For each cardiovascular risk factor, this paper summarizes its relationships with the cognitive outcomes. For

each risk factor we tabulate the main results of longitudinal epidemiological studies of dementia, MCI, and cognitive decline, including nonsignificant in addition to significant results. Beyond separate effects of these risk factors, we consider multiple causes that may underlie the development of AD and dementia, by discussing combination effects – involving these risk factors with each other and with other factors – which particularly affect cognitive compromise. Type 2 diabetes Table I presents studies examining risks of dementia, MCI, and cognitive Danusertib concentration decline Inhibitors,research,lifescience,medical in patients with type 2 diabetes and demonstrates, relatively consistently, increased risks for each of these outcomes. Type 2 diabetes has been demonstrated to increase risk for dementia in most,4-17 but not all,14,15 prospective epidemiological studies, Inhibitors,research,lifescience,medical with the highest odds ratios approaching 3-fold increased risk of dementia for diabetic individuals compared with nondiabetics.5 Many studies have also shown increased risk for AD and VaD (eg, ref 30). A recent study suggests that type 2 diabetes or impaired fasting glucose might be present in up to 80%

of Inhibitors,research,lifescience,medical patients with AD.27 A systematic review of the effect of diabetes on dementia and cognitive decline concludes that these should be considered consequences and disabling manifestations of diabetes.28 Recently, even prediabetes (defined as glucose >7.8 mmol/L but <11.0 mmol/L) was associated with dementia (HR 1.77; 95% CI 1.02-3.12) and AD (HR 1.98; 1.12-3.50).27 A few epidemiological studies have Inhibitors,research,lifescience,medical examined the longitudinal association between diabetes and MCI,7,19,20 a state of cognitive compromise preceding AD or frank dementia, and all showed significantly increased risk for subjects with diabetes. Impaired fasting Inhibitors,research,lifescience,medical glucose, a prediabetic condition, was also

associated with MCI.30 Numerous not studies have reported consistently increased risk of cognitive decline in diabetes.18-26 Diabetes is a complex metabolic disorder that is closely associated with other risk factors for dementia, such as age, hypertension, and the metabolic syndrome – a clustering of several commonly occurring disorders (including abdominal obesity, hypertriglyceridemia, low highdensity lipoprotein (HDL) level, and hypertension) that are often associated with diabetes.31 These risk factors, together with diabetes-specific characteristics (eg, age of onset, glycémie control, use of antidiabetes medications), demographic and socioeconomic factors, and genetic factors, might be important determinants of the increased risk of cognitive decline and dementia in individuals with diabetes.