Genetic predisposition to high circulating levels of interleukin 6 and risk for Alzheimer's disease. Discovery and replication - 02/01/25

Doi : 10.1016/j.tjpad.2024.100018

Sokratis Charisis ^a, Niki Mourtzi ^b, Matthew R. Scott ^c, Eva Ntanasi ^b, Eirini Mamalaki ^b,^d, Alexandros Hatzimanolis ^e, Alfredo Ramirez ^a,^f,^g,^h,ⁱ, Jean-Charles Lambert ^j, Mary Yannakoulia ^d, Mary Kosmidis ^k, Efthimios Dardiotis ^l, Georgios Hadjigeorgiou ^m, Paraskevi Sakka ⁿ, Claudia L Satizabal ^a, Alexa Beiser ^c, Qiong Yang ^c, Marios Κ. Georgakis ^o,^p,^q, Sudha Seshadri ^a, Nikolaos Scarmeas ^b,^r,^⁎
^a Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, UT Health San Antonio, San Antonio, TX, USA
^b 1st Department of Neurology, Aiginition Hospital, National and Kapodistrian University of Athens Medical School, Athens, Greece
^c Department of Biostatistics, Boston University School of Public Health
^d Department of Nutrition and Dietetics, Harokopio University, Athens, Greece
^e Department of Psychiatry, Aiginition Hospital, National and Kapodistrian University of Athens Medical School, Athens, Greece
^f Division of Neurogenetics and Molecular Psychiatry, Department of Psychiatry and Psychotherapy, University of Cologne, Medical Faculty, Cologne, Germany
^g Department of Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital Bonn, Bonn, Germany
^h German Center for Neurodegenerative Diseases (DZNE Bonn), Bonn, Germany
ⁱ Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
^j Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167-RID-AGE facteurs de risque et déterminants moléculaires des maladies liés au vieillissement, Lille, France
^k Lab of Cognitive Neuroscience, School of Psychology, Aristotle University of Thessaloniki, Thessaloniki, Greece
^l Department of Neurology, University Hospital of Larisa, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larisa, Greece
^m Department of Neurology, Medical School, University of Cyprus, Nicosia, Cyprus
ⁿ Athens Association of Alzheimer's Disease and Related Disorders, Marousi, Greece
^o Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
^p Program in Medical and Population Genetics, Broad Institute of Harvard and the Massachusetts Institute of Technology, Boston, MA, USA
^q Institute for Stroke and Dementia Research (ISD), University Hospital, Ludwig-Maximilians-University (LMU) Munich, Munich, Germany
^r Department of Neurology, The Gertrude H. Sergievsky Center, Taub Institute for Research in Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, USA

^⁎Correspondence author at: National and Kapodistrian University of Athens Medical School, 72 Vassilisis Sofias Avenue, Athens, 11528, Greece, Department of Neurology, Columbia University Medical Center, 622 West 168th Street, New York, NY 10032, USA.National and Kapodistrian University of Athens Medical School72 Vassilisis Sofias Avenue, Athens, 11528, Greece, Department of Neurology, Columbia University Medical Center622 West 168th StreetNew YorkNY10032USA

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Abstract

Importance

Aging is accompanied by immune dysregulation, which has been implicated in Alzheimer's disease (AD) pathogenesis. Individuals who are genetically predisposed to elevated levels of proinflammatory mediators might be at increased risk for AD.

Objective

To investigate whether genetic propensity for higher circulating levels of interleukin 6 (IL-6) is associated with AD risk.

Design

We analyzed data from the Hellenic Longitudinal Investigation of Aging and Diet (HELIAD). Mean follow-up was 2.9 (SD, 0.8) years. Baseline assessment was from 11/2009 to 11/2016, and cognitive follow-up from 01/2013 to 07/2019. Associations of interest were also examined in the UK Biobank (UKB) for replication purposes (mean follow-up was 12.9 (SD, 2.4) years; baseline assessment was from 12/2006 to 10/2010).

Setting

Population-based study.

Participants

The HELIAD sample included 622 participants ≥65 years of age without baseline dementia or amnestic mild cognitive impairment (aMCI-the prodromal stage of AD). The UKB sample included 142,637 participants ≥60 years of age without prevalent dementia.

Exposures

Genetic predisposition to elevated circulating levels of IL-6 was estimated using a polygenic risk score (PRS), calculated based on the summary statistics of a current GWAS meta-analysis.

Main Outcomes and Measures

AD and MCI diagnoses were based on standard clinical criteria [HELIAD], or hospital records and death registry data [UKB]. Associations with AD or aMCI incidence [HELIAD] and AD incidence [UKB] were examined with Cox regression models.

Results

In HELIAD, mean age was 73.4 (SD, 5.0) years; 363 (58%) women. An increase in IL-6 PRS by 1 standard deviation unit (SDU) was associated with up to a 43% increase in the risk for incident AD/aMCI (HR_{GWAS significance threshold of 0.01,} 1.43 [95%CI, 1.14 – 1.80]). In UKBB, mean age was 64.2 (SD, 2.8) years; 73,707 (52%) women. A 1 SDU increase in IL-6 PRS was associated with up to an 8% increase in the risk for incident AD (HR_{GWAS significance threshold of 0.2}, 1.08 [95%CI, 1.04 – 1.12]).

Conclusions and Relevance

Genetic predisposition to higher circulating levels of IL-6 was associated with an increased risk for AD, supporting the role of IL-6-related pathways in AD pathogenesis, and suggesting that genetic predisposition to proinflammatory states might trigger or accelerate AD-related neuropathology.

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Keywords : Interleukin 6, Polygenic risk score, Alzheimer's disease, Mild cognitive impairment, Dementia