Modifiable cardiovascular risk factors and genetics for targeted prevention of dementia.

Dementia is a major global challenge for health and social care in the 21st century. A third of individuals >65 years of age die with dementia, and worldwide incidence numbers are projected to be higher than 150 million by 2050. Dementia is, however, not an inevitable consequence of old age; 40% of dementia may theoretically be preventable. Alzheimer's disease (AD) accounts for approximately two-thirds of dementia cases and the major pathological hallmark of AD is accumulation of amyloid-ß. Nevertheless, the exact pathological mechanisms of AD remain unknown. Cardiovascular disease and dementia share several risk factors and dementia often coexists with cerebrovascular disease. In a public health perspective, prevention is crucial, and it is suggested that a 10% reduction in prevalence of cardiovascular risk factors could prevent more than nine million dementia cases worldwide by 2050. Yet this assumes causality between cardiovascular risk factors and dementia and adherence to the interventions over decades for a large number of individuals. Using genome-wide association studies, the entire genome can be scanned for disease/trait associated loci in a hypothesis-free manner, and the compiled genetic information is not only useful for pinpointing novel pathogenic pathways but also for risk assessments. This enables identification of individuals at high risk, who likely will benefit the most from a targeted intervention. Further optimization of the risk stratification can be done by adding cardiovascular risk factors. Additional studies are, however, highly needed to elucidate dementia pathogenesis and potential shared causal risk factors between cardiovascular disease and dementia.

Significance of lipids, lipoproteins, and apolipoproteins during the first 14-16 months of life.

BACKGROUND AND AIMS: The aims of this study were to investigate lipid parameters during the first 14-16 months of life, to identify influential factors, and to test whether high concentrations at birth predict high concentrations at 2- and 14-16 months. METHODS: The Copenhagen Baby Heart Study, including 13,354 umbilical cord blood samples and parallel venous blood samples from children and parents at birth (n = 444), 2 months (n = 364), and 14-16 months (n = 168), was used. RESULTS: Concentrations of lipids, lipoproteins, and apolipoproteins in umbilical cord blood samples correlated highly with venous blood samples from newborns. Concentrations of low-density lipoprotein (LDL) cholesterol, non-high-density lipoprotein (HDL) cholesterol, apolipoprotein B, and lipoprotein(a) increased stepwise from birth to 2 months to 14-16 months. Linear mixed models showed that concentrations of LDL cholesterol, non-HDL cholesterol, and lipoprotein(a) above the 80th percentile at birth were associated with significantly higher concentrations at 2 and 14-16 months. Finally, lipid concentrations differed according to sex, gestational age, birth weight, breastfeeding, and parental lipid concentrations. CONCLUSIONS: Lipid parameters changed during the first 14-16 months of life, and sex, gestational age, birth weight, breastfeeding, and high parental concentrations influenced concentrations. Children with high concentrations of atherogenic lipid traits at birth had higher concentrations at 2 and 14-16 months. These findings increase our knowledge of how lipid traits develop over the first 14-16 months of life and may help in deciding the optimal child age for universal familial hypercholesterolaemia screening.

Coagulation parameters in the newborn and infant - the Copenhagen Baby Heart and COMPARE studies.

OBJECTIVES: The coagulation system is not fully developed at birth and matures during the first months of infancy, complicating clinical decision making within hemostasis. This study evaluates coagulation parameters at birth and two months after birth, and tests whether cord blood can be used as a proxy for neonatal venous blood measurements. METHODS: The Copenhagen Baby Heart Study (CBHS) and the COMPARE study comprise 13,237 cord blood samples and 444 parallel neonatal venous blood samples, with a two month follow-up in 362 children. RESULTS: Because coagulation parameters differed according to gestational age (GA), all analyses were stratified by GA. For neonatal venous blood, reference intervals for activated partial thromboplastin time (APTT) and prothrombin time (PT) were 28-43 s and 33-61% for GA 37-39 and 24-38 s and 30-65% for GA 40-42. Reference intervals for international normalized ratio (INR) and thrombocyte count were 1.1-1.7 and 194-409 × 109/L for GA 37-39 and 1.2-1.8 and 188-433 × 109/L for GA 40-42. Correlation coefficients between umbilical cord and neonatal venous blood for APTT, PT, INR, and thrombocyte count were 0.68, 0.72, 0.69, and 0.77 respectively, and the distributions of the parameters did not differ between the two types of blood (all p-values>0.05). CONCLUSIONS: This study describes new GA dependent reference intervals for common coagulation parameters in newborns and suggests that cord blood may serve as a proxy for neonatal venous blood for these traits. Such data will likely improve clinical decision making within hemostasis among newborn and infant children.

