scholarly journals Examining the possible causal relationship between lung function, COPD and Alzheimer’s disease: a Mendelian randomisation study

2021 ◽  
Vol 8 (1) ◽  
pp. e000759
Author(s):  
Daniel Higbee ◽  
Raquel Granell ◽  
Esther Walton ◽  
Roxanna Korologou-Linden ◽  
George Davey Smith ◽  
...  
Keyword(s):  
Risk Factors ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Lung Function ◽  
Causal Relationship ◽  
Mendelian Randomisation ◽  
P Value ◽  
Unmeasured Confounding ◽  
Increased Risk ◽  
Shared Risk

RationaleLarge retrospective case-control studies have reported an association between chronic obstructive pulmonary disease (COPD), reduced lung function and an increased risk of Alzheimer’s disease. However, it remains unclear if these diseases are causally linked, or due to shared risk factors. Conventional observational epidemiology suffers from unmeasured confounding and reverse causation. Additional analyses addressing causality are required.ObjectivesTo examine a causal relationship between COPD, lung function and Alzheimer’s disease.MethodsUsing two-sample Mendelian randomisation, we used single nucleotide polymorphisms (SNPs) identified in a genome wide association study (GWAS) for lung function as instrumental variables (exposure). Additionally, we used SNPs discovered in a GWAS for COPD in those with moderate to very severe obstruction. The effect of these SNPs on Alzheimer’s disease (outcome) was taken from a GWAS based on a sample of 24 807 patients and 55 058 controls.ResultsWe found minimal evidence for an effect of either lung function (OR: 1.02 per SD; 95% CI 0.91 to 1.13; p value 0.68) or liability for COPD on Alzheimer’s disease (OR: 0.97 per SD; 95% CI 0.92 to 1.03; p value 0.40).ConclusionNeither reduced lung function nor liability COPD are likely to be causally associated with an increased risk of Alzheimer’s, any observed association is likely due to unmeasured confounding. Scientific attention and health prevention policy may be better focused on overlapping risk factors, rather than attempts to reduce risk of Alzheimer’s disease by targeting impaired lung function or COPD directly.

scholarly journals Examining the possible causal relationship between Lung Function, COPD and Alzheimers Disease. A Mendelian Randomization Study

2020 ◽  
Author(s):  
Daniel H Higbee ◽  
Raquel Granell ◽  
Esther Walton ◽  
Roxanna Korologou-Linden ◽  
George Davey Smith ◽  
...  
Keyword(s):  
Risk Factors ◽  
Lung Function ◽  
Causal Relationship ◽  
Mendelian Randomization ◽  
P Value ◽  
Alzheimers Disease ◽  
Unmeasured Confounding ◽  
A Genome ◽  
Increased Risk ◽  
Shared Risk

Rationale: Large retrospective case-control studies have reported an association between COPD, reduced lung function and an increased risk of Alzheimers disease. However, it remains unclear if these diseases are causally linked, or due to shared risk factors. Conventional observational epidemiology suffers from unmeasured confounding and reverse causation. Additional analyses addressing causality are required. Objectives: To examine a causal relationship between COPD, lung function and Alzheimers disease. Methods: Using two-sample Mendelian randomization, we utilised single nucleotide polymorphisms (SNPs) identified in a genome wide association study (GWAS) for lung function as instrumental variables (exposure). Additionally, we used SNPs discovered in a GWAS for COPD in those with moderate to very severe obstruction. The effect of these SNPs on Alzheimers disease (outcome) were taken from a GWAS based on a sample of 24,807 patients and 55,058 controls. Results: We found minimal evidence for an effect of either lung function (odds ratio [OR]:1.02 per SD; 95% confidence interval [CI]: 0.91, 1.13; p value 0.68). or liability for COPD on Alzheimers disease (OR: 0.97 per SD; 95% CI: 0.92, 1.03; p value 0.40). Conclusion: Neither reduced lung function nor liability COPD are likely to be causally associated with an increased risk of Alzheimers, any observed association is likely due to unmeasured confounding. Scientific attention and health prevention policy may be better focused on overlapping risk factors, rather than attempts to reduce risk of Alzheimers disease by targeting impaired lung function or COPD directly.

