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

Alzheimers Dement. 2019 Jul;15(7):951-960. doi: 10.1016/j.jalz.2019.03.012. Epub 2019 Jun 4.


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.

Keywords: Alzheimer's disease; Cortical thickness; Frontal cortex; Fusiform gyrus; Genetics; IL-1β; Inflammation; Occipital cortex; TLR4; Visuospatial and constructional abilities.

MeSH terms

  • Aged, 80 and over
  • Alzheimer Disease / genetics*
  • Autopsy
  • Biomarkers / cerebrospinal fluid*
  • Brain
  • Cohort Studies
  • Cytokines / cerebrospinal fluid*
  • Female
  • Humans
  • Inflammation*
  • Interleukin-1beta / cerebrospinal fluid*
  • Male
  • Neuropsychological Tests / statistics & numerical data
  • Quebec
  • Toll-Like Receptor 4 / genetics*


  • Biomarkers
  • Cytokines
  • IL1B protein, human
  • Interleukin-1beta
  • Toll-Like Receptor 4