Impact of metabolic dysfunction on cognition in humans.

PURPOSE OF REVIEW: The current review evaluates the recent literature on the impact of metabolic dysfunction in human cognition, focusing on epidemiological studies and meta-analyses of these. RECENT FINDINGS: Worldwide around 50 million people live with dementia, a number projected to triple by 2050. Recent reports from the Lancet Commission suggest that 40% of dementia cases may be preventable primarily by focusing on well established metabolic dysfunction components and cardiovascular risk factors. SUMMARY: There is robust evidence that type 2 diabetes and midlife hypertension increase risk of dementia in late life. Obesity and elevated levels of LDL cholesterol in midlife probably increase risk of dementia, but further research is needed in these areas. Physical activity, diet, alcohol, and smoking might also influence the risk of dementia through their effect on metabolic dysfunction. A key recommendation is to be ambitious about prevention, focusing on interventions to promote healthier lifestyles combating metabolic dysfunction. Only comprehensive multidomain and staff-requiring interventions are however efficient to maintain or improve cognition in at-risk individuals and will be unrealistic economic burdens for most societies to implement. Therefore, a risk score that identifies high-risk individuals will enable a targeted early intensive intervention toward those high-risk individuals that will benefit the most from a prevention against cardiovascular risk factors and metabolic dysfunction.

Impact of cardiovascular risk factors and genetics on 10-year absolute risk of dementia: risk charts for targeted prevention.

AIMS: Dementia is a major global challenge for health and social care in aging populations. A third of all dementia may be preventable due to cardiovascular risk factors. Intensive multi-domain intervention trials targeting primarily cardiovascular risk factors show improved cognitive function in people at risk. Such interventions will, however, be expensive to implement in all individuals at risk and will represent unrealistic economic tasks for most societies. Therefore, a risk score identifying high-risk individuals is warranted. METHODS AND RESULTS: In 61 664 individuals from two prospective cohorts of the Danish general population, we generated 10-year absolute risk scores for all-cause dementia from cardiovascular risk factors and genetics. In both sexes, 10-year absolute risk of all-cause dementia increased with increasing age, number of apolipoprotein E (APOE) ɛ4 alleles, number of genome-wide association studies (GWAS) risk alleles, and cardiovascular risk factors. The highest 10-year absolute risks of all-cause dementia seen in smoking women with diabetes, low education, APOE ɛ44 genotype, and 22-31 GWAS risk alleles were 6%, 23%, 48%, and 66% in those aged 50-59, 60-69, 70-79, and 80-100, respectively. Corresponding values for men were 5%, 19%, 42%, and 60%, respectively. CONCLUSION: Ten-year absolute risk of all-cause dementia increased with age, APOE ɛ4 alleles, GWAS risk alleles, diabetes, low education, and smoking in both women and men. Ten-year absolute risk charts for dementia will facilitate identification of high-risk individuals, those who likely will benefit the most from an early intervention against cardiovascular risk factors.

Blood-brain barrier transcytosis genes, risk of dementia and stroke: a prospective cohort study of 74,754 individuals.

To test whether genetic variants in PICALM, BIN1, CD2AP, and RIN3-suggested to be involved in blood-brain barrier amyloid-ß transcytosis pathways-associate with Alzheimer's disease, all dementia, suggested vascular dementia, and stroke, and whether such associations are independent of the strong ε4 APOE risk allele. In a prospective cohort study of 74,754 individuals from the general population we genotyped PICALM (rs10792832), BIN1 (rs6733839), CD2AP (rs10948363), and RIN3 (rs10498633), and generated a weighted and a simple allele score. Multifactorially adjusted hazard ratios for the fourth quartile versus the first quartile of the weighted allele score were 1.42 (95% confidence interval 1.22-1.64) for Alzheimer's disease, and 1.33 (1.19-1.48) for all dementia. For suggested vascular dementia and stroke the corresponding estimates were 1.71 (1.18-2.49) and 1.12 (1.04-1.22), respectively. Hazard ratios were similar after APOE adjustment. Genetic variants in PICALM, BIN1, CD2AP, and RIN3 are associated with increased risk of Alzheimer's disease, all dementia, and suggested vascular dementia independent of the strong APOE ε4 allele. These findings may suggest that clathrin-mediated endocytosis in clearance of amyloid-ß across the blood-brain barrier is important for the integrity of both brain tissue and cerebral vessels.