scholarly journals The vascular contribution to Alzheimer's disease

2010 ◽  
Vol 119 (10) ◽  
pp. 407-421 ◽  
Author(s):  
Robin Altman ◽  
John C. Rutledge
Keyword(s):  
Risk Factors ◽  
Alzheimer’S Disease ◽  
Cardiovascular Disease ◽  
Alzheimer's Disease ◽  
Neurovascular Unit ◽  
Blood Cholesterol ◽  
Atherosclerotic Cardiovascular Disease ◽  
Increased Risk ◽  
Aβ Amyloid ◽  
Shared Risk

AD (Alzheimer's disease) is a progressive neurodegenerative disease of unknown origin. Despite questions as to the underlying cause(s) of this disease, shared risk factors for both AD and atherosclerotic cardiovascular disease indicate that vascular mechanisms may critically contribute to the development and progression of both AD and atherosclerosis. An increased risk of developing AD is linked to the presence of the apoE4 (apolipoprotein E4) allele, which is also strongly associated with increased risk of developing atherosclerotic cardiovascular disease. Recent studies also indicate that cardiovascular risk factors, including elevated blood cholesterol and triacylglycerol (triglyceride), increase the likelihood of AD and vascular dementia. Lipids and lipoproteins in the circulation interact intimately with the cerebrovasculature, and may have important effects on its constituent brain microvascular endothelial cells and the adjoining astrocytes, which are components of the neurovascular unit. The present review will examine the potential mechanisms for understanding the contributions of vascular factors, including lipids, lipoproteins and cerebrovascular Aβ (amyloid β), to AD, and suggest therapeutic strategies for the attenuation of this devastating disease process. Specifically, we will focus on the actions of apoE, TGRLs (triacylglycerol-rich lipoproteins) and TGRL lipolysis products on injury of the neurovascular unit and increases in blood–brain barrier permeability.

scholarly journals Genetic Predisposition to Alzheimer’s Disease Is Associated with Enlargement of Perivascular Spaces in Centrum Semiovale Region

Genes ◽  
2021 ◽  
Vol 12 (6) ◽  
pp. 825
Author(s):  
Iacopo Ciampa ◽  
Grégory Operto ◽  
Carles Falcon ◽  
Carolina Minguillon ◽  
Manuel Castro de Moura ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Genetic Predisposition ◽  
Rating Scale ◽  
P Value ◽  
Perivascular Spaces ◽  
Centrum Semiovale ◽  
Logistic Regression Models ◽  
Visual Rating ◽  
Increased Risk

This study investigated whether genetic factors involved in Alzheimer’s disease (AD) are associated with enlargement of Perivascular Spaces (ePVS) in the brain. A total of 680 participants with T2-weighted MRI scans and genetic information were acquired from the ALFA study. ePVS in the basal ganglia (BG) and the centrum semiovale (CS) were assessed based on a validated visual rating scale. We used univariate and multivariate logistic regression models to investigate associations between ePVS in BG and CS with BIN1-rs744373, as well as APOE genotypes. We found a significant association of the BIN1-rs744373 polymorphism in the CS subscale (p value = 0.019; OR = 2.564), suggesting that G allele carriers have an increased risk of ePVS in comparison with A allele carriers. In stratified analysis by APOE-ε4 status (carriers vs. non-carriers), these results remained significant only for ε4 carriers (p value = 0.011; OR = 1.429). To our knowledge, the present study is the first suggesting that genetic predisposition for AD is associated with ePVS in CS. These findings provide evidence that underlying biological processes affecting AD may influence CS-ePVS.

scholarly journals Risk Factors for Progression to Alzheimer's Disease in African Americans in a Large National Cohort

2020 ◽  
Author(s):  
Yejin Kim ◽  
Sean I Savitz ◽  
Jessica Lee ◽  
Paul E Schulz ◽  
Luyao Chen ◽  
...  
Keyword(s):  
Risk Factors ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
African Americans ◽  
Treatment Effect ◽  
Senile Dementia ◽  
P Value ◽  
Racial Groups ◽  
Diagnosis Codes ◽  
National Cohort

