Abstract
Proteolytic fragments of amyloid and post-translational modification of tau species in Cerebrospinal fluid (CSF) as well as cerebral amyloid deposition are important biomarkers for Alzheimer’s Disease. We conducted genome-wide association study to identify genetic factors influencing CSF biomarker level, cerebral amyloid deposition, and disease progression. The genome-wide association study was performed via a meta-analysis of two non-overlapping discovery sample sets to identify genetic variants other than APOE ε4 predictive of the CSF biomarker level (Aβ1–42, t-Tau, p-Tau181P, t-Tau:Aβ1–42 ratio, and p-Tau181P:Aβ1–42 ratio) in patients enrolled in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) study. Loci passing a genome-wide significance threshold of P < 5 x 10−8 were followed-up for replication in an independent sample set. We also performed joint meta-analysis of both discovery sample sets together with the replication sample set. In the discovery phase, we identified variants in FRA10AC1 associated with CSF Aβ1–42 level passing the genome-wide significance threshold (directly genotyped SNV rs10509663 P FE = 1.1 x 10−9, imputed SNV rs116953792 P FE = 3.5 x 10−10), rs116953792 (P one-sided = 0.04) achieved replication. This association became stronger in the joint meta-analysis (directly genotyped SNV rs10509663 P FE = 1.7 x 10−9, imputed SNV rs116953792 P FE = 7.6 x 10−11). Additionally, we identified locus 15q21 (imputed SNV rs1503351 P FE = 4.0 x 10−8) associated with CSF Aβ1–42 level. No other variants passed the genome-wide significance threshold for other CSF biomarkers in either the discovery sample sets or joint analysis. Gene set enrichment analyses suggested that targeted genes mediated by miR-33, miR-146, and miR-193 were enriched in various GWAS analyses. This finding is particularly important because CSF biomarkers confer disease susceptibility and may be predictive of the likelihood of disease progression in Alzheimer’s Disease.
Highlights
Alzheimer’s Disease (AD) is the most common form of dementia and to date there is still no cure
Using the Alzheimer’s Disease Neuroimaging Initiative (ADNI) samples from ADNI-1 sample set, the APOE ε4 allele best discriminated AD from controls (CN) in a logistic regression model including Aβ1–42, t-tau, while the AD-like t-tau/Aβ1–42 profile was detected among mild cognitive impairment (MCI) patients who converted to AD in one year follow up.[5]
We performed a genome-wide association study via a meta-analysis of two discovery sample sets to identify genetic variants other than APOE ε4 predictive of the Cerebrospinal fluid (CSF) biomarker level (Aβ1–42, t-Tau, p-Tau181P, t-Tau:Aβ1–42 ratio, and p-Tau181P:Aβ1–42 ratio) in patients enrolled in the ADNI study, and followed-up by replication of any locus passing the genome-wide significance threshold of P < 5 x 10−8
Summary
Alzheimer’s Disease (AD) is the most common form of dementia and to date there is still no cure. Understanding the factors influencing cognitive decline of AD will enable us to better search for therapeutics to intervene or preempt this process. The combination of CSF Aβ1–42 (or Aβ1-42/p-tau181p) and t-tau predicted the conversion from MCI to AD.[7] In a small study, non-demented patients with severely impaired episodic memory (SIM) but with no moderate impairment (MIM) or no impairment (NIM) at baseline declined cognitively over time and progressed to dementia at a high rate, and this was accompanied by significant increase in CSF p-tau181P but not t-tau or Aβ1–42 during approximately 3 year follow-up.[8]
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