Genetically predicted telomere length and Alzheimer’s disease endophenotypes: a Mendelian randomization study

Rodríguez‐Fernández, Blanca; Vilor‐Tejedor, Natàlia; Arenaza‐Urquijo, Eider M.; Sánchez‐Benavides, Gonzalo; Suárez‐Calvet, Marc; Operto, Grégory; Minguillón, Carolina; Fauria, Karine; Kollmorgen, Gwendlyn; Suridjan, Ivonne; Moura, Manuel Castro de; Piñeyro, David; Esteller, Manel; Blennow, Kaj; Zetterberg, Henrik; Vivo, Immaculata De; Molinuevo, José Luís; Navarro, Arcadi; Gispert, Juan Domingo; Sala‐Vila, Aleix; Crous‐Bou, Marta; Akinci, Muge; Beteta, Annabella; Brugulat‐Serrat, Anna; Cacciaglia, Raffaele; Cañas, Alba; Cumplido, Irene; Deulofeu, Carme; Dominguez, Ruth; Emilio, Maria; Falcón, Carles; Fuentes, Sherezade; Grau‐Rivera, Oriol; Hernández, Laura; Genius, Patricia; Huesa, Gema; Huguet, J.; Palacios, Eva M.; Marne, Paula; Menchón, Tania; Milà‐Alomà, Marta; Peña‐Gomez, Cleofé; Polo, Albina; Pradas, Sandra; Salvadó, Gemma; Shekari, Mahnaz; Soteras, Anna; Stankeviciute, Laura; Vilanova, Marc

doi:10.1186/s13195-022-01101-9

Cited by 22 publications

(13 citation statements)

References 99 publications

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“…However, the current study only used a subset of UKB participants and the proxy score may not be an appropriate substitute for clinical LOAD status (17, 68). Despite the high genetic correlation, true LOAD cases in the full UKB sample have higher polygenic risk scores compared to proxy cases (27) and inconsistent results have been attributed to the use of the LOAD proxy score (69). The LOAD-by-proxy score is sensitive to recall bias, because the score is based on self-reported parental information by the participants.…”

Section: Resultsmentioning

confidence: 99%

Brain morphology mediating the effect of genetic risk variants on Alzheimer’s disease

Breddels,

Snihirova,

Pishva

et al. 2024

Preprint

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INTRODUCTION: Late-onset Alzheimers disease (LOAD) has been associated with alterations in the morphology of multiple brain structures and it is likely that disease mechanisms differ between brain regions. Coupling genetic determinants of LOAD with measures of brain morphology could localize and identify primary causal neurobiological pathways. METHODS: Mediation and Mendelian randomization (MR) analysis were performed using common genetic variation, T1 MRI and clinical data collected by UK Biobank and Alzheimers Disease Neuroimaging Initiative. RESULTS: Thickness of the entorhinal cortex and the volumes of the hippocampus, amygdala, choroid plexus and inferior lateral ventricle mediated the effect of APOE E4 on LOAD. MR showed that a thinner entorhinal cortex, a smaller hippocampus and amygdala, and a larger volume of the choroid plexus and inferior lateral ventricles, increased the risk of LOAD as well as vice versa. DISCUSSION: Combining neuroimaging and genetic data can give insight into the causal neuropathological pathways of LOAD.

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Section: Resultsmentioning

confidence: 99%

Brain morphology mediating the effect of genetic risk variants on Alzheimer’s disease

Breddels,

Snihirova,

Pishva

et al. 2024

Preprint

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“…Numerous studies have observed associations between shortened LTL and conditions such as Alzheimer’s disease 51 , atherosclerotic diseases 52 , type 2 diabetes 20 , and cancer 53 , which are also relatively common in sepsis patients. Recent research has indicated that biological age holds more therapeutic value than chronological age, as it is believed to offer a more precise prediction of health aging 6 , 8 , 54 .…”

Section: Discussionmentioning

confidence: 99%

Causal relationship between telomere length and sepsis: a bidirectional Mendelian randomization study

