P1‐053: Associations between TLR4 Asp299Gly variant and Alzheimer's‐related pathological biomarkers

TLR4 is a member of the Toll-like receptor family which plays a role in pathogen recognition and activation of innate immunity. A common missense mutation (Asp299Gly) in the extracellular domain of the receptor was found in association with a blunted inflammatory response to inhaled toxins in humans. Carriage of the minor 299Gly allele seems to exert a protective effect as it was overrepresented in a Sicilian cohort of centenarians (14.6%). Conversely, the frequency of the 299Gly allele was significantly lower in LOAD cases (3.1%) compared to controls (7.2%) in an Italian population sample. The objectives of the present study are to determine the frequency of the 299Gly allele in three independent cohorts and to correlate these findings with available Alzheimer-related pathological biomarkers. Genotyping was performed with Illumina BeadChips for DNA samples from the Quebec Founder Population (QFP, n=629) and Alzheimer's Disease Neuroimaging Initiative (ADNI, n=757). For the PREVENT-AD cohort (n=152), genotyping was performed using pyrosequencing. Classic AD biomarkers were measured by ELISA using CSF samples from the PREVENT-AD and ADNI cohorts. Structural and functional magnetic resonance imaging (MRI) was undertaken for a subgroup of participants. Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) was also evaluated for the PREVENT-AD cohort. In the QFP, the 299Gly allele was present in 6.3% of LOAD cases and 10.7% of aged-matched control subjects (p≤0.005). Healthy subjects enrolled in the PREVENT-AD study (with a first-degree family history of AD) were positive for the 299Gly allele in a proportion of 12.5%. In ADNI, the 299Gly allele was detected in 9.5% of AD cases, 9.9% of MCI patients and 11.2% of control subjects (baseline diagnostic, p≥0.05). Although not associated with the disease in the latter population, the 299Gly allele significantly correlated with higher CSF APOE levels measured in MCI patients. In unaffected subjects from the PREVENT-AD cohort, the 299Gly allele was significantly associated with enhanced cortical thickness and a higher RBANS visuospatial score. The presence of the 299Gly allele is clearly associated with neuroprotection. Targeting TLR4 signaling pathway could be considered for pharmacological intervention to prevent Alzheimer's disease.

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