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Importance An estimated 40% of dementia is potentially preventable by modifying 12 risk factors throughout the life course. However, robust evidence for most of these risk factors is lacking. Effective interventions should target risk factors in the causal pathway to dementia. Objective To comprehensively disentangle potentially causal aspects of modifiable risk factors for Alzheimer disease (AD) to inspire new drug targeting and improved prevention. Design, Setting, and Participants This genetic association study was conducted using 2-sample univariable and multivariable mendelian randomization. Independent genetic variants associated with modifiable risk factors were selected as instrumental variables from genomic consortia. Outcome data for AD were obtained from the European Alzheimer & Dementia Biobank (EADB), generated on August 31, 2021. Main analyses were conducted using the EADB clinically diagnosed end point data. All analyses were performed between April 12 and October 27, 2022. Exposures Genetically determined modifiable risk factors. Main Outcomes and Measures Odds ratios (ORs) and 95% CIs for AD were calculated per 1-unit change of genetically determined risk factors. Results The EADB-diagnosed cohort included 39 106 participants with clinically diagnosed AD and 401 577 control participants without AD. The mean age ranged from 72 to 83 years for participants with AD and 51 to 80 years for control participants. Among participants with AD, 54% to 75% were female, and among control participants, 48% to 60% were female. Genetically determined high-density lipoprotein (HDL) cholesterol concentrations were associated with increased odds of AD (OR per 1-SD increase, 1.10 [95% CI, 1.05-1.16]). Genetically determined high systolic blood pressure was associated with increased risk of AD after adjusting for diastolic blood pressure (OR per 10–mm Hg increase, 1.22 [95% CI, 1.02-1.46]). In a second analysis to minimiz, Importance: An estimated 40% of dementia is potentially preventable by modifying 12 risk factors throughout the life course. However, robust evidence for most of these risk factors is lacking. Effective interventions should target risk factors in the causal pathway to dementia. Objective: To comprehensively disentangle potentially causal aspects of modifiable risk factors for Alzheimer disease (AD) to inspire new drug targeting and improved prevention. Design, Setting, and Participants: This genetic association study was conducted using 2-sample univariable and multivariable mendelian randomization. Independent genetic variants associated with modifiable risk factors were selected as instrumental variables from genomic consortia. Outcome data for AD were obtained from the European Alzheimer & Dementia Biobank (EADB), generated on August 31, 2021. Main analyses were conducted using the EADB clinically diagnosed end point data. All analyses were performed between April 12 and October 27, 2022. Exposures: Genetically determined modifiable risk factors. Main Outcomes and Measures: Odds ratios (ORs) and 95% CIs for AD were calculated per 1-unit change of genetically determined risk factors. Results: The EADB-diagnosed cohort included 39106 participants with clinically diagnosed AD and 401577 control participants without AD. The mean age ranged from 72 to 83 years for participants with AD and 51 to 80 years for control participants. Among participants with AD, 54% to 75% were female, and among control participants, 48% to 60% were female. Genetically determined high-density lipoprotein (HDL) cholesterol concentrations were associated with increased odds of AD (OR per 1-SD increase, 1.10 [95% CI, 1.05-1.16]). Genetically determined high systolic blood pressure was associated with increased risk of AD after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.22 [95% CI, 1.02-1.46]). In a second analysis to minimize bias due to sample overlap, the enti

IMPORTANCE An estimated 40% of dementia is potentially preventable by modifying 12 risk factors throughout the life course. However, robust evidence for most of these risk factors is lacking. Effective interventions should target risk factors in the causal pathway to dementia. OBJECTIVE To comprehensively disentangle potentially causal aspects of modifiable risk factors for Alzheimer disease (AD) to inspire new drug targeting and improved prevention. DESIGN, SETTING, AND PARTICIPANTS This genetic association study was conducted using 2-sample univariable and multivariable mendelian randomization. Independent genetic variants associated with modifiable risk factors were selected as instrumental variables from genomic consortia. Outcome data for AD were obtained from the European Alzheimer & Dementia Biobank (EADB), generated on August 31, 2021. Main analyses were conducted using the EADB clinically diagnosed end point data. All analyses were performed between April 12 and October 27, 2022. EXPOSURES Genetically determined modifiable risk factors. MAIN OUTCOMES AND MEASURES Odds ratios (ORs) and 95% CIs for AD were calculated per 1-unit change of genetically determined risk factors. RESULTS The EADB-diagnosed cohort included 39106 participants with clinically diagnosed AD and 401577 control participants without AD. The mean age ranged from 72 to 83 years for participants with AD and 51 to 80 years for control participants. Among participants with AD, 54% to 75% were female, and among control participants, 48% to 60% were female. Genetically determined high-density lipoprotein (HDL) cholesterol concentrations were associated with increased odds of AD (OR per 1-SD increase, 1.10 [95% CI, 1.05-1.16]). Genetically determined high systolic blood pressure was associated with increased risk of AD after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.22 [95% CI, 1.02-1.46]). In a second analysis to minimize bias due to sample overlap, the entire UK Bio

