Abstract
The Plexin-A 4 (PLXNA4) gene, has recently been identified in genome wide association studies (GWAS), as a novel genetic player associated with Alzheimer's disease (AD). Additionally, PLXNA4 genetic variations were also found to increase AD risk by tau pathology in vitro. However, the potential roles of PLXNA4 variants in the amyloid-β (Aβ) pathology, were not evaluated. Five targeted loci capturing the top common variations in PLXNA4, were extracted using tagger methods. Multiple linear regression models were used to explore whether these variations can affect the cerebrospinal fluid (CSF) (Aβ1−42, T-tau, and P-tau) phenotypes in the Alzheimer's disease Neuroimaging Initiative (ADNI) dataset. We detected that two loci (rs6467431, rs67468325) were significantly associated with CSF Aβ1−42 levels in the hybrid population (rs6467431: P = 0.01376, rs67468325: P = 0.006536) and the significance remained after false discovery rate (FDR) correction (rs6467431: Pc = 0.03441, rs67468325: Pc = 0.03268). In the subgroup analysis, we further confirmed the association of rs6467431 in the cognitively normal (CN) subgroup (P = 0.01904, Pc = 0.04761). Furthermore, rs6467431-A carriers and rs67468325-G carriers showed higher CSF Aβ1−42 levels than non-carriers. Nevertheless, we did not detect any significant relationships between the levels of T-tau, P-tau and these PLXNA4 loci. Our findings provided preliminary evidence that PLXNA4 variants can confer AD risk through modulating the Aβ deposition.
Highlights
An estimated 47 million people had dementia in 2015 and this figure is projected to triple by 2050 (Livingston et al, 2017)
We aimed to explore the involvement of Plexin-A 4 (PLXNA4) variants in the underlying pathogenesis of Alzheimer’s disease (AD), by investigating the effects of PLXNA4 polymorphisms on the brain amyloid burden through Cerebrospinal fluid (CSF) phenotypes in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset
We found that two loci showed marked associations with the levels of CSF Aβ1−42, in the hybrid group and the difference reached the significance level in the false discovery rate (FDR) test
Summary
An estimated 47 million people had dementia in 2015 and this figure is projected to triple by 2050 (Livingston et al, 2017). AD is the leading cause of dementia and is one of the biggest health-care challenges of the twenty first century (Scheltens et al, 2016). The earliest recognizable pathological event in AD is brain amyloid-β aggregation (Bateman et al, 2012). As the initial event and the most important factor, it is responsible for a battery of downstream abnormalities in AD (Cummings et al, 2007; Mormino et al, 2009; Jack et al, 2010, 2013). Novel research criteria for AD in the preclinical phase, highlight the occurrence of amyloid pathology in the first stage of the disease (Sperling et al, 2011; Dubois et al, 2014).
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