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.

Unexpected, isolated activated partial thromboplastin time prolongation: A practical mini-review.

A common inquiry in coagulation laboratories is how to interpret an unexpected, isolated prolonged activated partial thromboplastin time (APTT). In this context, isolated means together with a normal prothrombin time (PT) and/or normal international normalized ratio (INR). This finding may lead to contact with laboratory doctors for further advice on a diagnostic strategy. Occasionally, the need for a diagnostic algorithm can be subacute, where surgery has to be postponed until an explanation for the isolated, prolonged APTT has been established. Activated partial thromboplastin time as a coagulation test was developed to monitor patients with hemophilia. Different APTT reagents display considerable differences in their sensitivity to deficiencies of coagulation factors. An isolated, prolonged APTT is seen in (a) individuals/patients with lupus anticoagulants, (b) patients in treatment with anticoagulants, mainly heparin, and (c) patients with deficiencies of specific coagulation factors. In this tutorial review, we summarize what may cause an isolated prolonged APTT and we present a simple diagnostic algorithm to differentiate between lupus anticoagulants (common) and factor deficiencies (rare). The identification of an isolated prolonged APTT as well as the underlying cause can be of the utmost importance in ensuring the correct therapeutic follow-up.

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.

Genetic variation in clusterin and risk of dementia and ischemic vascular disease in the general population: cohort studies and meta-analyses of 362,338 individuals.

BACKGROUND: Clusterin, also known as apolipoprotein J (apoJ), is one of the most abundantly expressed apolipoproteins in the brain after apolipoprotein E (apoE). Like the ε4 allele of the apolipoprotein E gene (APOE), the clusterin gene (CLU) is a risk locus for Alzheimer's disease, and may play additional roles in atherosclerosis pathogenesis. We tested whether genetic variation in CLU was associated with either Alzheimer's disease or atherosclerosis-related diseases. METHODS: We studied individual data on 103,987 participants from the Copenhagen General Population Study (CGPS) and the Copenhagen City Heart Study (CCHS). We genotyped a common CLU variant (rs9331896) and two common APOE variants (rs7412 and rs429358), defining the ε2, ε3, and ε4, alleles in CGPS and CCHS. All individuals in the CGPS and CCHS cohorts were followed from study inclusion to occurrence of event, death, emigration, or until 10 November 2014, whichever came first. Summary consortia data on 258,351 individuals from the International Genomics of Alzheimer's Project (IGAP) and the Coronary Artery Disease Genome-wide Replication and Meta-analysis plus the Coronary Artery Disease (C4D) Genetics and 1000-Genomes-based genome-wide association studies (CARDIoGRAMplusC4D) were used in meta-analyses. RESULTS: In CGPS and CCHS, multifactorially adjusted hazard ratios for Alzheimer's disease, all dementia, vascular dementia, ischemic cerebrovascular disease, and ischemic heart disease were 1.18 (1.07-1.30), 1.09 (1.02-1.17), 0.96 (0.80-1.17), 1.02 (0.97-1.07), and 0.97 (0.93-1.01) per T allele, respectively. Multifactorially adjusted hazard ratios for Alzheimer's disease and all dementia were 2.72 (2.45-3.01) and 2.21 (2.05-2.38) for the APOE ɛ4 allele. There was no interaction between rs9331896 in CLU and rs429358 (defining the ɛ4 allele) in APOE in predicting Alzheimer's disease or all dementia (P = 0.39 and P = 0.21). In a meta-analysis including consortium data, the overall fixed- and random-effects odds ratios for Alzheimer's disease per T allele were 1.16 (1.13-1.18) (I 2 = 0.0%; P for heterogeneity = 0.89). CONCLUSIONS: A common variant in CLU was associated with a high risk of Alzheimer's disease and all dementia in the general population but not with vascular dementia or ischemic vascular disease. Important novel aspects compared to previous studies are the incorporation of individual risk factor data, the exact causative ε4 allele, and several subtypes of dementia and atherosclerosis-related endpoints.

Complement C3 and Risk of Diabetic Microvascular Disease: A Cohort Study of 95202 Individuals from the General Population.