IMPORTANCE An estimated 40% of dementia is potentially preventable by modifying 12 risk factors throughout the life course. However, robust evidence for most of these risk factors is lacking. Effective interventions should target risk factors in the causal pathway to dementia. OBJECTIVE To comprehensively disentangle potentially causal aspects of modifiable risk factors for Alzheimer disease (AD) to inspire new drug targeting and improved prevention. DESIGN, SETTING, AND PARTICIPANTS This genetic association study was conducted using 2-sample univariable and multivariable mendelian randomization. Independent genetic variants associated with modifiable risk factors were selected as instrumental variables from genomic consortia. Outcome data for AD were obtained from the European Alzheimer & Dementia Biobank (EADB), generated on August 31, 2021. Main analyses were conducted using the EADB clinically diagnosed end point data. All analyses were performed between April 12 and October 27, 2022. EXPOSURES Genetically determined modifiable risk factors. MAIN OUTCOMES AND MEASURES Odds ratios (ORs) and 95% CIs for AD were calculated per 1-unit change of genetically determined risk factors. RESULTS The EADB-diagnosed cohort included 39106 participants with clinically diagnosed AD and 401577 control participants without AD. The mean age ranged from 72 to 83 years for participants with AD and 51 to 80 years for control participants. Among participants with AD, 54% to 75% were female, and among control participants, 48% to 60% were female. Genetically determined high-density lipoprotein (HDL) cholesterol concentrations were associated with increased odds of AD (OR per 1-SD increase, 1.10 [95% CI, 1.05-1.16]). Genetically determined high systolic blood pressure was associated with increased risk of AD after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.22 [95% CI, 1.02-1.46]). In a second analysis to minimize bias due to sample overlap, the entire UK Bio

IMPORTANCE An estimated 40% of dementia is potentially preventable by modifying 12 risk factors throughout the life course. However, robust evidence for most of these risk factors is lacking. Effective interventions should target risk factors in the causal pathway to dementia. OBJECTIVE To comprehensively disentangle potentially causal aspects of modifiable risk factors for Alzheimer disease (AD) to inspire new drug targeting and improved prevention. DESIGN, SETTING, AND PARTICIPANTS This genetic association study was conducted using 2-sample univariable and multivariable mendelian randomization. Independent genetic variants associated with modifiable risk factors were selected as instrumental variables from genomic consortia. Outcome data for AD were obtained from the European Alzheimer & Dementia Biobank (EADB), generated on August 31, 2021. Main analyses were conducted using the EADB clinically diagnosed end point data. All analyses were performed between April 12 and October 27, 2022. EXPOSURES Genetically determined modifiable risk factors. MAIN OUTCOMES AND MEASURES Odds ratios (ORs) and 95% CIs for AD were calculated per 1-unit change of genetically determined risk factors. RESULTS The EADB-diagnosed cohort included 39106 participants with clinically diagnosed AD and 401577 control participants without AD. The mean age ranged from 72 to 83 years for participants with AD and 51 to 80 years for control participants. Among participants with AD, 54% to 75% were female, and among control participants, 48% to 60% were female. Genetically determined high-density lipoprotein (HDL) cholesterol concentrations were associated with increased odds of AD (OR per 1-SD increase, 1.10 [95% CI, 1.05-1.16]). Genetically determined high systolic blood pressure was associated with increased risk of AD after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.22 [95% CI, 1.02-1.46]). In a second analysis to minimize bias due to sample overlap, the entire UK Bio

IMPORTANCE An estimated 40% of dementia is potentially preventable by modifying 12 risk factors throughout the life course. However, robust evidence for most of these risk factors is lacking. Effective interventions should target risk factors in the causal pathway to dementia. OBJECTIVE To comprehensively disentangle potentially causal aspects of modifiable risk factors for Alzheimer disease (AD) to inspire new drug targeting and improved prevention. DESIGN, SETTING, AND PARTICIPANTS This genetic association study was conducted using 2-sample univariable and multivariable mendelian randomization. Independent genetic variants associated with modifiable risk factors were selected as instrumental variables from genomic consortia. Outcome data for AD were obtained from the European Alzheimer & Dementia Biobank (EADB), generated on August 31, 2021. Main analyses were conducted using the EADB clinically diagnosed end point data. All analyses were performed between April 12 and October 27, 2022. EXPOSURES Genetically determined modifiable risk factors. MAIN OUTCOMES AND MEASURES Odds ratios (ORs) and 95% CIs for AD were calculated per 1-unit change of genetically determined risk factors. RESULTS The EADB-diagnosed cohort included 39106 participants with clinically diagnosed AD and 401577 control participants without AD. The mean age ranged from 72 to 83 years for participants with AD and 51 to 80 years for control participants. Among participants with AD, 54% to 75% were female, and among control participants, 48% to 60% were female. Genetically determined high-density lipoprotein (HDL) cholesterol concentrations were associated with increased odds of AD (OR per 1-SD increase, 1.10 [95% CI, 1.05-1.16]). Genetically determined high systolic blood pressure was associated with increased risk of AD after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.22 [95% CI, 1.02-1.46]). In a second analysis to minimize bias due to sample overlap, the entire UK Bio

Importance: An estimated 40% of dementia is potentially preventable by modifying 12 risk factors throughout the life course. However, robust evidence for most of these risk factors is lacking. Effective interventions should target risk factors in the causal pathway to dementia. Objective: To comprehensively disentangle potentially causal aspects of modifiable risk factors for Alzheimer disease (AD) to inspire new drug targeting and improved prevention. Design, Setting, and Participants: This genetic association study was conducted using 2-sample univariable and multivariable mendelian randomization. Independent genetic variants associated with modifiable risk factors were selected as instrumental variables from genomic consortia. Outcome data for AD were obtained from the European Alzheimer & Dementia Biobank (EADB), generated on August 31, 2021. Main analyses were conducted using the EADB clinically diagnosed end point data. All analyses were performed between April 12 and October 27, 2022. Exposures: Genetically determined modifiable risk factors. Main Outcomes and Measures: Odds ratios (ORs) and 95% CIs for AD were calculated per 1-unit change of genetically determined risk factors. Results: The EADB-diagnosed cohort included 39106 participants with clinically diagnosed AD and 401577 control participants without AD. The mean age ranged from 72 to 83 years for participants with AD and 51 to 80 years for control participants. Among participants with AD, 54% to 75% were female, and among control participants, 48% to 60% were female. Genetically determined high-density lipoprotein (HDL) cholesterol concentrations were associated with increased odds of AD (OR per 1-SD increase, 1.10 [95% CI, 1.05-1.16]). Genetically determined high systolic blood pressure was associated with increased risk of AD after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.22 [95% CI, 1.02-1.46]). In a second analysis to minimize bias due to sample overlap, the entire

