table i presents studies examining risks of dementia , mci , and cognitive decline 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 , but not all , prospective epidemiological studies , with the highest odds ratios approaching 3-fold increased risk of dementia for diabetic individuals compared with nondiabetics . 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 patients with ad . 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 . 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 ) . a few epidemiological studies have examined the longitudinal association between diabetes and mci , a state of cognitive compromise preceding ad or frank dementia , and all showed significantly increased risk for subjects with diabetes . 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 . these risk factors , together with diabetes - specific characteristics ( eg , age of onset , glycmie 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 . co - occurrence of diabetes and hypertension greatly increases the risk of dementia and of cognitive decline . high systolic blood pressure interacted with borderline diabetes and with frank diabetes multiplying the risk of ad . diabetes almost doubled the risk of dementia and ad in the rotterdam study , but diabetics taking insulin were at the highest risk ( rr 4.3 , 1.7 - 10.5 ) suggesting that more severe diabetes increases dementia risk . consistent with these observations , subjects with longer duration of diabetes or with diabetes complications had steeper cognitive decline . the potential mediating effect of apoe4 genotype and of age in the relationship between diabetes and dementia is less clear . participants with diabetes and the apoe4 allele had a risk ratio of 5.5 ( ci 2.2 - 13.7 ) for ad compared with those with neither risk factors in the honolulu asia aging study , and this was consistent with neuropathological findings . however , borderline diabetes was associated with ad only in non - apoe4 carriers in the kongsholmen study . the effect of age on the relationships between diabetes and dementia is also difficult to interpret . the relationship between diabetes and dementia in the framingham study was strongest for participants older than 75 but diabetes was not associated with accelerated cognitive decline in 85 + years of age participants in another study . this suggests that factors other than cvrfs ( ie , age , apoe genotype ) inter act with diabetes to increase the risk of cognitive compromise . several potential mechanisms underlying the association between diabetes and dementia have been proposed : - diabetes is associated with micro- and/or macrovascular disease which in turn increase the risk of cognitive decline and dementia 
  - defective insulin receptor signaling pathway ( irsp ) in the central nervous system ; the irsp is associated with vital brain processes including synaptic plasticity , neuroprotection , neurodegeneration , survival , growth , energy metabolism , and longevity . insulin receptors ( ir ) are abundant throughout the brain , and are expressed in especially high abundance in regions that support cognitive lunction . a , the main component of neuritic plaques , hallmark lesions of ad , decreases insulin affinity and reduces the binding of insulin to its receptor preventing rapid activation of specific kinases required for multiple cellular functions , including longterm potentiation ( ltp ) . soluble a oligomers were recently shown to significantly lower ir responses to insulin and to cause rapid and substantial loss of neuronal surface irs . the ir desensitization found in ad brains , hampers the release of a , from the intracellular to the extracellular compartment , which may be a mechanism for its neurotoxicity . - advanced glycation end products ( ages ) may have a crucial role in the relationship between diabetes and dementia . ages , which normally increase with age and faster with diabetes , are the products of naturally occurring reactions between reducing sugars , eg , glucose , and free amine - containing proteins or lipids . ad brains have significantly higher levels of ages than normal controls , and in in - vitro studies , ages contribute to the formation of amyloid plaques and neurofibrillary tangles . in a 24-week randomized double blind trial , metformin , and its resulting improved glycmie control , were associated with improved memory . rosiglitazone treatment of tg2576 mice ( transgenic mice overexpressing amyloid precursor protein ) resulted in better spatial learning and memory abilities and an approximately 25% reduction in ap42 levels . rosiglitazone therapy resulted in improved memory and selective attention while not affecting glucose levels in a study of 30 ad or mci nondiabetic subjects during a period of 6 months . a trial with 518 mild - to - moderate ad patients treated with rosiglitazone for 6 months reported significant improvement in cognition only in patients who did not possess an apoe4 allele . it should be noted that these encouraging results must be taken with caution in light of recent studies suggesting increased myocardial infarction and death from cardiovascular causes in rosiglitazone users . craft et al have performed several investigations examining the effect of intravenous insulin in nondiabetic elderly adults with ad . mild - to - moderate ad patients ' immediate and delayed recall were improved in hyperglycemic and hyperinsulinemic conditions compared with a saline control condition . substantially reduced neuritic plaques ( nps ) , the hallmark lesions of the ad brain , were found in the brains of diabetic subjects who during life received a combination of insulin and another antidiabetic medication . in a recent search of the literature by the cochrane control trial register , however , no appropriate studies were found for meta - analysis regarding the effect of treatment for type 2 diabetes and degree of metabolic control on the development of dementia . recently , the salsa studyreported decreased rates of cognitive decline in diabetic subjects receiving antidiabetic medications ( insulin or oral hypoglycemic ) compared with untreated diabetic subjects ( but see refs 8,16 ) . these studies are provocative and invite systematic investigation of the possible benefits of diabetes medications on cognition , but are not sufficient to draw