BACKGROUND: Whether the complement system is involved in the development of diabetic microvascular disease is unknown. We tested the hypothesis that high concentrations of complement C3 are associated with increased risk of diabetic retinopathy, nephropathy, and neuropathy in individuals from the general population. METHODS: We studied 95202 individuals from the general population with baseline measurements of complement C3, genotyped for rs1065489, rs429608, and rs448260 determining concentrations of complement C3, and enrolled in the Copenhagen General Population Study from 2003 through 2013, following them until April 10, 2013. Rs1065489, rs429608, and rs448260 were identified with genome-wide association scans in 3752 individuals from the Copenhagen City Heart Study. RESULTS: The cumulative incidence was increased from the lowest tertile to the highest tertile of complement C3 for diabetic retinopathy (log-rank trend, P = 1 × 10-20), nephropathy (P = 7 × 10-15), and neuropathy (P = 5 × 10-10). Multifactorially adjusted hazard ratios for a 1 SD higher concentration of complement C3 were 1.87 (95% CI, 1.61-2.18) for diabetic retinopathy, 1.90 (1.62-2.23) for diabetic nephropathy, and 1.56 (1.29-1.89) for diabetic neuropathy. The multifactorially adjusted hazard ratio for individuals with the highest vs lowest tertile of complement C3 was 3.29 (1.78-6.07) for retinopathy, 2.71 (1.42-5.16) for nephropathy, and 2.40 (1.26-4.54) for neuropathy. CONCLUSIONS: High baseline concentrations of complement C3 were associated with increased risk of diabetic retinopathy, nephropathy, and neuropathy in individuals from the general population. These epidemiological findings were substantiated by a Mendelian randomization approach, potentially indicating causality.

An updated Alzheimer hypothesis: Complement C3 and risk of Alzheimer's disease-A cohort study of 95,442 individuals.

INTRODUCTION: We tested the hypothesis that low plasma complement C3 is observationally and genetically associated with high risk of Alzheimer's disease (AD). METHODS: We studied 95,442 individuals enrolled in the Copenhagen General Population Study. In genetic analyses, we further included 8367 individuals from the Copenhagen City Heart Study. In the two studies, 1189 and 35 developed AD during median 8 years follow-up. RESULTS: The multifactorially adjusted hazard ratio for risk of AD for a one standard deviation lower levels of complement C3 was 1.11 (95% confidence interval: 1.04-1.19) in all individuals and 1.66 (1.33-2.07) in APOE ε44 carriers. In Mendelian randomization, the corresponding genetic estimates were 1.66 (1.05-2.63) overall and 1.99 (0.52-7.65) in APOE ε44 carriers. DISCUSSION: Low baseline levels of complement C3 were associated with high risk of AD. The risk was amplified in APOE ε44 highly susceptible individuals, and these findings were substantiated by a Mendelian randomization approach, potentially implying causality. Based on these findings, we present and thoroughly discuss an updated Alzheimer hypothesis incorporating low complement C3 levels.

Neutrophil Reactivity Intensity and misclassification of immature granulocytes.

INTRODUCTION: Immature granulocyte percentage (IG%) is an important biomarker for infection control. We observed spurious cases where the IG% was dramatically underestimated on the automated Sysmex XN-series hehmatology analyzer compared with manual differential. These cases were associated with high values of "Neutrophil Reactivity Intensity" (NEUT-RI), which should reflect the metabolic activity of the neutrophils. METHODS: We conducted a three-stage study to evaluate whether NEUT-RI could be utilized to screen for misclassified IG% results defined as the manual differential estimating a 10 percentage points higher IG% compared with the automated Sysmex differential. First, 124 patient samples were selected for 800-cell manual smear analysis based on their NEUT-RI values and compared with the automatic Sysmex IG% results. Next, 11 098 routine 110-cell manual smear analyses were compared with the corresponding Sysmex IG% results. Finally, during a 19-day period 160 additional patient samples underwent smear based on NEUT-RI values ≥56 fluorescence intensity (FI) to screen for misclassified results beyond our current smear practice. RESULTS: NEUT-RI ≥56 predicted IG% misclassification with 91% sensitivity and 88% specificity, but primarily when the internal Sysmex flag "Abnormal WBC Scattergram" was present. 90.1% of misclassified results were identified by this flag. Beyond our existing smear rules including this flag, NEUT-RI ≥56 FI had a positive predictive value below 1%. CONCLUSION: Both NEUT-RI and the internal Sysmex flag "Abnormal WBC Scattergram" work well to identify cases of IG% misclassification. However, in our setting NEUT-RI ≥56 FI had no meaningful additional predictive capacity to identify misclassifications beyond our current smear rules.

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.

Association of Rare APOE Missense Variants V236E and R251G With Risk of Alzheimer Disease.