IMPORTANCE An estimated 40% of dementia is potentially preventable by modifying 12 risk factors throughout the life course. However, robust evidence for most of these risk factors is lacking. Effective interventions should target risk factors in the causal pathway to dementia. OBJECTIVE To comprehensively disentangle potentially causal aspects of modifiable risk factors for Alzheimer disease (AD) to inspire new drug targeting and improved prevention. DESIGN, SETTING, AND PARTICIPANTS This genetic association study was conducted using 2-sample univariable and multivariable mendelian randomization. Independent genetic variants associated with modifiable risk factors were selected as instrumental variables from genomic consortia. Outcome data for AD were obtained from the European Alzheimer & Dementia Biobank (EADB), generated on August 31, 2021. Main analyses were conducted using the EADB clinically diagnosed end point data. All analyses were performed between April 12 and October 27, 2022. EXPOSURES Genetically determined modifiable risk factors. MAIN OUTCOMES AND MEASURES Odds ratios (ORs) and 95% CIs for AD were calculated per 1-unit change of genetically determined risk factors. RESULTS The EADB-diagnosed cohort included 39106 participants with clinically diagnosed AD and 401577 control participants without AD. The mean age ranged from 72 to 83 years for participants with AD and 51 to 80 years for control participants. Among participants with AD, 54% to 75% were female, and among control participants, 48% to 60% were female. Genetically determined high-density lipoprotein (HDL) cholesterol concentrations were associated with increased odds of AD (OR per 1-SD increase, 1.10 [95% CI, 1.05-1.16]). Genetically determined high systolic blood pressure was associated with increased risk of AD after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.22 [95% CI, 1.02-1.46]). In a second analysis to minimize bias due to sample overlap, the entire UK Bio

Importance: An estimated 40% of dementia is potentially preventable by modifying 12 risk factors throughout the life course. However, robust evidence for most of these risk factors is lacking. Effective interventions should target risk factors in the causal pathway to dementia. Objective: To comprehensively disentangle potentially causal aspects of modifiable risk factors for Alzheimer disease (AD) to inspire new drug targeting and improved prevention. Design, Setting, and Participants: This genetic association study was conducted using 2-sample univariable and multivariable mendelian randomization. Independent genetic variants associated with modifiable risk factors were selected as instrumental variables from genomic consortia. Outcome data for AD were obtained from the European Alzheimer & Dementia Biobank (EADB), generated on August 31, 2021. Main analyses were conducted using the EADB clinically diagnosed end point data. All analyses were performed between April 12 and October 27, 2022. Exposures: Genetically determined modifiable risk factors. Main Outcomes and Measures: Odds ratios (ORs) and 95% CIs for AD were calculated per 1-unit change of genetically determined risk factors. Results: The EADB-diagnosed cohort included 39106 participants with clinically diagnosed AD and 401577 control participants without AD. The mean age ranged from 72 to 83 years for participants with AD and 51 to 80 years for control participants. Among participants with AD, 54% to 75% were female, and among control participants, 48% to 60% were female. Genetically determined high-density lipoprotein (HDL) cholesterol concentrations were associated with increased odds of AD (OR per 1-SD increase, 1.10 [95% CI, 1.05-1.16]). Genetically determined high systolic blood pressure was associated with increased risk of AD after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.22 [95% CI, 1.02-1.46]). In a second analysis to minimize bias due to sample overlap, the enti

Importance: An estimated 40% of dementia is potentially preventable by modifying 12 risk factors throughout the life course. However, robust evidence for most of these risk factors is lacking. Effective interventions should target risk factors in the causal pathway to dementia. Objective: To comprehensively disentangle potentially causal aspects of modifiable risk factors for Alzheimer disease (AD) to inspire new drug targeting and improved prevention. Design, setting, and participants: This genetic association study was conducted using 2-sample univariable and multivariable mendelian randomization. Independent genetic variants associated with modifiable risk factors were selected as instrumental variables from genomic consortia. Outcome data for AD were obtained from the European Alzheimer & Dementia Biobank (EADB), generated on August 31, 2021. Main analyses were conducted using the EADB clinically diagnosed end point data. All analyses were performed between April 12 and October 27, 2022. Exposures: Genetically determined modifiable risk factors. Main outcomes and measures: Odds ratios (ORs) and 95% CIs for AD were calculated per 1-unit change of genetically determined risk factors. Results: The EADB-diagnosed cohort included 39 106 participants with clinically diagnosed AD and 401 577 control participants without AD. The mean age ranged from 72 to 83 years for participants with AD and 51 to 80 years for control participants. Among participants with AD, 54% to 75% were female, and among control participants, 48% to 60% were female. Genetically determined high-density lipoprotein (HDL) cholesterol concentrations were associated with increased odds of AD (OR per 1-SD increase, 1.10 [95% CI, 1.05-1.16]). Genetically determined high systolic blood pressure was associated with increased risk of AD after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.22 [95% CI, 1.02-1.46]). In a second analysis to minimize bias due to sample overlap, the entir

