CNTN5 is associated with disease risk and pathology throughout the Alzheimer's disease continuum.

Abstract

Contactins are a family of molecules that are involved in neuronal development. Contactin 5 (CNTN5) is a neuronal membrane protein that contributes to axonal targeting, synaptic formation and plasticity. A GWAS performed in a population isolate from Eastern Canada identified a polymorphism in the CNTN5 gene (rs1461684_G) which is associated with increased risk of developing Alzheimer's disease (AD). In order to further characterize the role of CNTN5 in AD, we used two cohorts (the "at-risk" pre-symptomatic PREVENT-AD and the symptomatic ROSMAP) to examine the association of CNTN5 genotype and protein levels with pathological hallmarks and clinical manifestations of AD. In the PREVENT-AD cohort, [18F]-AV1451 PET was used to measure Tau burden, Olink's primer extension assay was used to measure CNTN5 in plasma and CSF and ELISAs were used for Tau, Phospho Tau, and amyloid CSF levels. Participants were followed for at least 4 years. In the autopsied-confirmed ROSMAP cohort, Aß load and NFT density in the cortex were measured with immunocytochemistry, and cognition was assessed with the Mini-Mental State Examination (MMSE). In the ROSMAP cohort participants were followed throughout most of their adult life, until death. Homozigotes CNTN5 G variant had a 58% lower chance of developing cognitive decline than non-carriers and heterozygous subjects (p=0.033) (Fig 1a). Carriers of the GG variant showed less decline in MMSE scores compared to the other genotypes (p=0.042) (Fig 1b). CSF CNTN5 levels were higher in follow-up visits 12 (p=0.018), 24 (p=0.013) and 48 (p<0.001) months compared to baseline (Fig 2) and, were significantly higher in Controls compared to AD subjects (p<0.001) (Fig 3). CSF CNTN5 was positively correlated with PET TAU burden in the entorhinal cortex (p=0.029), with CSF Total Tau (p<0.001), Phospho Tau (p<0.001), Aß1-42(p=0.018) and Aß 1-40 (p=0.002) (Fig 4). There was no correlation between Plasma and CSF CNTN5 levels (p =0.37). There are no association between CNTN5 genotype and CERAD or Braak stages. These results show that the rs146168 variant of CNTN5 plays a role in the risk of developing AD and that CNTN5 CSF levels are strongly correlated with AD pathology, especially in the pre-symptomatic phase of the disease.