Several longitudinal studies suggest that elevated blood pressure levels or hypertension, both in midlife10,16,79,81 and closer to dementia ascertainment,80,88 are associated with increased risk of PLX4032 cost cognitive decline,21,85,86 MCI,84 dementia,78-89 and AD.34,88 However, some studies do not find these relationships,34,89,90 or even find that low blood pressure is associated with increased risk80,82 suggesting the possibility of a U-shaped relationship

between Inhibitors,research,lifescience,medical 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 pressure91,92 adding a level of complexity to the directionality of the relationship between hypertension Inhibitors,research,lifescience,medical and dementia. In addition, the impact of this risk factor on cognition depends on age. 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 Inhibitors,research,lifescience,medical old individuals with lower systolic blood pressure) in the Cache County study86 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 Inhibitors,research,lifescience,medical blood pressure and AD was strongest

among those who were never treated for hypertension,77 while in the Kungsholmen Study low diastolic blood pressure was associated with incident AD and dementia, particularly in persons who used antihypertensive medication.80 Antihypertensive medication has been shown to be associated with reduced incidence of AD,77,93,94 and with reduced rates of cognitive decline95 Inhibitors,research,lifescience,medical in additional longitudinal studies. The effect of antihypertensive use on risk of dementia was particularly pronounced in APOE4 carriers in one study96 and in men with longer duration of hypertensive medication use in another.97 Low diastolic blood pressure had a synergistic effect with APOE4 to significantly increase of the risk of AD, but antihypertensive medication counteracted the deleterious effect of high systolic blood pressure in subjects with the APOE4 allele.98 Six placebo-controlled antihypertensive trials had dementia or cognitive decline as their secondary outcomes.99-104 Reduced risk of incident dementia was found in one study102; 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.105,106 Additionally, direct relationships of hypertension with AD neuropathology have been found.