As mentioned in Previous Section, There Is Hypothesis For The Important Role Of Inflammation In The Pathogenesis Of Ad And Genes Involved In The Inflammatory Pathway Are Therefore Of High Interest As The Susceptibility Genes For Ad. Studies Showed That Microglia Surrounding Plaques Was Positive For Markers Related To Inflammation Such As Mhc Class Ii, Cox-2, Mcp-1, Tnf-α, Il-1β And Il-6.104)
In Addition, Elevated Levels Of Chemokines And Cytokines And Their Receptors Including Il-1α, Cxcr2, Ccr3, Ccr5 And Tgf-β Were Found In Post-mortem Ad Brains.129)
Epidemiological Studies Suggested Non-steroidal Anti-inflammatory Drugs (Nsaids) Might Be Beneficial In Preventing Or Delaying The Onset Of Ad,130
But Not Reversing The Pathology.132)
Based On These Observations And The On-going Studies Investigating The Relationship Between Inflammation And Ad, It Is Hypothesized That Aβ Aggregates Trigger Microglia And Astrocytes, Leading To Local Inflammation And Further Activate The Immune Response. This Resulted In The Activation Of Inflammatory Mediators Such As Tnf-α, Il-1β And Il-6, Causing Neuronal Cell Death And Further Activates Microglia And Astrocytes, Formed A Vicious Cycle Of Inflammatory Response.133
There were many genetic association studies investigating the relationship of polymorphisms of inflammatory-related genes including TNF-α, IL-1β, IL-6, IL-10, TLR-4 and COX-2 and the risk of AD. In addition, among the top 10 genes as listed in AlzGene, two of them are involved in the inflammatory pathway (CR1 and IL-8), suggesting the possible implication of inflammation in the pathogenesis of AD. Different TNF-α SNPs (-238, -308, -850, -863 and -1031) were investigated in genetic association studies and TNF-238, -863 and -1031 were reported to modulate the transcriptional activity of TNF-α gene and to be associated with risk of AD, with population specificity.46
AlzGene meta-analysis showed that TNF-1031 was significantly associated with the risk of AD, giving odds ratio of 1.35 (95% CI: 1.04-1.77). IL-1β-511 and IL-1β-3953 were the most widely studied SNPs in IL-1β for the risk of AD. However, the results of the published genetic association studies on the relationship between IL-1β and the risk of AD are still inconclusive.142
AlzGene meta-analysis showed that both SNPs were significantly associated with the risk of AD and another meta-analysis study confirmed the association of IL-1β-3953 but not IL-1β-511.33
Di Bona et al.44)
showed a remarkable heterogeneity among studies for IL-1β-511, therefore subgroup (Caucasians) meta-analysis was performed and yielded significant association to the risk of AD, with OR of 1.32 (95% CI: 1.03-1.69).44)
This finding suggested that there is hidden population stratification for some SNPs in the association to the risk of the trait and it is important to control for these variants for the data analysis.
Many groups performed genetic association studies on IL-6 and the risk of AD. The common SNPs for IL-6 being studied included -572, -174 and variable number tandem repeat (VNTR) polymorphism but there was no confirmed association.160
Interestingly, some studies showed no association of genetic polymorphisms on IL-6 and the risk of AD alone, but observed significantly increased risk of AD when combined with certain genotypes at other genes such as TNF-α and IL-10, suggesting there might be interaction effect between genes in modulating the risk of AD.168
IL-10 is an anti-inflammatory gene and several groups reported association of IL-10 polymorphisms and the risk of AD171
but the association is inconclusive with some studies reporting negative results.47
IL-10 polymorphisms were associated with IL-10 levels175
and clinical progression of AD,180)
suggesting its possible function as genetic marker for predicting disease progression. COX-2 is also at the top list of the inflammation-related genes implicating in the risk of AD, based on its important role in the pathophysiological process of inflammatory disease. Polymorphisms of COX-2 (-2319, -765, Ex10+837) were associated with the risk of AD181
and the use of COX-2 inhibitors has been suggested for treatment of AD.184
The advantage of using genetic marker for inflammatory genes in determining the risk of AD over measuring the level of inflammatory cytokines such as IL-1, IL-6, IL-10 or TNF-α, is the measurement will be less likely to be affected by the daily fluctuation. Several studies suggested that the increased level of inflammatory cytokines is associated with increased risk of AD. On the other hand, several genetic markers were associated with the predisposition of increased inflammatory cytokine levels. Therefore, it might be possible to predict one's risk of getting AD by genotyping those inflammatory genetic markers.
As observed in other common diseases, the SNPs associated with the risk of AD conferred a small effect to the risk of AD, giving the relative risk of the disease to the order of 1.1 to 2.0 and odds ratio rarely exceeding 3.33
For example, it is estimated the attributable fraction for ApoE was 25.5%, CLU was 8.9% and CR1 was 4%.51
Since AD is a complex disease and it is expected to be affected by multiple genes and polymorphisms, with each contributing a small effect on the disease risk. On the other hand, gene-gene interaction effect for the risk of AD was observed in a number of genes such as IL-1, IL-10 and TNF-α,168
testing multiple SNPs that were associated with the risk of AD might provide more information in the prediction.187)
Studies in other common diseases such as diabetes also suggested the use of multiple gene loci to predict disease risks.188)
Genetic profiling, by incorporating a panel of established genetic susceptibility factors to estimate one's risk to a disease might be useful in providing a more accurate diagnosis.189)
Each susceptibility locus contributed to the genetic risk score can be added up and weighed differently based on its prevalence and relative risk to the disease. For example, the genotype of ApoE is expected to be weighted more in the risk score. A cut-off score can then be determined base on the results of previous studies and algorithm to estimate the risk of the disease. In AD, genes showing significant association in GWASs of AD, inflammatory genes and ApoE will be promising candidate genes for the panel in genetic profiling for diagnosis of AD or predicting one's risk of conversion from MCI to AD. However, this approach is limited by the restricted predictive value of genetic markers in complex disease and by the interaction effect of environmental influences such as exposure to different environmental factors and epigenetic changes on the onset and progression of the disease. At this stage, genetic profiling will not be adequate for the diagnosis of AD but it might improve the accuracy and specificity of diagnosis in addition to the present clinical diagnosis and imaging techniques and possibly applied in the identification of pre-symptomatic AD patients.
In conclusion, a large collaborative efforts will be required to explore the genetic variations, including structural variation and epigenetic, in addition to the statistical algorithms to estimate the contribution of each susceptibility polymorphism to the overall disease risk of AD. Further research efforts are necessary to find out if in the future, genetic profiling in addition to the current clinical diagnosis might be useful in identifying subjects with high risk of AD predisposition and ultimately lead to early diagnosis and intervention of the disease.