Objectives: To investigate risk factors for progression to Alzheimer's disease and related dementias (ADRD) in African Americans and non-Hispanic Caucasians in a large US cohort. Design: A matched case-control design using electronic health records (EHRs) from 2000 - 2017. Setting: Cerner EHRs database covering more than 600 Cerner client hospitals. Participants: 79,120 patients aged 65 and older (#ADRD=39,560, #non ADRD older adults=39,560) from an initial cohort of 49,826,000 patients. Measurements: We converted ICD9 or ICD10 diagnosis codes into PheWas codes to increase clinical relevance. Then we detected ADRD as having both ADRD diagnosis codes and medications. We considered PheWas codes for Alzheimer's disease, dementia with cerebral degenerations, senile dementia, and vascular dementia. We considered ADRD medications including acetylcholine and memantine. Results: Using two-step propensity score matching, we built an African American cohort of 4,429 and a 4,570-person matched Caucasian cohort that was similar in terms of onset age, observation length, sex, and known ADRD risks (diabetes, vascular disease, heart disease, head injury, and obesity). Older African Americans had a statistically significant progression from cerebrovascular risk (transient ischemic attack) to ADRD incidence (treatment effect coefficient = 0.0978, p-value <0.000) whereas the matched Caucasians did not (treatment effect coefficient = 0.403, p-value = 0.196). Conclusion: Our extensive causal analysis using a nationwide EHR discovered disease progression pathways to ADRD. The carefully matched cohorts from different racial groups showed different progression, which partly explains the racial disparities in ADRD incidence.

scholarly journals Inflammation and Insulin Resistance as Risk Factors and Potential Therapeutic Targets for Alzheimer’s Disease

2021 ◽  
Vol 15 ◽  
Author(s):  
Angeles Vinuesa ◽  
Carlos Pomilio ◽  
Amal Gregosa ◽  
Melisa Bentivegna ◽  
Jessica Presa ◽  
...  
Keyword(s):  
Risk Factors ◽  
Alzheimer’S Disease ◽  
Insulin Resistance ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Brain Aging ◽  
Therapeutic Targets ◽  
Low Grade ◽  
Increased Risk ◽  
The Impact

Overnutrition and modern diets containing high proportions of saturated fat are among the major factors contributing to a low-grade state of inflammation, hyperglycemia and dyslipidemia. In the last decades, the global rise of type 2 diabetes and obesity prevalence has elicited a great interest in understanding how changes in metabolic function lead to an increased risk for premature brain aging and the development of neurodegenerative disorders such as Alzheimer’s disease (AD). Cognitive impairment and decreased neurogenic capacity could be a consequence of metabolic disturbances. In these scenarios, the interplay between inflammation and insulin resistance could represent a potential therapeutic target to prevent or ameliorate neurodegeneration and cognitive impairment. The present review aims to provide an update on the impact of metabolic stress pathways on AD with a focus on inflammation and insulin resistance as risk factors and therapeutic targets.

scholarly journals Anxiety and Depression as Risk Factors in Frontotemporal Dementia and Alzheimer’s Disease: The HUNT Study

2018 ◽  
Vol 8 (3) ◽  
pp. 414-425 ◽  
Author(s):  
Hege Rasmussen ◽  
Tor Atle Rosness ◽  
Ole Bosnes ◽  
Øyvind Salvesen ◽  
Marlen Knutli ◽  
...  
Keyword(s):  
Risk Factors ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Frontotemporal Dementia ◽  
Depression Scale ◽  
Health Study ◽  
Anxiety And Depression ◽  
Increased Risk ◽  
Hunt Study ◽  
Independent Risk Factors

Background: The roles of both anxiety and depression as risk factors for frontotemporal dementia (FTD) and Alzheimer’s disease (AD) have not been previously investigated together. Objective: To study anxiety and depression as independent risk factors for FTD and AD. Methods: Eighty-four patients with FTD and 556 patients with AD were compared with 117 cognitively healthy (CH), elderly individuals. Both cases and controls were participants in the second Health Study of Nord-Trøndelag (HUNT2) from 1995 to 1997, in which depression and anxiety were assessed with the Hospital Anxiety and Depression Scale (HADS). Results: Significant associations were found between anxiety and FTD and between depression and AD. A significantly increased risk of developing FTD was observed in patients who had reported anxiety on the HADS (p = 0.017) (odds ratio [OR]: 2.947, 95% confidence interval [CI]: 1.209–7.158) and a significantly increased risk of developing AD was observed in patients who had reported depression on the HADS (p = 0.016) (OR: 4.389, 95% CI: 1.311–14.690). Conclusion: Our study findings suggest that anxiety and depression may play different roles as risk factors for FTD and AD.

