**2. Complexity of the disease**

Alzheimer's disease is a complex multifactorial disorder, in which genetic predisposition and environmental factors interact with disease processes. The genetic polymorphism of amyloid precursor protein (APP) or genetic mutations of presenilin 1 (PSEN1) [2] or presenilin 2 (PSEN2) are well known to be the major genetic causes of familial early-onset AD (EOAD) [3– 6]. These mutations have been shown to induce a preferential generation of Aβ42 with a high propensity for aggregation [7]. On the other hand, the most common genetic risk factor for sporadic AD is the apolipoprotein E (APOE) gene (located on chromosome 19) [8]. Subsequent genome-wide association studies identified several new risk genes [9–11]: the gene for clusterin (CLU) also known as apolipoprotein J (localized on chromosome 8), the gene encoding the complement component (3b/4b) receptor 1 (CR1) (located on chromosome 1), the gene encoding PI-binding clathrin assembly protein (PICALM) (located on chromosome 11), the gene encoding the bridging integrator 1 (BIN1) (located on chromosome 2), and the disabled homolog 1 (DAB1) (located on chromosome 1). Later studies identified additional novel risk loci associated with late-onset AD such as SORL1, TREM2, MS4A, ABCA1 and 7, and CD33 [12]. The implication of these newly identified genes in the disease mechanism(s) are yet to be elucidated, with some evidence suggesting possible involvements in clearance dysfunction, lipid metabolism [13] (El gaamouch et al., 2016 in press), immune response and APP metabo‐ lism [14].

Studies conducted on cohorts composed of normal and AD twins not only showed the impact of genetic factors in AD [15], but also revealed a considerable importance of environmental factors in disease onset and development [16]. Environmental factors include socio-demo‐ graphic factors such as age, level of study, life style, physical activity, eating habits, and tobacco or alcohol consumption. Other comorbidities related to life style such as hypertension, dyslipidemia, and diabetes have also been associated with AD pathogenesis.

In this chapter, we elaborate some of these AD risk genes and environmental factors, as well as their involvements in the pathogenesis of AD based on the state of our current knowledge.
