br Introduction Type diabetes mellitus T DM and Alzheimer

Introduction Type 2 diabetes mellitus (T2DM) and Alzheimer\'s disease (AD) are the most common age-associated disorders and the prevalence of the diseases is increasing with population aging (Biessels et al., 2008; Exalto et al., 2012; Stumvoll et al., 2005; Umegaki, 2014). The epidemiological study (Strachan et al., 2011) shows that T2DM patients show a 1.5–2.0-fold increased risk of AD. In a longitudinal cohort study lasting up to 9years, the risk of developing AD was 65% higher in persons with diabetes than in non-diabetic controls (Arvanitakis et al., 2004). A community-based controlled study suggests that frank diabetes (35%) or glucose intolerance (46%) may be present in up to 80% of AD patients (Janson et al., 2004). Over a maximum 11years of follow-up, diabetic patients experienced a higher incidence of AD than non-diabetic subjects (0.48% vs. 0.37%) (Huang et al., 2014). Diabetes is associated with a 50–100% increased risk of AD (Biessels et al., 2008). The long preclinical phase of AD provides opportunity for intervention (Ballard et al., 2011). Compared to healthy individuals, the patients with mild cognitive impairment (MCI) have an increased risk to develop AD (Petersen et al., 1999). Therefore, early diagnosis of MCI is critical for developing efficient interventions to postpone or prevent AD. This requires developing new diagnostic tools to predict dementia among the high risk people with MCI. Since the pathophysiological events leading to dementia precede the clinical symptoms, biomarkers for MCI have become an area of great interest for both researchers and clinicians (Tan et al., 2014). The biomarker measurements are principally of Aminoallyl-dUTP - Cy3 amyloidosis (amyloid positron emission tomography, cerebrospinal fluid Aβ42) and neurodegeneration (medial temporal atrophy on MR, fluorodeoxyglucose positron emission tomography, CSF tau) (Bocchetta et al., 2015). However, these widely validated biomarkers are hampered by practical difficulty that severely limit their application in large populations. Thus, finding non-invasive and cost-effective biomarkers is of great importance for the early diagnosis. Olfactory dysfunction is an early clinical feature in AD patients (Devanand et al., 2010; Graves et al., 1999; Naka et al., 2010), which can predict the incidence of MCI and its conversion into AD (Rahayel et al., 2012). The apolipoprotein E (ApoE) ε4 allele is a dose-dependent risk factor for AD (Farrer et al., 1997; Weisgraber, 1994), and AD patients with ApoE ε4 usually show an earlier age of onset and a more rapid progression of the disease (Corder et al., 1993). Olfactory impairment together with ApoE ε4 genotype can be a marker for cognitive decline (Graves et al., 1999), although it is also reported that the ApoE gene plays a role in olfactory functioning that is independent of dementia conversion within 5years (Olofsson et al., 2010). Glycogen synthase kinase-3β (GSK-3β) is a serine/threonine kinase that regulates diverse cellular functions ranging from glycogen metabolism to gene transcription and cell survival (Grimes and Jope, 2001; Woodgett, 1990). The GSK-3β activity is increased in AD and MCI patients, and activation of GSK-3β causes tau hyperphosphorylation and Aβ overproduction (Hye et al., 2005; Pei et al., 1997; Plattner et al., 2006). These studies suggest that the olfactory dysfunction, GSK-3β activation and ApoE ε4 expression are predicting factors of cognitive impairments.
Methods
Results We screened 694 T2DM patients between Jan. 2012 and May 2015, and 646 of them met the inclusion criteria, thus were enrolled for the study (Fig. 1). Based on the recruiting time and the hospitals, 345 patients in 2 hospitals were assigned to the training set, and 301 of them in 3 hospitals were assigned to the validation set. According to Petersen\'s MCI criteria, the T2DM patients were divided into 85 T2DM with MCI (T2DM-MCI) and 260 T2DM without MCI (T2DM-nMCI) in the training set, and 201 T2DM-nMCI and 100 T2DM-MCI in the validation set.