Association of TLR4 with Alzheimer's disease risk and presymptomatic biomarkers of inflammation

doi:10.1016/j.jalz.2019.03.012

Alzheimer's & Dementia

Volume 15, Issue 7, July 2019, Pages 951-960

https://doi.org/10.1016/j.jalz.2019.03.012 Get rights and content

Abstract

Introduction

A coding variant in the TLR4 receptor (rs4986790), previously associated with longevity and Alzheimer's disease (AD) risk reduction, was examined in a population isolate (Québec Founder Population [QFP]) and in presymptomatic individuals with a parental history of AD (Pre-Symptomatic Evaluation of Novel or Experimental Treatment for Alzheimer's Disease [PREVENT-AD]).

Methods

Genotyping was performed using the Illumina HumanHap 550k (QFP) and the Illumina Omni2.5 beadchips (PREVENT-AD). Cognition was assessed using the Repeatable Battery for Assessment of Neuropsychological Status (RBANS). Whole-brain cortical thickness data were analyzed using CIVET 1.12. Cerebrospinal fluid concentrations of cytokines were obtained by using Milliplex.

Results

The minor allele of the rs4986790 polymorphism (G) is associated with a reduced risk of developing AD in the QFP, as well as higher visuospatial and constructional abilities, higher cortical thickness in visual-related regions, and stable cerebrospinal fluid IL-1β levels in the PREVENT-AD cohort.

Discussion

The rs4986790 G coding variant in the TLR4 gene appears to reduce AD risk through the modulation of IL-1β synthesis and secretion in the presymptomatic phase of the disease.

Section snippets

Background

Alzheimer's disease (AD) pathology is characterized by extracellular amyloid plaques [1], neuronal and synaptic loss [2], [3], intraneuronal neurofibrillary tangles [4], cortical thinning in the temporal, orbitofrontal, and parietal regions [5], and chronic inflammation [6]. New evidence suggests an association of inflammatory markers at midlife with worst performance on a word-recall test and lower brain volume in pathology-affected regions in AD [7]. Moreover, a recent study analyzing data

QFP cohort

In the QFP, the living AD subjects were 65 years or older and were diagnosed with probable AD based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria. The living age-matched control cases were also 65 years or older. These control cases were asymptomatic at the time of their recruitment based on the Mini-Mental State Examination score (adjusted for age and education >26) and the Montréal Cognitive Assessments (adjusted for education >26) [20]. Autopsied

Demographic characteristics of the AD subjects from the QFP cohort

Table 1 summarizes the demographic characteristics of the 44 AD brain samples obtained from the QFP cohort as a function of the rs4986790 variant (28 carriers of the AA genotype and 16 AG carriers). Owing to the low frequency of GG genotypes in this population, no GG carrier was present in our sample. There is no significant difference for age, gender distribution, postmortem interval, and APOE4 prevalence between AA and AG carriers.

Demographic characteristics of PREVENT-AD participants

Table 2 summarizes the demographic characteristics of the 136

Discussion

Recent evidence has revealed that inflammation might be a key player in prodromal AD [7], [9], [26]. Among the numerous actors implicated in the inflammatory process in AD, TLR4 has been identified as an important link between AD pathological processes and the downstream release of proinflammatory cytokines in both mouse models of AD [11], [12], [14], [27] and in human diseased brains [28]. In the last decade, the Asp299Gly coding variant (rs4986790) in the extracellular domain of TLR4 was

Acknowledgments

This study was supported by the Canadian Institutes of Health Research (MOP-119321), the Natural Sciences and Engineering Research Council of Canada (RGPIN-2015-03790), the J.-Louis Lévesque Foundation, the Lemaire Family Foundation, the McGill University and Genome Québec Innovation Centre, and the ICAO Charity Drive. Justin Miron and Cynthia Picard were supported by the Centre for Studies in the Prevention of Alzheimer's disease. Justin Miron was also supported by the Djavad Mowafaghian

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Featured ArticleAssociation of TLR4 with Alzheimer's disease risk and presymptomatic biomarkers of inflammation

Abstract

Introduction

Methods

Results

Discussion

Section snippets

Background

QFP cohort

Demographic characteristics of the AD subjects from the QFP cohort

Demographic characteristics of PREVENT-AD participants

Discussion

Acknowledgments

Biochem Biophys Res Commun

J Neurol Sci

Lancet Neurol

Neurosci Lett

Alzheimers Dement

Neuroimage

Neurosci Lett

Neurobiol Aging

Alzheimers Dement (Amst)

Neuroimage Clin

Alzheimers Dement (Amst)

Neuronal loss, neurofibrillary tangles and granulovacuolar degeneration in the hippocampus with ageing and dementia. A quantitative study

Acta Neuropathol

The fine structure of neurofibrillary tangles in Alzheimer's disease

J Neuropathol Exp Neurol

Focal decline of cortical thickness in Alzheimer's disease identified by computational neuroanatomy

Cereb Cortex

Inflammatory response in Alzheimer's disease

Tohoku J Exp Med

Midlife systemic inflammatory markers are associated with late-life brain volume: The ARIC study

Neurology

Early role of vascular dysregulation on late-onset Alzheimer's disease based on multifactorial data-driven analysis

Nat Commun

Pattern recognition receptors TLR4 and CD14 mediate response to respiratory syncytial virus

Nat Immunol

Gx-50 reduces beta-amyloid-induced TNF-alpha, IL-1beta, NO, and PGE2 expression and inhibits NF-kappaB signaling in a mouse model of Alzheimer's disease

Eur J Immunol

Toll-like receptors 2 and 4 mediate Abeta(1-42) activation of the innate immune response in a human monocytic cell line

J Neurochem

A comparative review of toll-like receptor 4 expression and functionality in different animal species

Front Immunol

Role of the toll-like receptor 4 in neuroinflammation in Alzheimer's disease

Cell Physiol Biochem

TLR4 polymorphisms and ageing: implications for the pathophysiology of age-related diseases

J Clin Immunol

Genealogical analysis of maternal and paternal lineages in the Quebec population

Hum Biol

Featured Article
Association of TLR4 with Alzheimer's disease risk and presymptomatic biomarkers of inflammation