Importance: An estimated 40% of dementia is potentially preventable by modifying 12 risk factors throughout the life course. However, robust evidence for most of these risk factors is lacking. Effective interventions should target risk factors in the causal pathway to dementia. Objective: To comprehensively disentangle potentially causal aspects of modifiable risk factors for Alzheimer disease (AD) to inspire new drug targeting and improved prevention. Design, setting, and participants: This genetic association study was conducted using 2-sample univariable and multivariable mendelian randomization. Independent genetic variants associated with modifiable risk factors were selected as instrumental variables from genomic consortia. Outcome data for AD were obtained from the European Alzheimer & Dementia Biobank (EADB), generated on August 31, 2021. Main analyses were conducted using the EADB clinically diagnosed end point data. All analyses were performed between April 12 and October 27, 2022. Exposures: Genetically determined modifiable risk factors. Main outcomes and measures: Odds ratios (ORs) and 95% CIs for AD were calculated per 1-unit change of genetically determined risk factors. Results: The EADB-diagnosed cohort included 39 106 participants with clinically diagnosed AD and 401 577 control participants without AD. The mean age ranged from 72 to 83 years for participants with AD and 51 to 80 years for control participants. Among participants with AD, 54% to 75% were female, and among control participants, 48% to 60% were female. Genetically determined high-density lipoprotein (HDL) cholesterol concentrations were associated with increased odds of AD (OR per 1-SD increase, 1.10 [95% CI, 1.05-1.16]). Genetically determined high systolic blood pressure was associated with increased risk of AD after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.22 [95% CI, 1.02-1.46]). In a second analysis to minimize bias due to sample overlap, the entire UK

Importance An estimated 40% of dementia is potentially preventable by modifying 12 risk factors throughout the life course. However, robust evidence for most of these risk factors is lacking. Effective interventions should target risk factors in the causal pathway to dementia. Objective To comprehensively disentangle potentially causal aspects of modifiable risk factors for Alzheimer disease (AD) to inspire new drug targeting and improved prevention. Design, Setting, and Participants This genetic association study was conducted using 2-sample univariable and multivariable mendelian randomization. Independent genetic variants associated with modifiable risk factors were selected as instrumental variables from genomic consortia. Outcome data for AD were obtained from the European Alzheimer & Dementia Biobank (EADB), generated on August 31, 2021. Main analyses were conducted using the EADB clinically diagnosed end point data. All analyses were performed between April 12 and October 27, 2022. Exposures Genetically determined modifiable risk factors. Main Outcomes and Measures Odds ratios (ORs) and 95% CIs for AD were calculated per 1-unit change of genetically determined risk factors. Results The EADB-diagnosed cohort included 39 106 participants with clinically diagnosed AD and 401 577 control participants without AD. The mean age ranged from 72 to 83 years for participants with AD and 51 to 80 years for control participants. Among participants with AD, 54% to 75% were female, and among control participants, 48% to 60% were female. Genetically determined high-density lipoprotein (HDL) cholesterol concentrations were associated with increased odds of AD (OR per 1-SD increase, 1.10 [95% CI, 1.05-1.16]). Genetically determined high systolic blood pressure was associated with increased risk of AD after adjusting for diastolic blood pressure (OR per 10–mm Hg increase, 1.22 [95% CI, 1.02-1.46]). In a second analysis to minimiz, Importance: An estimated 40% of dementia is potentially preventable by modifying 12 risk factors throughout the life course. However, robust evidence for most of these risk factors is lacking. Effective interventions should target risk factors in the causal pathway to dementia. Objective: To comprehensively disentangle potentially causal aspects of modifiable risk factors for Alzheimer disease (AD) to inspire new drug targeting and improved prevention. Design, Setting, and Participants: This genetic association study was conducted using 2-sample univariable and multivariable mendelian randomization. Independent genetic variants associated with modifiable risk factors were selected as instrumental variables from genomic consortia. Outcome data for AD were obtained from the European Alzheimer & Dementia Biobank (EADB), generated on August 31, 2021. Main analyses were conducted using the EADB clinically diagnosed end point data. All analyses were performed between April 12 and October 27, 2022. Exposures: Genetically determined modifiable risk factors. Main Outcomes and Measures: Odds ratios (ORs) and 95% CIs for AD were calculated per 1-unit change of genetically determined risk factors. Results: The EADB-diagnosed cohort included 39106 participants with clinically diagnosed AD and 401577 control participants without AD. The mean age ranged from 72 to 83 years for participants with AD and 51 to 80 years for control participants. Among participants with AD, 54% to 75% were female, and among control participants, 48% to 60% were female. Genetically determined high-density lipoprotein (HDL) cholesterol concentrations were associated with increased odds of AD (OR per 1-SD increase, 1.10 [95% CI, 1.05-1.16]). Genetically determined high systolic blood pressure was associated with increased risk of AD after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.22 [95% CI, 1.02-1.46]). In a second analysis to minimize bias due to sample overlap, the enti

Importance: An estimated 40% of dementia is potentially preventable by modifying 12 risk factors throughout the life course. However, robust evidence for most of these risk factors is lacking. Effective interventions should target risk factors in the causal pathway to dementia. Objective: To comprehensively disentangle potentially causal aspects of modifiable risk factors for Alzheimer disease (AD) to inspire new drug targeting and improved prevention. Design, Setting, and Participants: This genetic association study was conducted using 2-sample univariable and multivariable mendelian randomization. Independent genetic variants associated with modifiable risk factors were selected as instrumental variables from genomic consortia. Outcome data for AD were obtained from the European Alzheimer & Dementia Biobank (EADB), generated on August 31, 2021. Main analyses were conducted using the EADB clinically diagnosed end point data. All analyses were performed between April 12 and October 27, 2022. Exposures: Genetically determined modifiable risk factors. Main Outcomes and Measures: Odds ratios (ORs) and 95% CIs for AD were calculated per 1-unit change of genetically determined risk factors. Results: The EADB-diagnosed cohort included 39106 participants with clinically diagnosed AD and 401577 control participants without AD. The mean age ranged from 72 to 83 years for participants with AD and 51 to 80 years for control participants. Among participants with AD, 54% to 75% were female, and among control participants, 48% to 60% were female. Genetically determined high-density lipoprotein (HDL) cholesterol concentrations were associated with increased odds of AD (OR per 1-SD increase, 1.10 [95% CI, 1.05-1.16]). Genetically determined high systolic blood pressure was associated with increased risk of AD after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.22 [95% CI, 1.02-1.46]). In a second analysis to minimize bias due to sample overlap, the entire UK B

