**4. APP, PS, and other genes involved in Aβ biogenesis**

**2. Complexity of the disease**

226 Update on Dementia

lism [14].

**3. Aβ and tau**

trigger neuronal death [36, 37].

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‐

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,

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.

Aβ isoforms are 39–43 amino acid peptides present as soluble Aβ<sup>40</sup> or insoluble Aβ42. In physiological condition, Aβ<sup>40</sup> represents more than 90% of Aβ while Aβ<sup>42</sup> levels are less than 5%. A possible function of Aβ under physiological conditions may be inhibiting γ-secretase activity to generate more Aβ in a negative feedback control mechanism [17]. However, under pathological conditions, Aβ42 which is found in high concentrations in AD patients is prone to

Aggregated Aβ peptides, either soluble oligomers or fibrils, could induce a cascade of cellular events such as apoptosis [21–24], oxidative injury [24–26], alterations in kinase or phosphatase activities [26–29], microglial activation [30–32], and mitochondrial dysfunction [33–35], which

dyslipidemia, and diabetes have also been associated with AD pathogenesis.

aggregate lacking the ability to inhibit γ-secretase [18–20].

As stated above, accumulation and aggregation of Aβ peptide are part of the starting steps of AD. The accumulation can result from Aβ overproduction or an alteration of its clearance. Aβ peptide is derived from APP as a result of sequential cleavage by β- and γ-secretases [49]. Its elimination is mediated through proteolysis and/or lysosome degradation system.

Forty well-known APP gene missense mutations within Aβ coding regions or close to the processing sequence, are shown to result in an increase of Aβ fibril deposition [50, 51] accounting for an autosomal form of the disease: EOAD [52]. Among these mutations, A673V and E693D mutations have been associated to the autosomal recessive EOAD [37, 53], while 30 other dominant mutations were involved in autosomal dominant EOAD [53].

Interestingly, a recent study conducted on the Icelander population highlighted a mutation on APP gene that has a neuroprotective role in AD. It was reported that the A673T mutation of APP, which is close to BACE1 proteolytic site, protects against cognitive loss and AD devel‐ opment in old individuals. They also showed that this mutation reduced levels of Aβ40 and Aβ42 by approximately 40%. These results were later confirmed by another separate study [54].

APP is subjected to two independent proteolysis [55] known as non-amyloidogenic and amyloidogenic pathways. In non-amyloidogenic pathway, APP is cleaved by α-secretase ADAM within the Aβ amino acid sequence, thus preventing the formation of amyloid peptide fragment [5, 56–58]. ADAM belongs to the disintegrin and metalloproteinase domain protein family [59–61], and ADAM10 is the most represented α-secretase isoform in the brain. A few rare ADAM10 mutations have been associated with LOAD with evidence suggesting that these mutations disrupt α-secretase and increase Aβ deposition [62]. The amyloidogenic pathway is mediated by both β- and γ-secretases to generate Aβ. The γ-secretase, which catalyzes APP cleavage into toxic Aβ fragments, is formed by a complex formation of four components: PSEN1, PSEN2, nicastrin, APH-1, and PEN2 [53].

While APP mutations account for a small part of EOAD, mutations on PSEN1/PSEN2 have been identified as critical genes in EOAD [63], which are shown to increase Aβ42/Aβ40 ratios and promote Aβ42 accumulation [64, 65]. After proteolytic cleavage of full-length presenilin to generate N-terminal and C-terminal fragments and assembly into γ-secretase complex, γsecretase is transported to cell surface where it acts on APP processing and cleavage. Both PSEN1 and 2 mutations increase formation of Aβ species and deposition of amyloid plaques [63, 66, 67]. PSEN1 mutations by altering APP γ-secretase cleavage site promote Aβ42 genera‐ tion [68]. PSEN2 mutations lead to AD with a slower progression than PSEN1 mutations [67].

Besides their role in APP processing, presenilins are involved in many other cellular functions such as Notch signaling and differentiation [69], calcium homeostasis [70], gene expression via interaction with transcriptional coactivators like CREB-binding protein [71]. It was reported that PSEN1 exhibited neuroprotective functions through ephrin-B [72], and that defects in these functions with genetic modifications are implicated in AD pathogenesis. In AD trans‐ genic animal models, APP mutations or in combination with presenilin 1 mutations induced Aβ plaque formation similarly to what were seen in AD human brains [73]. Interestingly, comparatively to sporadic AD cases, patients with PSEN1 mutations had more senile plaques and NFTs developed in their brains, suggesting that PSEN1 may enhance tau deposition as well [74].
