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Genetic Factors Affecting Late-Onset Alzheimer’s Disease Susceptibility

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Abstract

Alzheimer’s disease is considered a progressive brain disease in the older population. Late-onset Alzheimer’s disease (LOAD) as a multifactorial dementia has a polygenic inheritance. Age, environment, and lifestyle along with a growing number of genetic factors have been reported as risk factors for LOAD. Our aim was to present results of LOAD association studies that have been done in northwestern Iran, and we also explored possible interactions with apolipoprotein E (APOE) status. We re-evaluated the association of these markers in dominant, recessive, and additive models. In all, 160 LOAD and 163 healthy control subjects of Azeri Turkish ethnicity were studied. The Chi-square test with Yates’ correction and Fisher’s exact test were used for statistical analysis. A Bonferroni-corrected p value, based on the number of statistical tests, was considered significant. Our results confirmed that chemokine receptor type 2 (CCR2), estrogen receptor 1 (ESR1), toll-like receptor 2 (TLR2), tumor necrosis factor alpha (TNF α), APOE, bridging integrator 1 (BIN1), and phosphatidylinositol-binding clathrin assembly protein (PICALM) are LOAD susceptibility loci in Azeri Turk ancestry populations. Among them, variants of CCR2, ESR1, TNF α, and APOE revealed associations in three different genetic models. After adjusting for APOE, the association (both allelic and genotypic) with CCR2, BIN1, and ESRα (PvuII) was evident only among subjects without the APOE ε4, whereas the association with CCR5, without Bonferroni correction, was significant only among subjects carrying the APOE ε4 allele. This result is an evidence of a synergistic and antagonistic effect of APOE on variant associations with LOAD.

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References

  • Abraham, R., Moskvina, V., Sims, R., Hollingworth, P., Morgan, A., Georgieva, L., et al. (2008). A genome-wide association study for late-onset Alzheimer’s disease using DNA pooling. BMC Medical Genomics, 1, 44.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Alberoni, M., Alfieri, P., Vesuviana, S., Amici, S., Antana, D., Appollonio, R. I., et al. (2000). The Dementia Study Group of the Italian Neurological Society. Guidelines for the diagnosis of dementia and Alzheimer’s disease. Neurological Sciences, 21, 187–194.

    Article  Google Scholar 

  • Alvarez, V., Mata, I. F., Gonzalez, P., Lahoz, C. H., Martínez, C., Peña, J., et al. (2002). Association between the TNFalpha-308 A/G polymorphism and the onset-age of Alzheimer disease. American Journal of Medical Genetics, 114(5), 574–577.

    Article  PubMed  Google Scholar 

  • American Psychiatric Association. (1994). Diagnostic and statistical manual of mental disorders (4th ed.). Washington, DC: American Psychological Association.

    Google Scholar 

  • Ando, K., Brion, J., Stygelbout, V., Suain, V., Authelet, M., Dedecker, R., et al. (2013). Clathrin adaptor CALM/PICALM is associated with neurofibrillary tangles and is cleaved in Alzheimer’s brains. Acta Neuropathologica, 125(6), 861–878.

    Article  PubMed  CAS  Google Scholar 

  • Avramopoulos, D. (2009). Genetics of Alzheimer’s disease: Recent advances. Genome Medicine, 1(3), 34.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Ba, F., Pang, P. K., Davidge, S. T., & Benishin, C. G. (2004). The neuroprotective effects of estrogen in SK-N-SH neuroblastoma cell cultures. Neurochemistry International, 44(6), 401–411.

    Article  PubMed  CAS  Google Scholar 

  • Balistreri, C. R., Grimaldi, M. P., Vasto, S., Listi, F., Chiappelli, M., Licastro, F., et al. (2006). Association between the polymorphism of CCR5 and Alzheimer’s disease: Results of a study performed on male and female patients from Northern Italy. Annals of the New York Academy of Sciences, 1089, 454–461.

    Article  PubMed  CAS  Google Scholar 

  • Becherini, L., Gennari, L., Masi, L., Mansani, R., Massart, F., Morelli, A., et al. (2000). Evidence of a linkage disequilibrium between polymorphisms in the human estrogen receptor alpha gene and their relationship to bone mass variation in postmenopausal Italian women. Human Molecular Genetics, 9(13), 2043–2050.

