Authors: Natalia Vilor‐Tejedor, Blanca Rodríguez‐Fernández, Marta Milà‐Alomà, Eider M Arenaza‐Urquijo, Marc Suárez‐Calvet, Gonzalo Sanchez‐Benavides, Oriol Grau‐Rivera, Carolina Minguillón, Karine Fauria, Henrik Zetterberg, Kaj Blennow, Gwendlyn Kollmorgen, Udo Eichenlaub, Juan Domingo Gispert, Immaculata DeVivo, Aleix Sala‐Vila, Jose Luis Molinuevo, Marta Crous‐Bou,
Published: 2020-12-07
DOI: 10.1002/alz.044720
Source: Full article
AbstractBackgroundTelomere length (TL) is a putative biomarker of biological aging and aging‐related outcomes. Observational studies are limited to conclude whether TL is causally associated with AD or a marker of an underlying pathological process. Mendelian randomization (MR) was developed for assessing causality using genetic variants in epidemiological research. Our main objective was to test the potential causal role of TL in cognitive performance, brain vulnerability and AD core biomarkers through an MR analysis.MethodsOur analysis was conducted in the context of the ALFA (ALzheimer and FAmilies) study. We created episodic memory, executive function and global cognitive composites. We calculated an AD signature as a composite measure reflecting cortical thickness of specific AD vulnerable regions. We measured cerebrospinal fluid (CSF) levels of amyloid‐β(Aβ)42, Aβ40, p‐tau, t‐tau and neurofilament light (NfL) using NeuroToolKit and Elecsys® immunoassays (Roche Diagnostics). Genome‐wide genotyping was performed. MR analyses using 3 Single Nucleotide Polymorphisms (SNPs) (rs2736100, rs9420907, rs755017) associated with TL identified in Genome‐wide Association studies (GWAS) were used as instrumental variables to determine the predicted effect of TL on AD endophenotypes: cognitive performance, AD signature, and AD biomarkers. Causal effects of TL were estimated using the inverse‐variance weighted method. Stratified analyses by APOE‐ɛ4 status were conducted.ResultsMR analysis revealed a significant association between SNPs predicting shorter TL and increased levels of NfL, supporting a potential causal role of TL on biomarkers of neuronal injury (Table 1; Figure 1). Additionally, we observed suggestive evidence of causality between shorter TL and worse episodic memory, and reduced cortical thickness in the AD signature (Table 1). Effect modification by APOE‐ɛ4 genotype was also suggested: associations between SNPs predicting short TL and worse cognitive performance, reduced thickness in the AD signature, and increased levels of NfL were only observed among APOE‐ɛ4 non‐carriers (Table 2).ConclusionsPreliminary results of our MR analysis showed an association between SNPs predicting shorter TL and AD endophenotypes, suggesting a potential causal role of telomeres in AD vulnerability, specifically in individuals not at increased genetic risk of AD. Further observational and genetic analyses in larger datasets are warranted to better understand these associations.