**8. Environmental factors**

Cohort studies have shown that educational levels play a critical role in neurodegenerative diseases. A lower education level was found to be associated with a higher risk of developing dementia [149–151]. Based on the hypothesis of cerebral cognitive reserve, intellectual training as indicated by educational levels could contribute to the development of neural networks through densification of synapses and increase of brain vascularization [152]. Intellectual solicitation could then maintain dense networks in working conditions according to "Use it or Lose it" principle. Besides levels of knowledge acquired during youth, intellectual stimulation as frequent practice of intellectual activities in adulthood [153] and older ages [154] appears to be associated with a lower risk of dementia.

Lifestyle has an impact on the risk to develop AD as well. Longitudinal studies conducted in Europe and USA demonstrated positive effects of wealth activities such as social, physical, and intellectual activities on decreased risks of AD [155]. Recent longitudinal studies conduct‐ ed in general population reported an association of regular practice and/or sustained physical activities with lower risks of cognitive decline and dementia [156–160].

Vascular diseases are precipitating factors for AD. The relationship between blood pressure and dementia is complex [161]. Some epidemiological studies suggest that depending on the period of life hypertension appeared (before or after age of 65), high blood pressure did not exhibit homogeneous effects on the risk of dementia. For example, untreated hypertension around age of 50 increased the risk of developing dementia by four-fold compared to indi‐ viduals with normal blood pressure [162].

Cholesterol, as an essential component of the brain, plays a critical role in regulation of amyloid plaque formation. However, results from numerous studies of the relationship between cholesterol levels and AD were rather contradictory [163]. Some studies showed that high levels of cholesterol were found to increase risks of dementia by two-fold. This hypothesis led to clinical trials testing the use of statins which lower cholesterol production as treatment of AD. Besides cholesterol, hyperglycemia affects the risks of developing vascular dementia and AD. The risk of dementia was increased by up to three-fold among individuals with diabetes [164].

Finally, the effect of nutrition on AD becomes a growing interest in recent years [164, 165]. Food intake plays a decisive role in the onset of systemic diseases such as hypertension, hyperlipidemia, diabetes, and cardiovascular disease which are closely associated to the risk of AD. Several cohort studies showed a relationship between antioxidant intake and lower risks of dementia and cognitive decline. Aging studies conducted in Europe demonstrated protective roles of fish consumption, which is rich in omega 3 polyunsaturated fatty acids (PUFA). The risk of cognitive decline was decreased in individuals displaying high omega 3 PUFA levels [166–168]. Interactions between fat dietary intake and genetic characteristics (including genes involved in lipid metabolism and transport) are implicated in this phenom‐ enon. For example, similar dietary intakes did not exhibit the same effects on cognitive function in individuals with different genetic heritage. Moreover, conflicted observations were reported from longitudinal studies of the association between nutrient involved in the cycle of homo‐ cysteine (including vitamins B6, B12, and folate) and the risk of dementia and/or cognitive deficit.
