, 0.52), adjusted for socioeconomic position and infant characteristics. Lack of association in a non-Western developed setting further suggests that observations concerning breastfeeding and blood pressure vary with setting, thereby casting doubt on causality.Link_to_subscribed_fulltex

Glucose-6-Phosphate Dehydrogenase Deficiency and Physical and Mental Health until Adolescence

<div><p>Background</p><p>To examine the association of glucose-6-phosphate dehydrogenase (G6PD) deficiency with adolescent physical and mental health, as effects of G6PD deficiency on health are rarely reported.</p><p>Methods</p><p>In a population-representative Chinese birth cohort: “Children of 1997” (n = 8,327), we estimated the adjusted associations of G6PD deficiency with growth using generalized estimating equations, with pubertal onset using interval censored regression, with hospitalization using Cox proportional hazards regression and with size, blood pressure, pubertal maturation and mental health using linear regression with multiple imputation and inverse probability weighting.</p><p>Results</p><p>Among 5,520 screened adolescents (66% follow-up), 4.8% boys and 0.5% girls had G6PD deficiency. G6PD-deficiency was not associated with birth weight-for-gestational age or length/height gain into adolescence, but was associated with lower childhood body mass index (BMI) gain (-0.38 z-score, 95% confidence interval (CI) -0.57, -0.20), adjusted for sex and parental education, and later onset of pubic hair development (time ratio = 1.029, 95% CI 1.007, 1.050). G6PD deficiency was not associated with blood pressure, height, BMI or mental health in adolescence, nor with serious infectious morbidity until adolescence.</p><p>Conclusions</p><p>G6PD deficient adolescents had broadly similar physical and mental health indicators, but transiently lower BMI gain and later pubic hair development, whose long-term implications warrant investigation.</p></div