**9. Conclusion**

Finally, estrogen receptor (ER) has been shown to regulate the risk of AD [80, 148]. Two ERs are involved in this regulation: ERα and β. While ERβ was found to downregulate APOE gene and protein expression, ERα acted on upregulation of APOE expression. Genetic polymor‐ phisms in both ER (rs4986938) and (rs2234693) have been associated with high risks of AD

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

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

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‐

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

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

activities with lower risks of cognitive decline and dementia [156–160].

[148].

232 Update on Dementia

[164].

**8. Environmental factors**

to be associated with a lower risk of dementia.

viduals with normal blood pressure [162].

It is clear that Alzheimer's disease (AD) that affects a growing number of individuals is a complex disease endowed with different facets. In this chapter, we summarize the state of knowledge in matters of research on AD based on studies that have contributed to major discoveries in the field. We provide a global overview about current understanding of the disease.

As we enunciated it above, there is a strong genetic predisposition to AD. Mutations and polymorphism in key genes such as APP, PSEN, and APOE affect different aspects of disease pathogenesis such as accumulation of aggregating proteins, defective clearance mechanism, lipid dyshomeostasis, neuronal dysfunction, and synaptic dysfunction. Environmental factors, which most of the time during evolution are responsible for genetic mutations, interact with genetic risk factors and contribute to AD development. Gender difference also has a consid‐ erable impact on the apparition of AD.

The complexity and multiplicity of these risk factors make AD an extremely difficult disease to treat. In fact, as of today, even if we have a better knowledge regarding some of these factors, researchers continue to discover new players. These findings raise the question of whether these factors are linked together, which ones are causes or consequences of the disease, how do they act: independently, or in an event cascade starting from a unique triggering factor. Many therapeutic approaches aimed at reducing clinical symptoms or preventing the disease have been developed and tested in clinical trials over the years. However, we have to ac‐ knowledge the fact that before we establish the cause and effect link between all these risk factors, and possibly provide a case-by-case treatment of the disease to individuals, it may be difficult to establish an effective treatment based on the heterogeneity of AD individuals.
