Extension of Mendelian Randomization to Identify Earliest Manifestations of Alzheimer’s Disease: Genetic Risk Score for Alzheimer’s Disease Reduces BMI by Age 50

2021 ◽  
Author(s):  
Willa D Brenowitz ◽  
Scott C Zimmerman ◽  
Teresa J Filshtein ◽  
Kristine Yaffe ◽  
Stefan Walter ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Weight Loss ◽  
Risk Score ◽  
Genetic Risk ◽  
Mendelian Randomization ◽  
Late Onset ◽  
Causal Effect ◽  
Genetic Risk Score ◽  
Sensitivity Analyses

Abstract Weight loss or lower Body Mass Index (BMI) may be an early symptom of Alzheimer’s disease (AD) but when this begins to emerge is difficult to estimate with traditional observational data. In an extension of Mendelian randomization, we used genetic risk for late-onset AD risk to estimate the causal effect of AD on BMI and the earliest ages at which AD-related weight loss (or lower BMI as a proxy) occurs. 407,386 UK Biobank participants enrolled 2007-2010 without dementia, aged 39-73, with Caucasian genetic ancestry, with BMI (kg/m2), and an AD genetic risk score (AD-GRS) based on 23 genetic variants. Using linear regressions, we tested the association of AD-GRS with BMI stratified by decade and calculated the age of divergence in BMI-trends between low and high AD-GRS. AD-GRS was not associated with BMI in 39-49 year-olds (β:0.00;95%CI:-0.03,0.03). AD-GRS was associated with lower BMI in 50-59 year-olds (β:-0.03; 95%CI:-0.06,-0.01) and 60-73 year-olds (β:-0.09;95%CI:-0.12,-0.07). Model-based BMI age-curves for high versus low AD-GRS began to diverge after age 47. Sensitivity analyses found no evidence for pleiotropy or survival bias. Longitudinal replication is needed; however, our findings suggest that AD genes may begin to reduce BMI decades prior to dementia diagnosis.

scholarly journals Using a genetic risk score to estimate the earliest age of Alzheimer’s disease-related physiologic change in Body Mass Index

2019 ◽  
Author(s):  
Willa D. Brenowitz ◽  
Scott C. Zimmerman ◽  
Teresa J. Filshtein ◽  
Kristine Yaffe ◽  
Stefan Walter ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Body Mass Index ◽  
Weight Loss ◽  
Body Mass ◽  
Risk Score ◽  
Genetic Risk ◽  
Genetic Risk Score ◽  
Genetic Ancestry ◽  
Uk Biobank

AbstractObjectivesWeight loss is common in the years before an Alzheimer’s disease (AD) diagnosis, likely due to changes in appetite and diet. The age at which this change in body mass index (BMI) emerges is unclear but may point to the earliest manifestations of AD, timing that may be important for identifying windows of intervention or risk reduction. We examined the association between AD genetic risk and cross-sectional BMI across adults in mid-to late-life as an innovative approach to determine the age at which BMI changes and may indicate preclinical AD.DesignObservational studySettingUK BiobankParticipants407,386 UK Biobank non-demented participants aged 39-70 with Caucasian genetic ancestry enrolled 2007-2010.Main Outcome MeasuresBMI (kg/m2) was constructed from height and weight measured during the initial visit. A genetic risk score for AD (AD-GRS) was calculated as a weighted sum of 23 genetic variants previously confirmed to be genome-wide significant predictors of AD (Z-scored). We evaluated whether the association of AD-GRS with BMI differed by age using linear regression with adjustment for sex and genetic ancestry, stratified by age grouping (40-60, 61+). We calculated the earliest age at which high AD-GRS predicted divergence in BMI compared to normal age-related BMI trends with linear and quadratic terms for age and interactions with AD-GRS.ResultsIn 39-49 year olds, AD-GRS was not significantly associated with lower BMI (0.00 kg/m2 per SD in AD-GRS; 95%CI: -0.03,0.03). In 50-59 year olds AD-GRS was associated with lower BMI (-0.03 kg/m2 per 1 SD in AD-GRS; 95%CI:-0.06,-0.01) and this association was stronger in 60-70 year olds (-0.09 kg/m2 per 1 SD in AD-GRS; 95%CI:-0.12,-0.07). Model-based BMI age-curves for people with high versus low AD-GRS scores began to diverge after age 47.InterpretationGenetic factors that increase AD risk begin to predict lower BMI in adults by age 50, with greater effect later in older ages. Weight loss may manifest as an early pathophysiologic change associated with AD.

scholarly journals Multigenomics Reveals the Causal Effect of Herpes Simplex Virus in Alzheimer’s Disease: A Two-Sample Mendelian Randomization Study

2022 ◽  
Vol 12 ◽  
Author(s):  
Yuwei Zhang ◽  
Jiaojiao Qu ◽  
Li Luo ◽  
Zhongshun Xu ◽  
Xiao Zou
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Sensitivity Analyses ◽  
Analysis Model ◽  
Simplex Virus ◽  
Hsv 1

In recent years, the herpes virus infectious hypothesis for Alzheimer’s disease (AD) has gained support from an increasing number of researchers. Herpes simplex virus (HSV) is a potential risk factor associated with AD. This study assessed whether HSV has a causal relationship with AD using a two-sample Mendelian randomization analysis model. Six single-nucleotide polymorphisms (SNPs) associated with HSV-1 and thirteen SNPs associated with HSV-2 were used as instrumental variables in the MR analysis. We estimated MR values of relevance between exposure and the risk of AD using inverse-variance weighted (IVW) method, MR-Egger regression (Egger), and weighted median estimator (WME). To make the conclusion more robust and reliable, sensitivity analyses and RadialMR were performed to evaluate the pleiotropy and heterogeneity. We found that anti-HSV-1 IgG measurements were not associated with risk of AD (OR, 0.96; 95% CI, 0.79–1.18; p = 0.736), and the same was true for HSV-2 (OR, 1.03; 95% CI, 0.94–1.12; p = 0.533). The findings indicated that any HSV infection does not appear to be a genetically valid target of intervention in AD.

