It is possible that the negative results from the RCTs done so far reflect the real inefficacy of the tested strategies in preventing dementia and AD. However, the apparent contradiction of results from observational and interventional studies could be explained by several factors: sellekchem 1. The intervention was done outside the time window during which management of a risk factor would reduce dementia risk: several risk factors exert their effect mainly during mid-life, whereas RCTs have been done in older adults. This is the case for vascular risk factors, which seem to be more relevant when the exposure occurs during mid-life. Moreover, the HRT research suggests that estrogens may have beneficial, neutral, or detrimental effects on the brain depending on age at treatment, type of menopause (natural versus medically or surgically induced), or stage of menopause [43].

This concept, called the ‘window of opportunity hypothesis’, is in agreement with the life-course approach model. There is evidence of neuroprotective effects of estrogens in women before the age of natural menopause and in the early postmenopausal stage (50 to 60 years), whereas estrogens initiated in late post-menopause (65 to 79 years) increase the risk of cognitive impairment and dementia [43,44]. Two RCTs are ongoing and both are due to be completed this year; one is testing the effect of HRT in early post-menopause (Kronos Early Estrogen Prevention Study, or KEEPS; ClinicalTrials.gov identifier NCT00623311) and the other is comparing the effects of HRT in early and late postmenopause (Early Versus Late Intervention Trial With Estradiol, or ELITE; ClinicalTrials.

gov identifier NCT00114517). 2. Short treatment and follow-up: many studies were of relatively short length. Thus, interventions have been implemented for a period that is not long enough to determine a neuroprotective effect, and the limited follow-up duration of many RCTs would not AV-951 allow detection of differences in dementia incidence. 3. The statistical power was inadequate since some RCTs had small samples and dementia has been considered a secondary endpoint in most clinical trials (for example, antihypertensive therapy). 4. The choice of compounds tested in RCTs using nutraceuticals was not optimal: although several products have been tested, supplement composition selleck is still a debated issue. For instance, whereas observational studies suggested that a balanced intake of different forms of vitamin E can be important for reducing dementia/AD risk, only one form (??-tocopherol) has been tested in RCTs, and the findings were conflicting [29,30,45,46]. Moreover, intake of high doses of ??-tocopherol supplements has been associated with increased hemorrhagic stroke and mortality risk [47]. 5.