Importance: An estimated 40% of dementia is potentially preventable by modifying 12 risk factors throughout the life course. However, robust evidence for most of these risk factors is lacking. Effective interventions should target risk factors in the causal pathway to dementia. Objective: To comprehensively disentangle potentially causal aspects of modifiable risk factors for Alzheimer disease (AD) to inspire new drug targeting and improved prevention. Design, setting, and participants: This genetic association study was conducted using 2-sample univariable and multivariable mendelian randomization. Independent genetic variants associated with modifiable risk factors were selected as instrumental variables from genomic consortia. Outcome data for AD were obtained from the European Alzheimer & Dementia Biobank (EADB), generated on August 31, 2021. Main analyses were conducted using the EADB clinically diagnosed end point data. All analyses were performed between April 12 and October 27, 2022. Exposures: Genetically determined modifiable risk factors. Main outcomes and measures: Odds ratios (ORs) and 95% CIs for AD were calculated per 1-unit change of genetically determined risk factors. Results: The EADB-diagnosed cohort included 39 106 participants with clinically diagnosed AD and 401 577 control participants without AD. The mean age ranged from 72 to 83 years for participants with AD and 51 to 80 years for control participants. Among participants with AD, 54% to 75% were female, and among control participants, 48% to 60% were female. Genetically determined high-density lipoprotein (HDL) cholesterol concentrations were associated with increased odds of AD (OR per 1-SD increase, 1.10 [95% CI, 1.05-1.16]). Genetically determined high systolic blood pressure was associated with increased risk of AD after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.22 [95% CI, 1.02-1.46]). In a second analysis to minimize bias due to sample overlap, the entire UK

Background and Aims Anti-inflammatory trials have shown considerable benefits for cardiovascular disease. High neutrophil counts, an easily accessible inflammation biomarker, are associated with atherosclerosis in experimental studies. This study aimed to investigate the associations between neutrophil counts and risk of nine cardiovascular endpoints using observational and genetic approaches. Methods Observational studies were conducted in the Copenhagen General Population Study (n = 101 730). Genetic studies were firstly performed using one-sample Mendelian randomization (MR) with individual-level data from the UK Biobank (n = 365 913); secondly, two-sample MR analyses were performed using summary-level data from the Blood Cell Consortium (n = 563 085). Outcomes included ischaemic heart disease, myocardial infarction, peripheral arterial disease, ischaemic cerebrovascular disease, ischaemic stroke, vascular-related dementia, vascular dementia, heart failure, and atrial fibrillation. Results Observational analyses showed associations between high neutrophil counts with high risks of all outcomes. In the UK Biobank, odds ratios (95% confidence intervals) per 1-SD higher genetically predicted neutrophil counts were 1.15 (1.08, 1.21) for ischaemic heart disease, 1.22 (1.12, 1.34) for myocardial infarction, and 1.19 (1.04, 1.36) for peripheral arterial disease; similar results were observed in men and women separately. In two-sample MR, corresponding estimates were 1.14 (1.05, 1.23) for ischaemic heart disease and 1.11 (1.02, 1.20) for myocardial infarction; multiple sensitivity analyses showed consistent results. No robust associations in two-sample MR analyses were found for other types of leucocytes. Conclusions Observational and genetically determined high neutrophil counts were associated with atherosclerotic cardiovascular disease, supporting that high blood neutrophil counts is a causal risk factor for atherosclerotic c, Background and Anti-inflammatory trials have shown considerable benefits for cardiovascular disease. High neutrophil counts, an easily ac-Aims cessible inflammation biomarker, are associated with atherosclerosis in experimental studies. This study aimed to investigate the associations between neutrophil counts and risk of nine cardiovascular endpoints using observational and genetic approaches. Methods Observational studies were conducted in the Copenhagen General Population Study (n = 101 730). Genetic studies were firstly performed using one-sample Mendelian randomization (MR) with individual-level data from the UK Biobank (n = 365 913); secondly, two-sample MR analyses were performed using summary-level data from the Blood Cell Consortium (n = 563 085). Outcomes included ischaemic heart disease, myocardial infarction, peripheral arterial disease, ischaemic cerebrovascular disease, ischaemic stroke, vascular-related dementia, vascular dementia, heart failure, and atrial fibrillation. Results Observational analyses showed associations between high neutrophil counts with high risks of all outcomes. In the UK Biobank, odds ratios (95% confidence intervals) per 1-SD higher genetically predicted neutrophil counts were 1.15 (1.08, 1.21) for ischaemic heart disease, 1.22 (1.12, 1.34) for myocardial infarction, and 1.19 (1.04, 1.36) for peripheral arterial disease; similar results were observed in men and women separately. In two-sample MR, corresponding estimates were 1.14 (1.05, 1.23) for ischaemic heart disease and 1.11 (1.02, 1.20) for myocardial infarction; multiple sensitivity analyses showed consistent results. No robust associations in two-sample MR analyses were found for other types of leucocytes. Conclusions Observational and genetically determined high neutrophil counts were associated with atherosclerotic cardiovascular disease, supporting that high blood neutrophil counts is a causal risk factor for atherosclerotic cardiovascular disease.