Self-reported and genetically predicted coffee consumption and smoking in dementia: A Mendelian randomization study.

BACKGROUND AND AIMS: Studies of self-reported coffee consumption and smoking on risk of dementia have shown results conflicting with two-sample Mendelian randomization studies. We tested the hypotheses that coffee consumption and smoking influence risk of dementia using observational and one-sample Mendelian randomization designs with individual level data. METHODS: We included 114,551 individuals from two Danish general population cohorts (median age 58 years). First, we tested whether high self-reported coffee consumption/smoking were associated with risk of dementia. Second, whether genetically predicted high coffee consumption/smoking due to variation near CYP1A1/AHR/CHRNA3 genes were associated with risk of dementia. RESULTS: We observed 3,784 dementia events. Moderate self-reported coffee consumption was associated with low risk of all dementia and non-Alzheimer's dementia, with a similar trend for Alzheimer's disease. Genetically predicted high coffee consumption was associated with high risk of all dementia (hazard ratio [95% confidence interval] per +1 cup/day: 1.20 [1.01-1.42]), with a similar trend for non-Alzheimer's dementia (1.23 [0.95-1.53]). High self-reported smoking was associated with high risk of non-Alzheimer's dementia. High genetically predicted smoking was associated with a trend towards high risk of all dementia and Alzheimer's disease (hazard ratios per +1 pack-year: 1.04 [0.96-1.11]) and 1.06 [0.97-1.16]). CONCLUSIONS: Moderate self-reported coffee consumption was associated with low risk of all and non-Alzheimer's dementia, while high genetically predicted coffee consumption was associated with a trend towards the opposite. High self-reported smoking was associated with high risk of non-Alzheimer's dementia, with a similar trend for genetically predicted smoking on all dementia and Alzheimer's disease.

Plasma high-density lipoprotein cholesterol and risk of dementia: observational and genetic studies.

AIMS: The association of plasma high-density lipoprotein (HDL) cholesterol with risk of dementia is unclear. We, therefore, tested the hypothesis that high levels of plasma HDL cholesterol are associated with increased risk of dementia and whether a potential association is of a causal nature. METHODS AND RESULTS: In two prospective population-based studies, the Copenhagen General Population Study and the Copenhagen City Heart Study (N = 111 984 individuals), we first tested whether high plasma HDL cholesterol is associated with increased risk of any dementia and its subtypes. These analyses in men and women separately were adjusted multifactorially for other risk factors including apolipoprotein E (APOE) genotype. Second, taking advantage of two-sample Mendelian randomization, we tested whether genetically elevated HDL cholesterol was causally associated with Alzheimer's disease using publicly available consortia data on 643 836 individuals. Observationally, multifactorially adjusted Cox regression restricted cubic spline models showed that both men and women with extreme high HDL cholesterol concentrations had increased risk of any dementia and of Alzheimer's disease. Men in the 96th-99th and 100th vs. the 41st-60th percentiles of HDL cholesterol had multifactorially including APOE genotype adjusted hazard ratios of 1.66 (95% confidence interval 1.30-2.11) and 2.00 (1.35-2.98) for any dementia and 1.59 (1.16-2.20) and 1.87 (1.11-3.16) for Alzheimer's disease. Corresponding estimates for women were 0.94 (0.74-1.18) and 1.45 (1.03-2.05) for any dementia and 0.94 (0.70-1.26) and 1.69 (1.13-2.53) for Alzheimer's disease. Genetically, the two-sample Mendelian randomization odds ratio for Alzheimer's disease per 1 SD increase in HDL cholesterol was 0.92 (0.74-1.10) in the IGAP2019 consortium and 0.98 (0.95-1.00) in the ADSP/IGAP/PGC-ALZ/UKB consortium. Similar estimates were observed in sex stratified analyses. CONCLUSION: High plasma HDL cholesterol was observationally associated with increased risk of any dementia and Alzheimer's disease, suggesting that HDL cholesterol can be used as an easily accessible plasma biomarker for individual risk assessment.

Physical activity in leisure time and at work and risk of dementia: A prospective cohort study of 117,616 individuals.

