1. Director Medical Sciences Division, Ramos Law, Northglenn, CO 80260; 2. Chief Science Officer, Neuroganics, Northglenn, CO 80260
email: DrDon@neuroganicslabs.com
Synopsis: Kunkle, B.W., Grenier–Boley, B., Sims, R. et al. Genetic meta–analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing. Nat Genet 51, 414–430 (2019)
A large genome-wide association meta-analysis was conducted on 94,437 individuals clinically diagnosed with late-onset Alzheimer’s disease (LOAD). The study (Kunkle et al., 2019) confirmed 20 previous LOAD risk loci and identified five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were previously linked to Alzheimer’s or dementia. Fine- mapping of the human leukocyte antigen (HLA) region found the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. The HLA genes play a crucial role in regulating the immune system’s function. Analyses of risk genes and pathways showed enrichment for additional rare variants. This study highlights the significant role of the immune system and the connection to the development of dementia.
Synopsis
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and memory loss. The majority of genetic risk factors for AD remain uncharacterized despite previous work identifying 19 common variant signals in addition to APOE gene influencing the risk for late-onset Alzheimer’s disease (LOAD) (onset age >65 years). The International Genomics of Alzheimer’s Project (IGAP) aimed to search for additional genetic signals contributing to LOAD by conducting a genome-wide association study (GWAS) meta- analysis of non-Hispanic White (NHW) individuals.
Method
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and memory loss. The majority of genetic risk factors for AD remain uncharacterized despite previous work identifying 19 common variant signals in addition to APOE gene influencing the risk for late-onset Alzheimer’s disease (LOAD) (onset age >65 years). The International Genomics of Alzheimer’s Project (IGAP) aimed to search for additional genetic signals contributing to LOAD by conducting a genome-wide association study (GWAS) meta- analysis of non-Hispanic White (NHW) individuals.
Results
The study found that the HLA region was prioritized as the top candidate gene in the major histocompatibility complex (MHC) locus, which is known for its complex genetic organization and highly polymorphic nature. Further investigation of the locus in a larger sample revealed risk effects of HLA-DQA101:02, HLA-DRB115:01, and HLA- DQB106:02 alleles. These alleles form the HLA- DQA101:02~HLA-DQB106:02~HLA-DRB115:01 (DR15) haplotype, which was found to be associated with Alzheimer’s disease risk and previously discovered in a small study in the Tunisian population and in a large Alzheimer’s Disease Genetics Consortium analysis. ADAM10 was ranked as the top gene in the ADAM10 locus and is known to be an important α-secretase in the brain that has a role in the non-amyloidogenic pathway of APP metabolism. The levels of angiotensin-converting enzyme (ACE) in cerebrospinal fluid are linked to levels of Aβ and risk of LOAD. Studies have shown that ACE can reduce toxicity and aggregation of Aβ. Angiotensin II, produced through ACE, plays a role in neuropathological processes in Alzheimer’s and is now being targeted in clinical trials.
Health Implications
The results suggest the possibility of shared or interacting mechanisms and co-morbidities among diseases like Alzheimer’s and autoimmune disorders, like multiple sclerosis. These findings point to potential shared and/or interacting mechanisms and co-morbidities in the MHC locus.
Individuals may be screened for gene variants that make them more vulnerable to genetic risk factors by undergoing genetic testing, such as DNA sequencing or genotyping. These tests can identify specific genetic variations that may increase the risk of developing certain diseases, including dementia. Furthermore, it may be hypothesized that infection-mediated or vaccine-induced immune system hyperactivation could potentially initiate or accelerate latent disease processes leading to serious adverse events in genetically vulnerable individuals (Perricone et al., 2014).
Diet and lifestyle choices can play a role in mitigating genetic risk for dementia and other diseases. For example, it is known that a diet rich in anti-inflammatory foods, such as fruits and vegetables, and low in saturated fats and refined carbohydrates, can help reduce the risk of developing Alzheimer’s disease. Regular physical activity and cognitive training can also help improve cognitive function and reduce the risk of developing dementia.
Conclusion
The study conducted by the International Genomics of Alzheimer’s Project found that the immune system gene network DR15 haplotype in the HLA region has a central role in Alzheimer’s disease risk. The findings point to potential shared and/or interacting mechanisms and co- morbidities in the MHC locus. The results have important implications for individuals who may be at risk for Alzheimer’s disease. The findings emphasize the need recognize the role of the immune system gene network and its activation in cognitive decline, dementia and ultimately Alzheimer’s disease.
| Gene Variant | Gene | Effect Size | Frequency | Significance |
|---|---|---|---|---|
| rs7920721_G | ECHDC3 | 0.08 | 39% | 1.8 x 10-11 |
| rs138190086_A | ACE | 0.26 | 2% | 5.3 x 10-9 |
| rs593742_G | ADAM10 | -0.07 | 30% | 6.8 x 10-9 |
| rs12881735_C | SLC24A4 | -0.08 | 22% | 7.4 x 10-9 |
| rs2830500_A | ADAMTS1 | -0.07 | 31% | 2.6 x 10-8 |
| rs71618613_C | SUCLG2P4 | -0.29 | 1.0% | 3.3 x 10-7 |
| rs35868327_A | FST | -0.32 | 2% | 2.6 x 10-7 |
| rs114812713_C | OARD1 | 0.32 | 3% | 2.1 x 10-7 |
| rs62039712_A | WWOX | 0.17 | 12% | 3.7 x 10-7 |
| rs4735340_A | NDUFAF6 | -0.06 | 48% | 9.2 x 10-8 |
| rs7295246_G | ADAMTS20 | 0.06 | 41% | 3.9 x 10-7 |
| rs10467994_C | SPPL2A | -0.06 | 33% | 4.3 x 10-7 |
| rs7185636_C | IQCK | -0.08 | 18% | 2.4 x 10-8 |
| rs2632516_C | MIR142/TSPOAP1-AS1d | -0.06 | 44% | 5.3 x 10-8 |
Table 1. Gene Variant, Effect Size, Frequency, and Significance for novel variants associated with increased or decreased risk of Alzheimer’s disease. (Adapted from Kunkle et al. 2019).
- References
Kunkle, B.W., Grenier-Boley, B., Sims, R. et al. (2019). Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing. Nat Genet 51, 414–430. Perricone C, Ceccarelli F, Nesher G, Borella E, Odeh Q, Conti F, et al. Immune thrombocytopenic purpura (ITP) associated with vaccinations: a review of reported cases. Immunol Res. 2014;60(2-3):226-35.