These efforts have led to the broad consensus that dementia is a multi-factorial disorder caused by several interrelated mechanisms in which the interaction of genetic and environmental factors plays the major role (Table ?(Table11). Table 1 Risk and protective factors for dementia and Alzheimer’s disease kinase inhibitor Ponatinib The pathways that lead from different risk factors to dementia are not fully understood, but several etiological hypotheses have been proposed: the vascular hypothesis, inflammatory hypothesis, oxidative stress hypothesis, toxic hypothesis, and psychosocial hypothesis [5,6]. These theories highlight potential links of various risk factors to both the vascular and the neurodegenerative brain pathologies that can cause dementia, justifying the validity of dementia syndrome as target for prevention [7,8].

A recent report commissioned by the National Institutes of Health (NIH) and issued by the Agency for Healthcare Research and Quality (AHRQ) concluded that current research evidence on many risk and protective factors for cognitive decline and AD is not of sufficient strength, thus recommendations for preventing these conditions cannot be made [9,10]. Another previous review yielded similar conclusions [11]. These negative perspectives have been criticized since epidemiological evidence that the use of antihypertensive medications, cessation of smoking, and increasing physical activity produce cognitive benefits in older adults is not inadequate [12], and the analytical strategy used in the evidence-based review did not take into account the life-course perspective [13].

In fact, observational longitudinal studies clearly show that the risk of late-life dementia is determined by exposures to multiple factors experienced over the life span and that the effect of specific risk/protective factors depends largely on age. Thus, a life-course perspective is relevant for chronic disorders (such as dementia) that have a long latent period. It allows the identification of time windows when exposures have their greatest effect on outcome and assessment of whether cumulative exposures could have multiplicative or additive effects over the life course [6]. Age-dependent associations with dementia/AD have been suggested for several aging-related medical conditions.

For example, elevated blood pressure, body mass index (BMI), and total cholesterol levels at a young age and in middle age (< 65 years) are associated with an increased risk of dementia and Cilengitide AD, and having lower values make it clear in late life (> 75 years) is also associated with subsequent development of dementia/AD [14-19]. Diabetes mellitus has been associated with increased risk of dementia and AD over adult life, but the risk is stronger when diabetes occurs in mid-life than in late-life [20]. Current smoking is another major risk factor for dementia and AD, and, given the worldwide prevalence of smoking, about 14% of all AD cases are potentially attributable to this risk factor [21].