**5. Genetic risk factors in sporadic AD**

Among all identified genetic factors involved in the disease, APOE gene has been extensively studied over the past decade or so. APOE is a major risk gene associated with AD, is located on chromosome 19 [75], and encodes for apolipoprotein E, a 34-kDa lipid binding protein involved in triglycerides and cholesterol transport [76–81]. Three ApoE isoforms which differ by single amino acid substitutions have been found in humans: ApoE2, ApoE3, and ApoE4. ApoE4 carriers present with high levels of cholesterol and LDL in the plasma, which predis‐ pose the carriers to cardiovascular disease and AD [82]. ApoE4 carriers contribute to about 50% of AD cases. While ApoE2 decreases the risk and delays the onset of AD [53], ApoE4 multiplies the risk of EOAD and late-onset AD (LOAD) by approximately 3-fold for hetero‐ zygous and 10-fold for homozygous carriers [62]. ApoE4 is shown to increase amyloid plaque formation by altering Aβ clearance [83] and promoting fibrillary aggregations [84].

New methods of genetic mapping of single-nucleotide polymorphisms (SNP) provided new information regarding genes involved in increasing or decreasing the risk of AD. Besides wellestablished AD risk genes described above, nine additional AD-related genes including complement receptor 1 (CR1), bridging integrator 1 (BIN1), clusterin (CLU), phosphatidyli‐ nositol-binding clathrin assembly protein (PICALM), MS4A4/MS4A6E, CD2AP, CD33, EPHA1, and ATP-binding cassette transporter (ABCA7) have been unveiled by genome-wide association and sequencing studies [85, 86].

The CR1 gene polymorphism rs6656401 was the first found to be associated with AD in European population [85]. A study conducted on two Canadian cohorts further showed that polymorphisms in CR1 (rs6656401 and rs3818361), BIN1 (rs7561528), and CD33 (rs3865444) are highly associated with LOAD [87]. The CD33 polymorphism seems to provide neuropro‐ tection against AD through inhibition of CD33 expression with a subsequent decrease in brain Aβ42 levels [88].

Recent studies have also identified a risk gene: the triggering receptor expressed on myeloid cells 2 (TREM2) encodes an immune receptor preferentially expressed in microglia, which are involved in inflammation and phagocytosis [89–91]. TREM2 is localized in cerebral regions where AD pathologies exhibit [90, 92, 93]. Some evidence suggests that activated TREM2 is involved in Aβ clearance during AD [94, 95]. A study reported that TREM2 mutations prevent its physiological function in Aβ clearance [90]. Autosomal recessive loss-of-function mutations of TREM2 are associated with increased risks of AD leading to development of early-onset dementia [96].

TREM2 receptor is found to be cleaved in the ectodomain to release a soluble fragment (sTREM2) that is detectable in cerebrospinal fluid (CSF) [96, 97]. A cross-sectional study reported that sTREM2 levels in the CSF of AD patients were higher than in controls while TREM2 variant (R136Q, D87N, Q33X, or T66M) carriers exhibited lower levels of CSF sTREM2. Interestingly, R47H variant carriers displayed significantly higher levels of CSF sTREM2 than non-carriers, suggesting that this variant different from other variants, increases AD risk through a mechanism not necessarily involving TREM2 protein expression. This study also showed that elevated sTREM2 levels in the CSF were strongly correlated with levels of tau and hyper-phosphorylated tau but not with Aβ42 levels [96, 98]. These observations have been reproduced by another study [97], implicating that elevated CSF sTREM2 levels could be used as a potential biomarker for early symptomatic phase of AD.

ATP-binding cassette subfamily B member (ABCB) gene has been reported to play a role in AD pathogenesis as well. ABCB encodes P-glycoprotein (P-gp) which is essential for Aβ clearance, and its inhibition as a consequence of genetic polymorphisms prevented Aβ clearance in an AD mouse model [99]. Decrease in P-gp expression levels was found to correlate with increased Aβ deposition [100].

Finally, a recent meta-analysis in combination with sequencing study identified five novel genes associated with AD: HLA-DRB5–HLA-DRB1, PTK2B, SORL1, SLC24A4-RIN3, and DSG2 [101]. Their functional roles in disease mechanisms are yet to be characterized.