conclusions . the relationships of hypertension with dementia and cognitive decline are less straight forward , as shown in table ii . several longitudinal studies suggest that elevated blood pressure levels or hypertension , both in midlife and closer to dementia ascertainment , are associated with increased risk of cognitive decline , mci , dementia , and ad . however , some studies do not find these relationships , or even find that low blood pressure is associated with increased risk suggesting the possibility of a u - shaped relationship between blood pressure and cognition . all the studies reporting negative or opposite results measured blood pressure closer to dementia ascertainment , suggesting that : i ) hypertension is a risk factor for dementia several decades later ; and ii ) high or low blood pressure are associated with incipient dementia . it has been suggested that the dementing process per se might affect blood pressure adding a level of complexity to the directionality of the relationship between hypertension and dementia . consistent with the latter , systolic blood pressure > 160 at baseline was associated with steeper rates of cognitive decline in 85 + individuals ( compared with younger hypertensive or oldest old individuals with lower systolic blood pressure ) in the cache county study 
  another reason for differences among results is the effect of use of antihypertensive medication . for example , in the honolulu asia aging study , the association between high blood pressure and ad was strongest among those who were never treated for hypertension , while in the kungsholmen study low diastolic blood pressure was associated with incident ad and dementia , particularly in persons who used antihypertensive medication . antihypertensive medication has been shown to be associated with reduced incidence of ad , and with reduced rates of cognitive decline in additional longitudinal studies . the effect of antihypertensive use on risk of dementia was particularly pronounced in apoe4 carriers in one study and in men with longer duration of hypertensive medication use in another . low diastolic blood pressure had a synergistic effect with apoe4 to significantly increase the risk of ad , but antihypertensive medication counteracted the deleterious effect of high systolic blood pressure in subjects with the apoe4 allele . six placebo - controlled antihypertensive trials had dementia or cognitive decline as their secondary outcomes . reduced risk of incident dementia was found in one study ; other studies found reduced cognitive decline or dementia risk only in post hoc analysis . in a meta - analysis combining these data , the combined hazard ratio favored treatment ( iir 0.87 , ci 0.76 - 1.00 ) . cerebrovascular disease resulting from hypertension is one major reason for increased risk of dementia and cognitive decline in hypertensive subjects . elevated systolic and diastolic blood pressure in midlife was associated with a greater number of nps and neurofibrillary tangles ( nfts ) , respectively . similarly , hypertension was associated with increased extent of nps and nfts in non - demented , middle - aged individuals . hypertension may cause changes in vessel walls which may lead to hypoperfusion , ischemia , or hypoxia of the brain , all of which have been related to the development of ad pathology . an association between high blood pressure and hippocampal atrophy was only found in individuals not treated for hypertension , and lower nps and nfts were found in the brains of subjects who were taking antihypertensive medication and who did not have cerebrovascular disease , suggesting that hypertension medication may have an effect on ad neuropathology . the studies described in this section suggest that the interpretation of results of associations of hypertension with cognition has to be cautious and should take into consideration antihypertensive medication use , apoe genotype , subjects ' age , and the presence of other cvrfs . similarly to the relationships between hypertension and cognitive compromise , most of the studies found total cholesterol measured in midlife to be a significant predictor of subsequent dementia , mci , or cognitive decline 
 ( table iii ) . total cholesterol in midlife was also associated with ad in some studies and especially with concomitant hypertension . studies assessing cholesterol levels later in life have been less consistent in their ability to show a predictive effect for later cognitive decline . several studies did not find a relationship between cholesterol and dementia or even found an inverse association . the two studies examining mci as an outcome did not find an association with cholesterol . the question of association between cholesterol and ad is of particular interest because apoe is the principal cholesterol carrier protein in the brain , the apoe-4 allele is a marker of both increased risk of ad and increased plasma cholesterol concentration . nonetheless , very few studies report having examined the interactions of cholesterol , apoe genotype , and ad or dementia risk . high cholesterol in late life was associated with higher ad risk in apoe4 noncarriers only , but this association was found only in apoe4 carriers in another study . moderate decrease in cholesterol from midlife to late life was associated with more impaired cognitive status , especially- in apoe4 carriers . biochemical and cell biology studies suggest that altered cholesterol metabolism in neurons may underlie pathological processes of ad . a polymorphism of cyp46 , a gene playing a major role in hydroxylation of cholesterol and thereby mediating its removal from the brain , was associated with increased a load in brain tissue . it was also associated with increased a peptides and phosphorylated tau protein in cerebrospinal fluid ( csf ) . consistent with this observation , cholesterol was higher with increasing certainty of ad neuropath ological diagnosis . however , high cholesterol was not associated with increased neuritic plaques in the neocortex or hippocampus , or with ap levels in csf . since cholesterol increases atherosclerosis which in turn is associated with dysregulation of cerebral blood flow and hypoperfusion , the effects of cholesterol on dementia risk might not depend only on ap mechanisms but also on vascular mechanisms . 
