Association of the CX3CR1-V249I Variant with Neurofibrillary Pathology Progression in Late-Onset Alzheimer's Disease.
Neuroinflammation and microglial dysfunction have a prominent role in the pathogenesis of late-onset Alzheimer's disease (LOAD). CX3CR1 is a microglia-specific gene involved in microglia-neuron crosstalk and neuroinflammation. Numerous evidence show the involvement of CX3CR1 in AD. The aim of this study was to investigate if some functional genetic variants of this gene could influence on LOAD's outcome, in a neuropathologically confirmed Spanish cohort. We designed an open, pragmatic, case-control retrospective study including a total of 475 subjects (205 pathologically confirmed AD cases and 270 controls). We analyzed the association of the two CX3CR1 functional variants (V249I, rs3732379; and T280M, rs3732378) with neurofibrillary pathology progression rate according to Braak's staging system, age at onset (AAO), survival time, and risk of suffering LOAD. We found that individuals heterozygous for CX3CR1-V249I presented a lower neurofibrillary pathology stage at death (OR = 0.42, 95%CI [0.23, 0.74], p = 0.003, adj-p = 0.013) than the other genotypes. Eighty percent of the subjects homozygous for 249I had higher neurofibrillary pathology progression (Braak's stage VI). Moreover, homozygosis for 280M and 249I could be associated with a higher AAO in the subgroups of AD with Lewy bodies and without Lewy bodies. These CX3CR1 genetic variants could represent new modifying factors of pathology progression and age at onset in LOAD. These results provide further evidence of the involvement of CX3CR1 pathway and microglia/macrophages in the pathogenesis of LOAD.
Biochemistry and Molecular Biology Unit, Department of Biomedical Sciences, Faculty of Medicine-IDIBAPS, University of Barcelona, Barcelona, Spain.
Alan
A
López-López
Neurological Tissue Bank of the Biobank, Hospital Clinic, IDIBAPS, Barcelona, Spain.
Ellen
E
Gelpi
Biochemistry and Molecular Biology Unit, Department of Biomedical Sciences, Faculty of Medicine-IDIBAPS, University of Barcelona, Barcelona, Spain.|Miami Clinical and Translational Science Institute, University of Miami, Miami, Florida, USA.
Diana Maria
DM
Lopategui
Biochemistry and Molecular Biology Unit, Department of Biomedical Sciences, Faculty of Medicine-IDIBAPS, University of Barcelona, Barcelona, Spain. josevidal@ub.edu.|Institut de Neurociencies, University of Barcelona, Barcelona, Spain. josevidal@ub.edu.
Jose M
http://orcid.org/0000-0001-5667-4133
JM
Vidal-Taboada
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology; D000073883:CX3C Chemokine Receptor 1 / Q000235:genetics*; D016022:Case-Control Studies; D002525:Cerebellar Cortex / Q000473:pathology; D015331:Cohort Studies; D018450:Disease Progression; D005260:Female; D056726:Genetic Association Studies / Q000379:methods*; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D016874:Neurofibrillary Tangles / Q000235:genetics* / Q000473:pathology; D011897:Random Allocation; D012189:Retrospective Studies
D000073883:CX3C Chemokine Receptor 1; C095235:CX3CR1 protein, human
Age at onset; Alzheimer disease; CX3CR1; Fractalkine receptor (OMIM 601470); Modifying gene; Progression