scholarly journals Clusterin accumulates in synapses in Alzheimer’s disease and is increased in apolipoprotein E4 carriers

2019 ◽  
Vol 1 (1) ◽  
Author(s):  
Rosemary J Jackson ◽  
Jamie Rose ◽  
Jane Tulloch ◽  
Chris Henstridge ◽  
Colin Smith ◽  
...  
Keyword(s):  
Risk Factors ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Beta ◽  
Genetic Risk ◽  
Genetic Risk Factors ◽  
Data Link ◽  
Increased Risk ◽  
Synapse Degeneration ◽  
Models Of Disease

Abstract One of the major challenges in developing effective therapeutic strategies for Alzheimer’s disease is understanding how genetic risk factors contribute to neurodegeneration. The apolipoprotein epsilon 4 isoform (APOE4) and variants in the Clusterin (CLU) gene (also known as apolipoprotein J) are associated with increased risk of developing Alzheimer’s. Our previous work demonstrated that APOE4 exacerbates synapse degeneration and synaptic accumulation of toxic oligomeric amyloid beta in human Alzheimer’s and mouse models of disease. Here, we observe clusterin in synapses in human Alzheimer's disease brain. The percentage of synapses containing clusterin is higher in APOE4 carriers than APOE3 carriers. Furthermore, we observe oligomeric amyloid beta accumulation within synapses containing clusterin which is also higher in APOE4 carriers. These data link two genetic risk factors with synapse degeneration in Alzheimer’s and support a potential role for clusterin working with APOE in causing synaptic damage.

scholarly journals Deciphering the causal relationship between blood metabolites and Alzheimer’s Disease: a Mendelian Randomization study

2020 ◽  
Author(s):  
Jodie Lord ◽  
Bradley Jermy ◽  
Rebecca Green ◽  
Andrew Wong ◽  
Jin Xu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Causal Relationship ◽  
Bayesian Model Averaging ◽  
Association Studies ◽  
High Density Lipoproteins ◽  
Mendelian Randomisation ◽  
Blood Metabolites ◽  
Genome Wide Association Studies ◽  
Causal Pathway

AbstractThere are currently no disease modifying treatments for Alzheimer’s Disease (AD). Epidemiological studies have highlighted blood metabolites as potential biomarkers, but possible confounding and reverse causation prevent causal conclusions. Here, we investigated whether nineteen metabolites previously associated with midlife cognitive function, are on the causal pathway to AD.Summary statistics from the largest Genome-Wide Association Studies (GWAS) for AD and for metabolites were used to perform bi-directional univariable Mendelian Randomisation (MR). Bayesian model averaging MR (MR-BMA) was additionally performed to address high correlation between metabolites and to identify metabolite combinations which may be on the AD causal pathway.Univariable MR indicated three Extra-Large High-Density Lipoproteins (XL.HDL) to be on the causal pathway to AD: Free Cholesterol (XL.HDL.FC: OR=0.86, 95% CI=0.78-0.94), Total Lipids (XL.HDL.L: OR=0.88, 95% CI=0.80-0.97), and Phospholipids (XL.HDL.PL: OR=0.87, 95% CI=0.81-0.97); significant at an adjusted threshold of p<0.009. MR-BMA corroborated XL.HDL.FC to be amongst the top three causal metabolites, additionally to Total Cholesterol in XL.HDL (XL.HDL.C) and Glycoprotein Acetyls (GP) (posterior probabilities=0.112, 0.113, 0.287 respectively). Both XL.HDL.C and GP also demonstrated suggestive evidence of univariable causal associations (XL.HDL.C:OR=0.88, 95% CI=0.79-0.99; GP:OR=1.2, 95% CI=1.05-1.38); significant at the 5% level.This study offers insight into the causal relationship between metabolites previously demonstrating association with mid-life cognition, and AD. It highlights GP in addition to several XL.HDLs as causal candidates which warrant further investigation. As the pathological changes underpinning AD are thought to develop decades prior to symptom onset, progressing these findings could hold special value in informing future risk reduction strategies.