BACKGROUND AND AIMS: Up to 40% of all dementia cases may be preventable, primarily by treating or acting on well-established cardiovascular risk factors such as diabetes, hypertension, smoking, and physical inactivity. Whether physical inactivity is associated with risk of non-Alzheimer's dementia - a disease influenced by cardiovascular risk factors - and whether a given association differs for physical activity in leisure time and at work remains unknown. METHODS: We conducted a prospective cohort study including 117,616 individuals from the Copenhagen General Population Study and the Copenhagen City Heart Study with up to 43 years of follow-up. RESULTS: Multifactorially adjusted hazard ratios for low versus high physical activity at leisure time was 1.60 (95% confidence interval 1.40-1.83) for non-Alzheimer's dementia and 0.94 (0.80-1.11) for Alzheimer's disease. Corresponding values for non-Alzheimer's dementia after additional adjustment for physical activity at work or apolipoprotein E (APOE) genotype were 1.60 (1.40-1.83) and 1.82 (1.34-2.15). Multifactorially and APOE adjusted hazard ratios for high versus low physical activity at work were 1.50 (1.10-2.05) for non-Alzheimer's dementia and 1.62 (1.14-2.31) for Alzheimer's disease. When combining the two types of physical activity, physical activity in leisure time had the strongest relationship with risk of non-Alzheimer's dementia. CONCLUSIONS: Physical inactivity in leisure time was associated with increased risk of non-Alzheimer's dementia, independent of modifiable risk factors and physical activity at work. The present study thus provides evidence for public health advice on physical activity in leisure time for the vascular part of dementia.

Markers of Kidney Function in Early Childhood and Association With Maternal Comorbidity.

Importance: Kidney functional capacity is low at birth but doubles during the first 2 weeks of life and reaches near-adult levels at age 1 to 2 years. Existing reference intervals for markers of kidney function in newborns are mostly based on preterm newborns, newborns with illness, or small cohorts of term newborns, and the consequences of maternal comorbidities for newborn kidney function are sparsely described. Objective: To establish robust reference intervals for creatinine and urea in healthy children in early childhood and to assess whether maternal comorbidity is associated with newborn creatinine and urea concentrations. Design, Setting, and Participants: This multicenter, prospective, population-based cohort study assessed data and umbilical cord blood samples from participants in the Copenhagen Baby Heart Study (CBHS) who were born between April 1, 2016, and October 31, 2018, and venous blood samples from a subsample of CBHS participants who were enrolled in the COMPARE study between May 3, 2017, and November 4, 2018. Cord blood samples of 13 354 newborns from the CBHS and corresponding venous blood samples of 444 of those newborns from the COMPARE study were included. Blood samples were collected at birth, age 2 months, and age 14 to 16 months, with follow-up completed on February 12, 2020. Healthy nonadmitted term newborns from maternity wards at 3 hospitals in the Capital Region of Denmark were included. Exposures: Maternal comorbidity. Main Outcomes and Measures: Creatinine and urea concentrations. Results: Among 13 354 newborns in the CBHS cohort, characteristics of 12 938 children were stratified by sex and gestational age (GA). Of those, 6567 children (50.8%) were male; 5259 children (40.6%) were born at 37 to 39 weeks' GA, and 7679 children (59.4%) were born at 40 to 42 weeks' GA. Compared with children born at 40 to 42 weeks' GA, those born at 37 to 39 weeks' GA had lower birth weight, Apgar scores at 5 minutes, placental weight, and placental-fetal weight ratio. Children born at 37 to 39 weeks' GA vs those born at 40 to 42 weeks' GA were more frequently small for GA at birth and more likely to have placental insufficiency and exposure to maternal preeclampsia, maternal diabetes, maternal kidney disease, and maternal hypertension. Among children born at 37 to 39 weeks' GA, reference intervals were 0.54 to 1.08 mg/dL for creatinine and 5.32 to 14.67 mg/dL for urea; among children born at 40 to 42 weeks' GA, reference intervals were 0.57 to 1.19 mg/dL for creatinine and 5.60 to 14.85 mg/dL for urea. At birth, multifactorially adjusted odds ratios among children exposed to preeclampsia were 9.40 (95% CI, 1.68-52.54) for a venous creatinine concentration higher than the upper reference limit, 4.29 (95% CI, 1.32-13.93) for a venous creatinine concentration higher than the 90th percentile, and 3.10 (95% CI, 1.14-8.46) for a venous creatinine concentration higher than the 80th percentile. Conclusions and Relevance: In this study, improved reference intervals for creatinine and urea concentrations were generated. Preeclampsia was associated with an increased risk of high newborn creatinine concentrations, suggesting that newborns of mothers with preeclampsia need closer observation of their kidney function.