Genome-wide Association Study Of Cerebrospinal Neurofilament Light Levels In Non-demented Elders

Background: Neurofilament light(NFL)is a main component of neurofilaments,which can be measured in cerebrospinal fluid.When axonal membrane integrity is disrupted,NFL will be released into the extracellular space and may diffuse into cerebrospinal fluid(CSF).CSF NFL concentrations are associated with varieties of pathological conditions,including Alzheimer's disease(AD),vascular dementia,frontotemporal dementia and amyotrophic lateral sclerosis.Besides,elevated CSF NFL levels are also found in normal cognitive aging and early clinical stage of AD.However,little is known about the early influence of genetic factors on the increase in CSF NFL levels.Here,we performed a genome-wide association study(GWAS)of non-demented elders(cognitively normal(CN)or diagnosed with mild cognitive impairment(MCI))to identify novel genetic variants that modulate the levels of CSF NFL prior to the diagnosis of AD.Method: This GWAS consisted of 169 mild cognitive impairment subjects and 94 cognitively normal subjects from the Alzheimer's Disease Neuroimaging Initiative 1(ADNI-1)cohort.Analyses of associations between CSF NFL and genetic polymorphisms were performed using an additive genetic model.The novel single nucleotide polymorphisms(SNPs)identified by GWAS were further examined for their correlations with other AD-related phenotypes at baseline and during follow-up using multiple linear regression model and mixed effects model respectively.Survival analysis was performed to evaluate the respective risks of progression from CN to prodromal AD among populations with different genotypes.Result: Two novel SNPs(rs465401 and rs460420),both near the ADAMTS1 gene on chromosome 21,showed genome-wide significant associations with CSF NFL.The minor allele(A)of rs465401 was also associated with higher CSF total tau(t-tau)levels,lower amyloid-?(A?)levels as well as greater longitudinal changes in both A? and t-tau among the CN group.Furthermore,the Cox proportional hazards models showed increased risks for prodromal AD among the cognitive normal AA homozygotes.Conclusion: We found that two SNPs(rs465401 and rs460420)were associated with CSF NFL in non-demented elders.Our study provides insight into the relationship of genetic variants with CSF NFL and AD-related phenotypes.Although the pathogenic mechanism remains unclear,the associations identified in this study may make the SNPs and ADAMTS1 gene ideal candidates for future genetic studies on aging and neurodegenerative disorders.