Xu,

Zhu,

Zhang

2024

Sci Rep

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Numerous observational studies have elucidated a connection between leukocyte telomere length (LTL) and sepsis, yet its fundamental cause remains enigmatic. Thus, the current study’s objective is to employ a bidirectional Mendelian randomization (MR) approach to scrutinize the causality between LTL and sepsis. We selected single nucleotide polymorphisms (SNPs) associated with LTL (n = 472,174) and sepsis from a genome-wide association study (GWAS), including Sepsis (n = 486,484, ncase = 11,643), Sepsis (28 day death in critical care) (n = 431,365, ncase = 347), Sepsis (under 75) (n = 462,869, ncase = 11,568), Sepsis (28 day death) (n = 486,484, ncase = 1896), and Sepsis (critical care) (n = 431,365, ncase = 1380), as instrumental variables (IVs). The inverse variance weighted (IVW) MR method was employed as the primary approach, and various sensitivity analyses were conducted to assess the validity of this instrument and potential pleiotropy. Using the IVW method, we uncovered a potential causal relationship between genetically predicted LTL reduction and increased susceptibility to sepsis, with an odds ratio (OR) of 1.161 [95% confidence interval (CI) 1.039–1.297, p = 0.008]. However, reverse MR analysis did not indicate any impact of sepsis on LTL. Our forward MR study highlights a potential causal relationship between LTL as an exposure and increased susceptibility to sepsis. Specifically, our findings suggest that individuals with genetically determined shorter LTL may be at an increased risk of developing sepsis. This may contribute to the development of novel diagnostic and therapeutic strategies for the prevention, diagnosis, and treatment of sepsis.

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“…This multifaceted approach enhances our understanding of how molecular differences correlate with in vivo neuroimaging phenotypes 59 . Additionally, our incorporation of techniques such as Mendelian Randomization provides a means to establish causal links between modifiable risk factors and AD pathology, including its subsequent consequences, 60 ultimately influencing the potential to establish primary and secondary prevention strategies during the primary and preclinical stages 61 …”

Section: Discussionmentioning

confidence: 99%

Genetic characterization of the ALFA study: Uncovering genetic profiles in the Alzheimer's continuum

Vilor‐Tejedor,

Genius,

Rodríguez‐Fernández

et al. 2023

Alzheimer's & Dementia

Self Cite

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INTRODUCTIONIn 2013, the ALzheimer's and FAmilies (ALFA) project was established to investigate pathophysiological changes in preclinical Alzheimer's disease (AD), and to foster research on early detection and preventive interventions.METHODSWe conducted a comprehensive genetic characterization of ALFA participants with respect to neurodegenerative/cerebrovascular diseases, AD biomarkers, brain endophenotypes, risk factors and aging biomarkers. We placed particular emphasis on amyloid/tau status and assessed gender differences. Multiple polygenic risk scores were computed to capture different aspects of genetic predisposition. We additionally compared AD risk in ALFA to that across the full disease spectrum from the Alzheimer's Disease Neuroimaging Initiative (ADNI).RESULTSResults show that the ALFA project has been successful at establishing a cohort of cognitively unimpaired individuals at high genetic predisposition of AD.DISCUSSIONIt is, therefore, well‐suited to study early pathophysiological changes in the preclinical AD continuum.Highlights Prevalence of ε4 carriers in ALzheimer and FAmilies (ALFA) is higher than in the general European population The ALFA study is highly enriched in Alzheimer's disease (AD) genetic risk factors beyond APOE AD genetic profiles in ALFA are similar to clinical groups along the continuum ALFA has succeeded in establishing a cohort of cognitively unimpaired individuals at high genetic AD risk ALFA is well suited to study pathogenic events/early pathophysiological changes in AD

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Genetically predicted telomere length and Alzheimer’s disease endophenotypes: a Mendelian randomization study

Cited by 22 publications

References 99 publications

Brain morphology mediating the effect of genetic risk variants on Alzheimer’s disease

Brain morphology mediating the effect of genetic risk variants on Alzheimer’s disease

Causal relationship between telomere length and sepsis: a bidirectional Mendelian randomization study

Genetic characterization of the ALFA study: Uncovering genetic profiles in the Alzheimer's continuum

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