High-density lipoprotein (HDL) cholesterol has for decades been considered as the “good cholesterol” due to its inverse association with cardiovascular disease (CVD) risk in observational studies. However, human genetic studies have failed to establish a direct causal association between low HDL cholesterol concentrations and CVD. Moreover, the development of HDL cholesterol-increasing drugs has been pursued, yet their efficacy in reducing cardiovascular risk has been limited. Interestingly, recent studies now uncover unexpected relationships between high HDL cholesterol concentrations and several diseases. These studies, including 2 significant recent investigations, observe associations between high HDL cholesterol concentrations, all-cause mortality, cardiovascular mortality, and Alzheimer disease (1, 2). This perspective aims to summarize and discuss these emerging findings and their potential implications for our understanding of HDL cholesterol and for its use in clinical practice, focusing on the complex interplay between HDL cholesterol, disease risk, and underlying mechanisms.

Background and Aims Anti-inflammatory trials have shown considerable benefits for cardiovascular disease. High neutrophil counts, an easily accessible inflammation biomarker, are associated with atherosclerosis in experimental studies. This study aimed to investigate the associations between neutrophil counts and risk of nine cardiovascular endpoints using observational and genetic approaches. Methods Observational studies were conducted in the Copenhagen General Population Study (n = 101 730). Genetic studies were firstly performed using one-sample Mendelian randomization (MR) with individual-level data from the UK Biobank (n = 365 913); secondly, two-sample MR analyses were performed using summary-level data from the Blood Cell Consortium (n = 563 085). Outcomes included ischaemic heart disease, myocardial infarction, peripheral arterial disease, ischaemic cerebrovascular disease, ischaemic stroke, vascular-related dementia, vascular dementia, heart failure, and atrial fibrillation. Results Observational analyses showed associations between high neutrophil counts with high risks of all outcomes. In the UK Biobank, odds ratios (95% confidence intervals) per 1-SD higher genetically predicted neutrophil counts were 1.15 (1.08, 1.21) for ischaemic heart disease, 1.22 (1.12, 1.34) for myocardial infarction, and 1.19 (1.04, 1.36) for peripheral arterial disease; similar results were observed in men and women separately. In two-sample MR, corresponding estimates were 1.14 (1.05, 1.23) for ischaemic heart disease and 1.11 (1.02, 1.20) for myocardial infarction; multiple sensitivity analyses showed consistent results. No robust associations in two-sample MR analyses were found for other types of leucocytes. Conclusions Observational and genetically determined high neutrophil counts were associated with atherosclerotic cardiovascular disease, supporting that high blood neutrophil counts is a causal risk factor for atherosclerotic c, Background and Anti-inflammatory trials have shown considerable benefits for cardiovascular disease. High neutrophil counts, an easily ac-Aims cessible inflammation biomarker, are associated with atherosclerosis in experimental studies. This study aimed to investigate the associations between neutrophil counts and risk of nine cardiovascular endpoints using observational and genetic approaches. Methods Observational studies were conducted in the Copenhagen General Population Study (n = 101 730). Genetic studies were firstly performed using one-sample Mendelian randomization (MR) with individual-level data from the UK Biobank (n = 365 913); secondly, two-sample MR analyses were performed using summary-level data from the Blood Cell Consortium (n = 563 085). Outcomes included ischaemic heart disease, myocardial infarction, peripheral arterial disease, ischaemic cerebrovascular disease, ischaemic stroke, vascular-related dementia, vascular dementia, heart failure, and atrial fibrillation. Results Observational analyses showed associations between high neutrophil counts with high risks of all outcomes. In the UK Biobank, odds ratios (95% confidence intervals) per 1-SD higher genetically predicted neutrophil counts were 1.15 (1.08, 1.21) for ischaemic heart disease, 1.22 (1.12, 1.34) for myocardial infarction, and 1.19 (1.04, 1.36) for peripheral arterial disease; similar results were observed in men and women separately. In two-sample MR, corresponding estimates were 1.14 (1.05, 1.23) for ischaemic heart disease and 1.11 (1.02, 1.20) for myocardial infarction; multiple sensitivity analyses showed consistent results. No robust associations in two-sample MR analyses were found for other types of leucocytes. Conclusions Observational and genetically determined high neutrophil counts were associated with atherosclerotic cardiovascular disease, supporting that high blood neutrophil counts is a causal risk factor for atherosclerotic cardiovascular disease.

Importance: Emerging evidence implicates a role for neuroinflammation in Alzheimer disease (AD) pathogenesis, predominantly involving the innate immune system. Blood leukocyte counts are easily accessible markers of immune function; however, their association with the risk of AD is unknown. Objective: To investigate the observational and genetic associations between types of blood leukocytes and risk of AD. Design, Setting, and Participants: In a cohort study comprising observational and genetic analyses, the Copenhagen General Population Study prospective cohort (n = 101582) was used for the observational analyses. For the genetic studies, nonlinearity was first evaluated for the association between leukocyte cell counts and AD risk using individual-level data from the UK Biobank (n = 365913). Subsequently, a 2-sample mendelian randomization framework was applied using genetic instruments for blood leukocyte counts (n = 563 085); for AD, the European Alzheimer & Dementia Biobank was used, including 85934 individuals with AD and 401577 controls and the International Genomics of Alzheimer's Project, including 21982 individuals with AD and 41944 controls. Exposures: Observational and genetically determined types of blood leukocyte counts. Main Outcomes and Measures: Hazard ratios (HRs) and 95% CIs for AD of cell count percentile groups in observational studies and odds ratios (ORs) and 95% CIs for AD per 1 SD genetically determined cell counts. Results: This cohort study included 101582 participants (55 891 [55.0%] women) with a median age of 58 years (IQR, 48-67 years); of these, 1588 individuals developed AD. Multivariable-adjusted HRs for participants in the less than 5th vs the 25th to 75th (reference) percentile group were 1.24 (95% CI, 0.99-1.54) for blood monocytes and 1.25 for blood eosinophils (95% CI, 1.05-1.50). For participants in the greater than 95th vs the 25th to 75th percentile group, the HR was 1.30 (95% CI, 1.06-1.61) for blood neutrophils. G

