Association of the CX3CR1-V249I Variant with Neurofibrillary Pathology Progression in Late-Onset Alzheimer’ s Disease Alan López-López 1 & Ellen Gelpi 2 & Diana Maria Lopategui 1,3 & Jose M. Vidal-Taboada 1,4 Received: 8 January 2017 /Accepted: 14 March 2017 # Springer Science+Business Media New York 2017 Abstract 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 neu- roinflammation. 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 het- erozygous for CX3CR1-V249I presented a lower neurofibril- lary 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 associ- ated with a higher AAO in the subgroups of AD with Lewy bodies and without Lewy bodies. These CX3CR1 genetic var- iants could represent new modifying factors of pathology pro- gression 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. Keywords Alzheimer disease . CX3CR1 . Fractalkine receptor (OMIM 601470) . Modifying gene . Progression . Age at onset Introduction Alzheimer’ s disease (AD) is the most common type of demen- tia in our clinical setting. It mostly affects the elderly, and its prevalence reaches up to 45% in the population older than 85. Characterized by a progressive and serious decline in cogni- tive, memory, and language functions, it leads to severe dis- ability and dependence with an enormous personal, familial, and social impact [1]. Although the ultimate cause of AD remains unknown for most cases, the pathogenesis of the disorder has been widely studied: an abnormal excision of amyloid precursor protein (APP) leads to the parenchymal and vascular deposition of insoluble fibrils of beta-peptide and to the formation of neu- ritic plaques and amyloid angiopathy. This phenomenon is accompanied by an abnormal activity of several neuronal ki- nases, which in turn lead to oxidative stress, mitochondrial dysfunction, activation and recruitment of microglia and as- trocytes, and in some cases, to hyperphosphorylation, abnor- mal configuration, and accumulation of Tau protein. This last event destabilizes neuronal microtubules and generates Electronic supplementary material The online version of this article (doi:10.1007/s12035-017-0489-3) contains supplementary material, which is available to authorized users. * Jose M. Vidal-Taboada josevidal@ub.edu; josevidalt@gmail.com 1 Biochemistry and Molecular Biology Unit, Department of Biomedical Sciences, Faculty of Medicine–IDIBAPS, University of Barcelona, Barcelona, Spain 2 Neurological Tissue Bank of the Biobank, Hospital Clinic, IDIBAPS, Barcelona, Spain 3 Miami Clinical and Translational Science Institute, University of Miami, Miami, Florida, USA 4 Institut de Neurociencies, University of Barcelona, Barcelona, Spain Mol Neurobiol DOI 10.1007/s12035-017-0489-3