Importance: The APOE ε2 and APOE ε4 alleles are the strongest protective and risk-increasing, respectively, genetic variants for late-onset Alzheimer disease (AD). However, the mechanisms linking APOE to AD-particularly the apoE protein's role in AD pathogenesis and how this is affected by APOE variants-remain poorly understood. Identifying missense variants in addition to APOE ε2 and APOE ε4 could provide critical new insights, but given the low frequency of additional missense variants, AD genetic cohorts have previously been too small to interrogate this question robustly. Objective: To determine whether rare missense variants on APOE are associated with AD risk. Design, Setting, and Participants: Association with case-control status was tested in a sequenced discovery sample (stage 1) and followed up in several microarray imputed cohorts as well as the UK Biobank whole-exome sequencing resource using a proxy-AD phenotype (stages 2 and 3). This study combined case-control, family-based, population-based, and longitudinal AD-related cohorts that recruited referred and volunteer participants. Stage 1 included 37 409 nonunique participants of European or admixed European ancestry, with 11 868 individuals with AD and 11 934 controls passing analysis inclusion criteria. In stages 2 and 3, 475 473 participants were considered across 8 cohorts, of which 84 513 individuals with AD and proxy-AD and 328 372 controls passed inclusion criteria. Selection criteria were cohort specific, and this study was performed a posteriori on individuals who were genotyped. Among the available genotypes, 76 195 were excluded. All data were retrieved between September 2015 and November 2021 and analyzed between April and November 2021. Main Outcomes and Measures: In primary analyses, the AD risk associated with each missense variant was estimated, as appropriate, with either linear mixed-model regression or logistic regression. In secondary analyses, associations were estimated with age at onset using linear mixed-model regression and risk of conversion to AD using competing-risk regression. Results: A total of 544 384 participants were analyzed in the primary case-control analysis; 312 476 (57.4%) were female, and the mean (SD; range) age was 64.9 (15.2; 40-110) years. Two missense variants were associated with a 2-fold to 3-fold decreased AD risk: APOE ε4 (R251G) (odds ratio, 0.44; 95% CI, 0.33-0.59; P = 4.7 × 10-8) and APOE ε3 (V236E) (odds ratio, 0.37; 95% CI, 0.25-0.56; P = 1.9 × 10-6). Additionally, the cumulative incidence of AD in carriers of these variants was found to grow more slowly with age compared with noncarriers. Conclusions and Relevance: In this genetic association study, a novel variant associated with AD was identified: R251G always coinherited with ε4 on the APOE gene, which mitigates the ε4-associated AD risk. The protective effect of the V236E variant, which is always coinherited with ε3 on the APOE gene, was also confirmed. The location of these variants confirms that the carboxyl-terminal portion of apoE plays an important role in AD pathogenesis. The large risk reductions reported here suggest that protein chemistry and functional assays of these variants should be pursued, as they have the potential to guide drug development targeting APOE.

Plasma levels of apolipoprotein E, APOE genotype and risk of dementia and ischemic heart disease: A review.

Dementia is one of the major causes of disability in later life, and ischemic heart disease is a leading cause of morbidity and mortality. Apolipoprotein E (apoE) plays a pivotal role in lipoprotein metabolism in the brain and in the periphery, and is implicated in both dementia and ischemic heart disease. Peripherally, liver-derived apoE is the main source of plasma apoE. Approximately half of plasma apoE is associated with triglyceride-rich lipoproteins, where apoE serves as the main ligand for the low density lipoprotein (LDL) receptor and the LDL receptor Related Protein (LRP). In the brain, apoE is produced mainly by astrocytes. Astrocyte-derived apoE is pivotal for cerebral cholesterol metabolism and clearance of ß-amyloid, a major pathological hallmark of Alzheimer disease. Plasma levels of apoE and other lipids and lipoproteins are under strong genetic influence by the APOE polymorphism, and the ε4 allele is a strong genetic risk factor for Alzheimer disease. The characteristics of the APOE polymorphism thus suggest the qualitative importance of apoE, whereas studies of familial absolute apoE deficiency suggest a quantitative importance of plasma apoE levels in lipid metabolism. Whether plasma levels of apoE are associated with increased risk of dementia and ischemic heart disease, and whether these associations are independent of the APOE polymorphism and of lipids and lipoproteins has only recently been established. The aim of this review is to summarize and discuss the current epidemiological and biological evidence for an association of plasma levels of apoE with risk of dementia and ischemic heart disease.

[Diabetic retinopathy during pregnancy]. / Diabetisk retinopati under graviditet.

INTRODUCTION: The aim was to evaluate the prevalence and progression of diabetic retinopathy during pregnancy in women with type 1 or type 2 diabetes. MATERIAL AND METHODS: Dilated fundal photography was performed at approximately 10 and 28 gestational weeks in 58 and 18 women with type 1 and type 2 diabetes, respectively. Retinopathy was classified as five stages +/- macular oedema. Progression was defined as deterioration corresponding to at least one stage between the two examinations. Clinical parameters were obtained from the medical records. RESULTS: Diabetic retinopathy was found in 36 (62%) women with type 1 and three (17%) with type 2 diabetes at the first examination. In 26 (34%) retinopathy progressed; four women developed proliferations, three macular oedema and three reduction of visual acuity >/=0.2 on Snellen's chart in at least one eye. HbA1c in early pregnancy was the only significant predictor of progression (odds ratio = 1.75, 95% confidence interval = 1.09-2.82). Progression of retinopathy also tended to be associated with type 1 diabetes and long diabetes duration. CONCLUSION: The risk of progression of diabetic retinopathy during pregnancy was considerable, especially among women with high HbA1c values in early pregnancy. A few women developed proliferations, macular oedema and reduction of visual acuity. Development of sight-threatening alterations during pregnancy remains a clinical problem.