Importance: Emerging evidence implicates a role for neuroinflammation in Alzheimer disease (AD) pathogenesis, predominantly involving the innate immune system. Blood leukocyte counts are easily accessible markers of immune function; however, their association with the risk of AD is unknown. Objective: To investigate the observational and genetic associations between types of blood leukocytes and risk of AD. Design, Setting, and Participants: In a cohort study comprising observational and genetic analyses, the Copenhagen General Population Study prospective cohort (n = 101582) was used for the observational analyses. For the genetic studies, nonlinearity was first evaluated for the association between leukocyte cell counts and AD risk using individual-level data from the UK Biobank (n = 365913). Subsequently, a 2-sample mendelian randomization framework was applied using genetic instruments for blood leukocyte counts (n = 563 085); for AD, the European Alzheimer & Dementia Biobank was used, including 85934 individuals with AD and 401577 controls and the International Genomics of Alzheimer's Project, including 21982 individuals with AD and 41944 controls. Exposures: Observational and genetically determined types of blood leukocyte counts. Main Outcomes and Measures: Hazard ratios (HRs) and 95% CIs for AD of cell count percentile groups in observational studies and odds ratios (ORs) and 95% CIs for AD per 1 SD genetically determined cell counts. Results: This cohort study included 101582 participants (55 891 [55.0%] women) with a median age of 58 years (IQR, 48-67 years); of these, 1588 individuals developed AD. Multivariable-adjusted HRs for participants in the less than 5th vs the 25th to 75th (reference) percentile group were 1.24 (95% CI, 0.99-1.54) for blood monocytes and 1.25 for blood eosinophils (95% CI, 1.05-1.50). For participants in the greater than 95th vs the 25th to 75th percentile group, the HR was 1.30 (95% CI, 1.06-1.61) for blood neutrophils. G

For the new requirements of engineering certification, a modular teaching plan of engineering project management is proposed that is also combined with the professional features of vehicle engineering. Specifically, the teaching objectives of this course are established by engineering certification. Meanwhile, the course content is modularized and adopted different teaching method, such as lecture, interactive module, heuristic teaching method, etc. The improvement plan of course fully focuses on student-centered and output-oriented principle which strengthens the initiative of students to master basic theory knowledge. And it is helpful for students to have the ability to meet the engineering certification standards.

For the new requirements of engineering certification, a modular teaching plan of engineering project management is proposed that is also combined with the professional features of vehicle engineering. Specifically, the teaching objectives of this course are established by engineering certification. Meanwhile, the course content is modularized and adopted different teaching method, such as lecture, interactive module, heuristic teaching method, etc. The improvement plan of course fully focuses on student-centered and output-oriented principle which strengthens the initiative of students to master basic theory knowledge. And it is helpful for students to have the ability to meet the engineering certification standards.

For the new requirements of engineering certification, a modular teaching plan of engineering project management is proposed that is also combined with the professional features of vehicle engineering. Specifically, the teaching objectives of this course are established by engineering certification. Meanwhile, the course content is modularized and adopted different teaching method, such as lecture, interactive module, heuristic teaching method, etc. The improvement plan of course fully focuses on student-centered and output-oriented principle which strengthens the initiative of students to master basic theory knowledge. And it is helpful for students to have the ability to meet the engineering certification standards.

For the new requirements of engineering certification, a modular teaching plan of engineering project management is proposed that is also combined with the professional features of vehicle engineering. Specifically, the teaching objectives of this course are established by engineering certification. Meanwhile, the course content is modularized and adopted different teaching method, such as lecture, interactive module, heuristic teaching method, etc. The improvement plan of course fully focuses on student-centered and output-oriented principle which strengthens the initiative of students to master basic theory knowledge. And it is helpful for students to have the ability to meet the engineering certification standards.

This article is focused on the teaching methodology for Engineering Project Management course. The course is an elementary and core course for automotive engineering major based on the requirement of professional accreditation of engineering programs. The course can be described as a course with big scale and more emphasized on industry. Three teaching methodologies have been used to coordinating with the course features: case-study learning, mission-driven learning, project-driven learning and flipped-classroom learning. The article addressed how the three methods have been applied in teaching. Meanwhile, the article also mentioned that a multi-methods evaluation should be more precise for evaluating students’ abilities.

This article is focused on the teaching methodology for Engineering Project Management course. The course is an elementary and core course for automotive engineering major based on the requirement of professional accreditation of engineering programs. The course can be described as a course with big scale and more emphasized on industry. Three teaching methodologies have been used to coordinating with the course features: case-study learning, mission-driven learning, project-driven learning and flipped-classroom learning. The article addressed how the three methods have been applied in teaching. Meanwhile, the article also mentioned that a multi-methods evaluation should be more precise for evaluating students’ abilities.