    Article  PubMed  CAS  Google Scholar 

  • Beecham, G. W., Hamilton, K., Naj, A. C., Martin, E. R., Huentelman, M., Myers, A. J., et al. (2014). Genome-wide association meta-analysis of neuropathologic features of Alzheimer’s disease and related dementias. PLoS Genetics, 10(9), e1004606.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Beecham, G. W., Martin, E. R., Li, Y. J., Slifer, M. A., Gilbert, J. R., Haines, J. L., et al. (2009). Genome-wide association study implicates a chromosome 12 risk locus for late-onset Alzheimer disease. American Journal of Human Genetics, 84(1), 35–43.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Bertram, L., Schjeide, B. M., Hooli, B., Mullin, K., Hiltunen, M., Soininen, H., et al. (2008). No association between CALHM1 and Alzheimer’s disease risk. Cell, 135(6), 993–994. (author reply 994–996).

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Bertram, L., & Tanzi, R. E. (2012). The genetics of Alzheimer’s disease. Progress in Molecular Biology and Translational Science, 107, 79–100.

    Article  PubMed  CAS  Google Scholar 

  • Biagioni, M. C., & Galvin, J. E. (2011). Using biomarkers to improve detection of Alzheimer’s disease. Neurodegenerative Disease Management, 1(2), 127–139.

    Article  PubMed Central  PubMed  Google Scholar 

  • Biffi, A., Anderson, C. D., Desikan, R. S., Sabuncu, M., Cortellini, L., Schmansky, N., et al. (2010). Genetic variation and neuroimaging measures in Alzheimer disease. Archives of Neurology, 67(6), 677–685.

    Article  PubMed Central  PubMed  Google Scholar 

  • Bird, T. D. (2008). Genetic aspects of Alzheimer disease. Genetics in Medicine, 10(4), 231–239.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Blacker, D., Bertram, L., Saunders, A. J., Moscarillo, T. J., Albert, M. S., Wiener, H., et al. (2003). Genetics Initiative Alzheimer’s Disease Study Group: Results of a high-resolution genome screen of 437 Alzheimer’s disease families. Human Molecular Genetics, 2(1), 23–32.

    Article  Google Scholar 

  • Blacker, D., Haines, J. L., Rodes, L., Terwedow, H., Go, R. C., Harrell, L. E., et al. (1997). ApoE-4 and age at onset of Alzheimer’s disease: The NIMH genetics initiative. Neurology, 48(1), 139–147.

    Article  PubMed  CAS  Google Scholar 

  • Blomqvist, M. E., Reynolds, C., Katzov, H., Feuk, L., Andreasen, N., Bogdanovic, N., et al. (2006). Towards compendia of negative genetic association studies: An example for Alzheimer disease. Human Genetics, 119(1–2), 29–37.

    Article  PubMed  CAS  Google Scholar 

  • Boada, M., Antúnez, C., López-Arrieta, J., Galán, J. J., Morón, F. J., Hernández, I., et al. (2010). CALHM1 P86L polymorphism is associated with late-onset Alzheimer’s disease in a recessive model. Journal of Alzheimer’s Disease, 20(1), 247–251.

    PubMed  CAS  Google Scholar 

  • Brandi, M. L., Becherini, L., Gennari, L., Racchi, M., Bianchetti, A., Nacmias, B., et al. (1999). Association of the estrogen receptor alpha gene polymorphisms with sporadic Alzheimer’s disease. Biochemical and Biophysical Research Communications, 265(2), 335–338.

    Article  PubMed  CAS  Google Scholar 

  • Bsibsi, M., Ravid, R., Gveric, D., & Noort, J. M. (2002). Broad expression of Toll like receptors in the human central nervous system. Journal of Neuropathology and Experimental Neurology, 61(11), 1013–1021.

    Article  PubMed  CAS  Google Scholar 

  • Cacabelos, R., Fernandez-Novoa, L., Lombardi, V., Kubota, Y., & Takeda, M. (2005). Molecular genetics of Alzheimer’s disease and aging. Methods and Findings in Experimental and Clinical Pharmacology, 27, 1–573.

    PubMed  Google Scholar 

  • Carrasquillo, M. M., Belbin, O., Hunter, T. A., Ma, L., Bisceglio, G. D., Zou, F., et al. (2010). Replication of CLU, CR1, and PICALM associations with alzheimer disease. Archives of Neurology, 67(8), 961–964.

