br Conflict of interest statement br Introduction The global

Conflict of interest statement
Introduction The global prevalence of Alzheimer's disease (AD) is expected to increase to 106 million in 2050 from 30 million in 2010 (Brookmeyer et al., 2007), which will further impose a significant economic burden on health systems and society as a whole (Brookmeyer et al., 2007). It has been reported that one-third of AD cases globally may be attributable to modifiable risk factors such as type 2 diabetes, hypertension, obesity, dyslipidemia, smoking, physical inactivity, smoking, and depression (Peters et al., 2008). Though these factors explain a large proportion of the risk of AD, its pathogenesis is still not fully established as the causal effects of these factors on AD risk are uncertain and other potential risk factors appear to be involved in AD development. There is therefore a need to critically evaluate putative risk factors that LY83583 may have causal significance and help prioritize targets for effective prevention and management. Serum gamma-glutamyltransferase (GGT), a marker of liver injury and excessive alcohol consumption and also known to have pro-oxidant and pro-inflammatory properties (Emdin et al., 2005); has been linked with an increased risk of several chronic disease outcomes, including vascular and non-vascular conditions (Kunutsor et al., 2014a; Kunutsor, 2016; Kunutsor et al., 2015a; Kunutsor et al., 2015c; Kunutsor et al., 2014c; Kunutsor and Laukkanen, 2016). In a recent assessment of the prospective association of baseline and long-term values of GGT with risk of dementia as well as AD in a population-based cohort of middle-aged to older Finnish men, we have demonstrated independent and log-linear associations between GGT and both outcomes (Kunutsor and Laukkanen, 2016). We reported multivariate adjusted hazard ratios of 1.33 and 1.24 for dementia and AD respectively per 1 standard deviation (SD) increase in baseline serum GGT. On correction for regression dilution, the corresponding estimates were respectively 1.51 and 1.37 per 1 SD increase in long-term serum GGT. In another recent longitudinal study conducted in older individuals, Praetorius Björk and Johansson demonstrated higher GGT concentrations to be associated with cognitive decline prior to death and vascular dementia in late life (Praetorius Bjork and Johansson, 2017). It is however unclear whether the association between GGT and AD is free of unobserved confounding and/or reverse causation (Keavney, 2002; Petitti and Freedman, 2005). In the present study, we aimed to investigate whether the association between elevated GGT concentrations and increased AD risk is causal, using publicly available data of genome-wide association studies (GWAS) on liver enzymes and the International Genomics of Alzheimer's Project (IGAP), which is the largest genome-wide meta-analysis of AD reported to date (Lambert et al., 2013).
Methods
Results
Discussion Given the previously observed association between elevated GGT concentrations and higher risk of AD, our aim within the present study was to investigate if the association was causal. Utilizing summary statistics of large-scale published GWAS, there was no evidence of an association between genetically determined serum GGT and risk of AD. These findings suggest that the observational association between GGT and AD might not be causal. Gamma-glutamyltransferase has been linked with the development of several vascular and non-vascular outcomes (Kunutsor et al., 2014a; Kunutsor et al., 2014b; Kunutsor et al., 2015c; Kunutsor et al., 2014c; Kunutsor et al., 2015b; Kunutsor et al., 2014d) and these relationships have been attributed to its pro-inflammatory and pro-oxidant properties (Emdin et al., 2005) as well as its direct involvement in atheromatous plaque formation (Franzini et al., 2009; Paolicchi et al., 2004). Gamma-glutamyltransferase may be linked to dementia or AD via these pathways (Kunutsor and Laukkanen, 2016), given the involvement of these processes in the development of these neurodegenerative conditions (Breteler, 2000; Gackowski et al., 2008; McGeer and McGeer, 2013; Yavuz et al., 2008; Zafrilla et al., 2006). Gamma-glutamyltransferase is also strongly related with metabolic abnormalities such as metabolic syndrome (Kunutsor et al., 2015b), obesity (Marchesini et al., 2005), and non-alcoholic fatty liver disease (Angulo, 2002), which are relevant to the development of AD (Kivimaki et al., 2017; Seo et al., 2016).