  because of some epidemiological studies suggesting an increased risk of dementia in individuals with elevated cholesterol , and because of the biological plausibility underlying this relationship , the protective effect of statins ( 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors ) , among the most widely prescribed cholesterollowering medications , was postulated . prospective epidemiological studies are inconsistent but not contradictor ) ' in their results , with several finding that statin use is associated with decreased risk of ad and dementia and others finding no associations . a cochrane review concluded that there is no conclusive evidence to recommend statins to reduce the risk of ad , but that there is a growing body of biological and epidemiological evidence suggesting that lowering cholesterol might retard the pathogenesis of ad . blood elevations of inflammatory markers , specifically- creactive protein ( crp ) and interleukin-6 ( il-6),have been shown to be risk factors for dementia ( table iv ) . combination of high levels of several inflammatory markers in the conselice study of brain aging was associated with increasing hazard ratios for dementia , and specifically high crp / il-6 ratios ( hr=1.6 , 1.03 - 2.4 ) . as shown in table tv , high levels of inflammatory markers are of interest are the results of the health , aging and body composition ( abc ) study , in which subjects with the metabolic syndrome and high levels of inflammatory markers ( il-6 and crp ) had significantly higher rates of cognitive decline than subjects with the metabolic syndrome but low levels of blood markers of inflammation . the effect of higher il-6 levels on global and memory function decline was stronger in apoe4 carriers than in non - carriers in the leiden 85 + study , and was associated with steeper global cognitive decline only in apoe4 carriers in the rotterdam study . these observations again suggest that interpretation of relationships between inflammation and cognitive compromise have to be cautious and take into consideration of other factors . these longitudinal studies are consistent with the in vitro and in vivo studies of neurobiological mechanisms associated with cognitive function , suggesting a potential role of inflammation in the development of cognitive compromise . several lines of evidence support the importance of inflammation in the pathogenesis of cognitive impairment and ad . acute - phase proteins , cytokines , chemokines , and their receptors are upregulated in brains of ad patients . the abundance of activated microglia , the primary neuronal immune surveillance cell , is a relatively early pathogenic event in patients with ad . proinflammatory cytokines augment amyloid precursor protein ( app ) , and in turn , a induces further release of cytokines . in addition , gene polymorphisms of several inflammatory mediators have been associated with increased risk of ad . based on the epidemiological and biological evidence , nonsteroidal anti - inflammatory drugs ( nsaids ) are potential candidate drugs for treatment of ad . however , except for a clinical trial with indomethacin in which beneficial results were found , trials with nsaids show either nonsignificant beneficial trends or no benefits . the failure of these trials might have been for methodological reasons ( short follow - up period , inadequate time of intervention , or insufficient dosing ) . the relationships of the four reviewed cardiovascular risk factors with dementia and cognitive decline are complex . composites of the risk factors seem to increase in a dose - dependent fashion the risk for dementia , suggesting an accumulating effect of these factors on neuronal stress . in the relatively few studies that have reported interactions of risk factors moreover , the effect of each of the risk factors discussed in this review seem to depend on apoe genotype . if the underlying biological mechanism depends on multiple risk factors for its full expression , the apparent effect of a single risk factor would depend on whether the others were present . this may be crucial for understanding the effects on cognition of drugs treating these risk factors . thus , these considerations may profoundry affect the results of clinical trials and at least partially explain why epidemiological associations are seldom reflected in clinical trials .
as life expectancy in the united states continues to increase , the projected numbers of elderly people who will develop dementia will grow rapidly . 
 this paper reviews four well - established cardiovascular risk factors ( type 2 diabetes , hypertension , cholesterol , and inflammation ) , for which there is longitudinal epidemiological evidence of increased risk of dementia , alzheimer 's disease , mild cognitive impairment , and cognitive decline . 
 these risk factors are of special interest because of their potential modif lability , which may affect the course of cognitive compromise . 
 diabetes is the cardiovascular risk factor ( cvrf ) most consistently associated with cognition . 
 hypertension in midlife is consistently associated with cognition , but its associations with late - life hypertension are less clear . 
 total cholesterol is not consistently associated with cognition , interleukin-6 and c - reactive protein are inflammatory markers relatively consistently associated with cognition . 
 composites of the cvrfs increase the risk for dementia in a dose - dependent fashion , suggesting a cumulative effect of these factors on neuronal stress . in the relatively few studies that have reported interactions of risk factors 
 , they potentiate each other . 
 the effect of each of these risk factors varies according to apolipoprotein e genotype , it may be that the effect of these risk factors varies according to the presence of the others , and these complex relationships underlie the biological mechanisms of cognitive compromise 
 . this may be crucial for understanding the effects on cognition of druqs and other approaches , such as lifestyle chanqe , for treatinq these risk factors .