scholarly journals Environmental factors influencing the link between APOE ε4 and Alzheimer's disease (AD) risk

2018 ◽  
Vol 31 (2) ◽  
pp. 305-306 ◽  
Author(s):  
Keith Fluegge
Keyword(s):  
Risk Factors ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Genetic Risk ◽  
Temporal Relationship ◽  
Disease Risk ◽  
Apoe Ε4 ◽  
Factors Influencing ◽  
Increased Risk ◽  
Ε4 Allele

While APOE ε4 allele is considered a genetic risk factor for Alzheimer's disease (AD), no relation existed between APOE ε4 and AD in the Yoruba in Nigeria among cohorts included in early prevalence waves. The authors’ explanation that other disease susceptibilities may provoke earlier mortality is inconsistent with the Yoruba having a lower incidence of disease risk factors. Cohort enrichment in 2001 has altered the authors’ conclusions; Yorba participants homozygous, and not heterozygous, for the ε4 allele had significantly increased risk for AD (HR = 2.95, p = 0.0002) (Hendrie et al., 2014). This is a critical revelation, yet it is not clear why such a temporal relationship exists between risk genotypes and AD among the Yoruba. This letter proposes an explanation.

scholarly journals Type-2 diabetes and risk of dementia: observational and Mendelian randomisation studies in 1 million individuals

2020 ◽  
Vol 29 ◽  
Author(s):  
Jesper Qvist Thomassen ◽  
Janne Schurmann Tolstrup ◽  
Marianne Benn ◽  
Ruth Frikke-Schmidt
Keyword(s):  
Alzheimer’S Disease ◽  
Type 2 Diabetes ◽  
Alzheimer's Disease ◽  
Vascular Dementia ◽  
Mendelian Randomisation ◽  
Nationwide Study ◽  
Increased Risk ◽  
Civil Status ◽  
Causal Nature

Abstract Aims In observational studies, type-2 diabetes is associated with increased risk of dementia; however, the causal nature of this association remains unanswered. In an unselected nationwide study of all Danes, we wanted to test whether type-2 diabetes is associated with dementia subtypes, and to test whether potential associations are of a causal nature. Methods In the current study of nationwide observational registry data in all Danes above the age of 65 years (n = 784 434) combined with genetic consortia data on 213 370 individuals, we investigated the associations between type-2 diabetes and Alzheimer's disease, vascular dementia, unspecified dementia and all-cause dementia, and whether observational associations were of a causal nature by applying a two-sample Mendelian randomisation strategy. We addressed key biases inherent in Mendelian randomisation approaches. Results Important confounders (age, ethnicity, size of community, region, civil status and education level) were captured on all 784 434 individuals and adjusted for in the models. Multifactorial adjusted hazard ratios were 1.13 (1.06–1.21) for Alzheimer's disease, 1.98 (1.83–2.14) for vascular dementia, 1.53 (1.48–1.59) for unspecified dementia and 1.48 (1.44–1.53) for all-cause dementia in persons with type-2 diabetes v. without. Results were similar for men and women. The two-sample Mendelian randomisation estimate for the association between the genetic instrument and Alzheimer's disease was 1.04 (0.98–1.10), consistent with sensitivity estimates, addressing pleiotropy, measurement bias and weak instrument bias. Conclusions In a nationwide study of all Danes above the age of 65 years, we show that type-2 diabetes is associated with major subtypes of dementia – with particularly strong associations for vascular dementia and unspecified dementia – the two types of dementia with the most obvious vascular pathologies. Although the present two-sample Mendelian randomisation approach using genetic consortia data suggests that type-2 diabetes is not a direct cause of Alzheimer's disease, we were unable to test the causal nature of type-2 diabetes for vascular dementia and unspecified dementia, because no publicly available genetic consortia data yet exist for these dementia endpoints. The causal nature of type-2 diabetes for dementia with vascular pathologies is pivotal questions to solve for future public health recommendations and therapeutic advice.

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