This article is focused on the teaching methodology for Engineering Project Management course. The course is an elementary and core course for automotive engineering major based on the requirement of professional accreditation of engineering programs. The course can be described as a course with big scale and more emphasized on industry. Three teaching methodologies have been used to coordinating with the course features: case-study learning, mission-driven learning, project-driven learning and flipped-classroom learning. The article addressed how the three methods have been applied in teaching. Meanwhile, the article also mentioned that a multi-methods evaluation should be more precise for evaluating students’ abilities.

This article is focused on the teaching methodology for Engineering Project Management course. The course is an elementary and core course for automotive engineering major based on the requirement of professional accreditation of engineering programs. The course can be described as a course with big scale and more emphasized on industry. Three teaching methodologies have been used to coordinating with the course features: case-study learning, mission-driven learning, project-driven learning and flipped-classroom learning. The article addressed how the three methods have been applied in teaching. Meanwhile, the article also mentioned that a multi-methods evaluation should be more precise for evaluating students’ abilities.

Claudins, the integral tight junction (TJ) proteins that regulate paracellular permeability and cell polarity, are frequently dysregulated in cancer; however, their role in neoplastic progression is unclear. Here, we demonstrated that knockout of Cldn18, a claudin family member highly expressed in lung alveolar epithelium, leads to lung enlargement, parenchymal expansion, increased abundance and proliferation of known distal lung progenitors, the alveolar epithelial type II (AT2) cells, activation of Yes-associated protein (YAP), increased organ size, and tumorigenesis in mice. Inhibition of YAP decreased proliferation and colony-forming efficiency (CFE) of Cldn18-/- AT2 cells and prevented increased lung size, while CLDN18 overexpression decreased YAP nuclear localization, cell proliferation, CFE, and YAP transcriptional activity. CLDN18 and YAP interacted and colocalized at cell-cell contacts, while loss of CLDN18 decreased YAP interaction with Hippo kinases p-LATS1/2. Additionally, Cldn18-/- mice had increased propensity to develop lung adenocarcinomas (LuAd) with age, and human LuAd showed stage-dependent reduction of CLDN18.1. These results establish CLDN18 as a regulator of YAP activity that serves to restrict organ size, progenitor cell proliferation, and tumorigenesis, and suggest a mechanism whereby TJ disruption may promote progenitor proliferation to enhance repair following injury.

AimTo identify functional lung adenocarcinoma (LUAD) risk SNPs.Materials & methodsEighteen validated LUAD risk SNPs (p ≤ 5 × 10-8) and 930 SNPs in high linkage disequilibrium (r2 > 0.5) were integrated with epigenomic information from primary human alveolar epithelial cells. Enhancer-associated SNPs likely affecting transcription factor-binding sites were predicted. Three SNPs were functionally investigated using luciferase assays, expression quantitative trait loci and cancer-specific expression.ResultsForty-seven SNPs mapped to putative enhancers; 11 located to open chromatin. Of these, seven altered predicted transcription factor-binding motifs. Rs6942067 showed allele-specific luciferase expression and expression quantitative trait loci analysis indicates that it influences expression of DCBLD1, a gene that encodes an unknown membrane protein and is overexpressed in LUAD.ConclusionIntegration of candidate LUAD risk SNPS with epigenomic marks from normal alveolar epithelium identified numerous candidate functional LUAD risk SNPs including rs6942067, which appears to affect DCBLD1 expression. Data deposition: Data are provided in GEO record GSE84273.

Claudins, the integral tight junction (TJ) proteins that regulate paracellular permeability and cell polarity, are frequently dysregulated in cancer; however, their role in neoplastic progression is unclear. Here, we demonstrated that knockout of Cldn18, a claudin family member highly expressed in lung alveolar epithelium, leads to lung enlargement, parenchymal expansion, increased abundance and proliferation of known distal lung progenitors, the alveolar epithelial type II (AT2) cells, activation of Yes-associated protein (YAP), increased organ size, and tumorigenesis in mice. Inhibition of YAP decreased proliferation and colony-forming efficiency (CFE) of Cldn18-/- AT2 cells and prevented increased lung size, while CLDN18 overexpression decreased YAP nuclear localization, cell proliferation, CFE, and YAP transcriptional activity. CLDN18 and YAP interacted and colocalized at cell-cell contacts, while loss of CLDN18 decreased YAP interaction with Hippo kinases p-LATS1/2. Additionally, Cldn18-/- mice had increased propensity to develop lung adenocarcinomas (LuAd) with age, and human LuAd showed stage-dependent reduction of CLDN18.1. These results establish CLDN18 as a regulator of YAP activity that serves to restrict organ size, progenitor cell proliferation, and tumorigenesis, and suggest a mechanism whereby TJ disruption may promote progenitor proliferation to enhance repair following injury.

AimTo identify functional lung adenocarcinoma (LUAD) risk SNPs.Materials & methodsEighteen validated LUAD risk SNPs (p ≤ 5 × 10-8) and 930 SNPs in high linkage disequilibrium (r2 > 0.5) were integrated with epigenomic information from primary human alveolar epithelial cells. Enhancer-associated SNPs likely affecting transcription factor-binding sites were predicted. Three SNPs were functionally investigated using luciferase assays, expression quantitative trait loci and cancer-specific expression.ResultsForty-seven SNPs mapped to putative enhancers; 11 located to open chromatin. Of these, seven altered predicted transcription factor-binding motifs. Rs6942067 showed allele-specific luciferase expression and expression quantitative trait loci analysis indicates that it influences expression of DCBLD1, a gene that encodes an unknown membrane protein and is overexpressed in LUAD.ConclusionIntegration of candidate LUAD risk SNPS with epigenomic marks from normal alveolar epithelium identified numerous candidate functional LUAD risk SNPs including rs6942067, which appears to affect DCBLD1 expression. Data deposition: Data are provided in GEO record GSE84273.