Metabolic Syndrome as putative independent associated/risk factor for Alzheimer’Disease and Mild Cognitive Impairment

Metabolic syndrome (MetS) is a cluster of vascular risk factors [1] that is well established to increase the risk of diabetes, cardiovascular disease, and stroke [2, 3]. MetS also appears to increase the risk of age-associated cognitive decline, overall dementia, and vascular dementia (VaD) in particular [4], but the role of MetS in Alzheimer’s disease (AD) remains inconclusive from the contrasting findings reported so far [5–11]. Amnestic Mild Cognitive Impairment (aMCI) is presumably a pathological-based prodromal stage of AD with an annual rate of conversion to dementia of 5 to 10% in community-based populations [12] and 10 to 15% among those in specialty clinics [13]. Only a few studies have investigated the relationship between MetS and MCI [14–16] and they provided very limited findings to form firm conclusions on the role of MetS in aMCI and AD. The Multiple Outcomes of Raloxifene Evaluation (MORE) study showed an association between MetS and an increased risk of developing cognitive impairment (defined as a composite outcome comprising clinically adjudicated dementia or MCI or cognitive impairment not clinically adjudicated) during a 4-year period in older women [15]. The study showed that the number of MetS components increased the risk of developing cognitive impairment with hyperglycemia as the only MetS component associated with a higher risk of cognitive impairment. Unfortunately, this study lacked the power to analyze the effect of MetS on the risk of developing MCI or AD alone. Subsequently, a cross-sectional, population-based study with 1,969 participants from Olmsted Country, MN, USA, found no significant association of MetS with MCI overall or aMCI, and only the combination of MetS and high levels of inflammation was significantly associated with non-amnestic MCI (naMCI) [14]. More recently, the Italian Longitudinal Study of Ageing (ILSA) reported no significant differences in overall risk of developing incident MCI in non-cognitively impaired individuals with MetS compared with those without MetS over 3.5-year follow-up [16]. APOE- 4 genotype has been found to be associated with an increased risk of AD [17] and conversion from MCI to AD [18]. The association of APOE-Σ4 with AD is reduced in older cases [19], however, none of the abovementioned research has examined the modifying effects of APOE-Σ4 and age on the association between MetS and aMCI. In the present dissertation, the association between MetS and aMCI in a population sample of older adults from the CogItA study was studied. I investigated whether MetS and its individual components, were associated with aMCI. I also investigated the possible effects of APOE-Σ4 genotype status and age in influencing the association between MetS and aMCI and MetS and AD . I hypothesized that among individuals carrying the APOE-Σ4 allele there would be an association between MetS and aMCI and AD.