scholarly journals P4-574: FUNCTIONAL CONNECTIVITY HYPOSYNCHRONIZATION IN A GROUP OF COGNITIVELY INTACT OLDER FEMALES: THE USE OF A GENETIC RISK SCORE FOR ALZHEIMER'S DISEASE

2019 ◽  
Vol 15 ◽  
pp. P1539-P1540
Author(s):  
Inmaculada Concepción Rodríguez Rojo ◽  
Pablo Cuesta ◽  
Ernesto Pereda ◽  
Ricardo Bruña Fernández ◽  
Ana Barabash ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Functional Connectivity ◽  
Risk Score ◽  
Genetic Risk ◽  
Genetic Risk Score ◽  
Cognitively Intact

Social Isolation, Social Interaction, and Alzheimer’s Disease: A Mendelian Randomization Study

2021 ◽  
Vol 80 (2) ◽  
pp. 665-672
Author(s):  
Ling-Xiao Shen ◽  
Yu-Xiang Yang ◽  
Kevin Kuo ◽  
Hong-Qi Li ◽  
Shi-Dong Chen ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Social Interaction ◽  
Social Isolation ◽  
Social Engagement ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Sensitivity Analyses ◽  
Epidemiological Methods ◽  
Sports Club

Background: Social isolation and social interaction have been suggested to be associated with Alzheimer’s disease. However, the causality cannot be unambiguously assessed as traditional epidemiological methods are easily subject to unmeasured confounders and potential bias. Objective: To examine bidirectional relationships between social isolation, social interaction, and Alzheimer’s disease using Mendelian randomization method for assessing potential causal inference. Methods: This bidirectional two-sample Mendelian randomization study used independent genetic variants associated with social isolation and social interaction (n = 302,567–487,647), and Alzheimer’s disease (n = 455,258). MR analyses were performed using the inverse-variance-weighted (IVW) as the main MR analytical method to estimate the causal effect. For sensitivity analyses, we applied weighted median, MR Egger to further assess the credibility of the causal effect. Results: Of the five types of social engagement examined in our study, only one showed evidence of an association with the risk of Alzheimer’s disease. Attendance at a gym or sports club (IVW OR per SD change: 0.670; 95% CI: 0.463–0.970; p = 0.034) was inversely associated with the risk of Alzheimer’s disease. We also found that AD may reduce the attendance at religious group (IVW OR per SD change: 1.017; 95% CI: 1.005–1.030; p = 0.004). Conclusion: This study suggests that regular attendance at a gym or sports club is causally associated with reduced risk of Alzheimer’s disease. Further studies are warranted to elucidate potential mechanisms.

scholarly journals Mendelian randomization provides evidence for a causal effect of higher serum IGF-1 concentration on risk of hip and knee osteoarthritis

Rheumatology ◽  
2020 ◽  
Author(s):  
April Hartley ◽  
Eleanor Sanderson ◽  
Lavinia Paternoster ◽  
Alexander Teumer ◽  
Robert C Kaplan ◽  
...  
Keyword(s):  
Risk Score ◽  
Genetic Risk ◽  
Odds Ratio ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Genetic Risk Score ◽  
Uk Biobank ◽  
Knee Oa ◽  
Increased Risk

Abstract Objectives How insulin-like growth factor-1 (IGF-1) is related to OA is not well understood. We determined relationships between IGF-1 and hospital-diagnosed hand, hip and knee OA in UK Biobank, using Mendelian randomization (MR) to determine causality. Methods Serum IGF-1 was assessed by chemiluminescent immunoassay. OA was determined using Hospital Episode Statistics. One-sample MR (1SMR) was performed using two-stage least-squares regression, with an unweighted IGF-1 genetic risk score as an instrument. Multivariable MR included BMI as an additional exposure (instrumented by BMI genetic risk score). MR analyses were adjusted for sex, genotyping chip and principal components. We then performed two-sample MR (2SMR) using summary statistics from Cohorts for Heart and Aging Research in Genetic Epidemiology (CHARGE) (IGF-1, N = 30 884) and the recent genome-wide association study meta-analysis (N = 455 221) of UK Biobank and Arthritis Research UK OA Genetics (arcOGEN). Results A total of 332 092 adults in UK Biobank had complete data. Their mean (s.d.) age was 56.5 (8.0) years and 54% were female. IGF-1 was observationally related to a reduced odds of hand OA [odds ratio per doubling = 0.87 (95% CI 0.82, 0.93)], and an increased odds of hip OA [1.04 (1.01, 1.07)], but was unrelated to knee OA [0.99 (0.96, 1.01)]. Using 1SMR, we found strong evidence for an increased risk of hip [odds ratio per s.d. increase = 1.57 (1.21, 2.01)] and knee [1.30 (1.07, 1.58)] OA with increasing IGF-1 concentration. By contrast, we found no evidence for a causal effect of IGF-1 concentration on hand OA [0.98 (0.57, 1.70)]. Results were consistent when estimated using 2SMR and in multivariable MR analyses accounting for BMI. Conclusion We have found evidence that increased serum IGF-1 is causally related to higher risk of hip and knee OA.

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