    Article  PubMed Central  PubMed  Google Scholar 

  • Chiueh, C., Lee, S., Andoh, T., & Murphy, D. (2003). Induction of antioxidative and antiapoptotic thioredoxin supports neuroprotective hypothesis of estrogen. Endocrine, 21(1), 27–31.

    Article  PubMed  CAS  Google Scholar 

  • Collins, J. S., Perry, R. T., Watson, B., Harrell, L. E., Acton, R. T., Blacker, D., et al. (2000). Association of a haplotype for tumor necrosis factor in siblings with late-onset Alzheimer disease: The NIMH Alzheimer Disease Genetics Initiative. American Journal of Medical Genetics, 96(6), 823–830.

    Article  PubMed  CAS  Google Scholar 

  • Combarros, O., Infante, J., Llorca, J., Peña, N., Fernández-Viadero, C., & Berciano, J. (2004). The chemokine receptor CCR5-Delta32 gene mutation is not protective against Alzheimer’s disease. Neuroscience Letters, 366(3), 312–314.

    Article  PubMed  CAS  Google Scholar 

  • Combarros, O., Riancho, J. A., Arozamena, J., Mateo, I., Llorca, J., Infante, J., et al. (2007). Interaction between estrogen receptor-alpha and butyrylcholinesterase genes modulates Alzheimer’s disease risk. Journal of Neurology, 254(9), 1290–1292.

    Article  PubMed  Google Scholar 

  • Coon, K. D., Myers, A. J., Craig, D. W., Webster, J. A., Pearson, J. V., Lince, D. H., et al. (2007). A high-density whole-genome association study reveals that APOE is the major susceptibility gene for sporadic late-onset Alzheimer’s disease. Journal of Clinical Psychiatry, 68(4), 613–618.

    Article  PubMed  CAS  Google Scholar 

  • Corbo, R. M., Gambina, G., Ruggeri, M., & Scacchi, R. (2006). Association of estrogen receptor alpha (ESR1) PvuII and XbaI polymorphisms with sporadic Alzheimer’s disease and their effect on apolipoprotein E concentrations. Dementia and Geriatric Cognitive Disorders, 22(1), 67–72.

    Article  PubMed  CAS  Google Scholar 

  • Corder, E. H., Saunders, A. M., Risch, N. J., Strittmatter, W. J., Schmechel, D. E., Gaskell, P. C., et al. (1994). Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease. Nature Genetics, 7(2), 180–184.

    Article  PubMed  CAS  Google Scholar 

  • Corneveaux, J., Myers, A. J., Allen, A. N., Pruzin, J., Ramirez, M., Engel, A., et al. (2010). Association of CR1, CLU and PICALM with Alzheimer’s disease in a cohort of clinically characterized and neuropathologically verified individuals. Human Molecular Genetics, 19(16), 3295–3301.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Cui, P. J., Zheng, L., Cao, L., Wang, Y., Deng, Y. L., Wang, G., et al. (2009). CALHM1 P86L polymorphism is a risk factor for Alzheimer’s disease in the Chinese population. Journal of Alzheimer’s Disease, 19(1), 31–35.

    CAS  Google Scholar 

  • Culpan, D., MacGowan, S. H., Ford, J. M., Nicoll, J. A., Griffin, W. S., Dewar, D., et al. (2003). Tumour necrosis factor-alpha gene polymorphisms and Alzheimer’s disease. Neuroscience Letters, 350(1), 61–65.

    Article  PubMed  CAS  Google Scholar 

  • Defina, P. A., Moser, S. O., Glenn, M., Lichtenstein, J. D., & Fellus, J. (2013). Alzheimer’s disease clinical and research update for health care practitioners. Journal of Aging Research, 2013, 207178.

    Article  PubMed Central  PubMed  Google Scholar 

  • Dreses-Werringloer, U., Lambert, J. C., Vingtdeux, V., Zhao, H., Vais, H., Siebert, A., et al. (2008). A polymorphism in CALHM1 influences Ca2+ homeostasis, Abeta levels, and Alzheimer’s disease risk. Cell, 133(7), 1149–1161.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Ertekin-Taner, N. (2007). Genetics of Alzheimer’s disease: A centennial review. Neurologic Clinics, 25(3), 611–667.

    Article  PubMed Central  PubMed  Google Scholar 

  • Ertekin-Taner, N. (2010). Genetics of Alzheimer disease in the pre- and post-GWAS era. Alzheimer’s Research & Therapy, 2(1), 3.

    Article  CAS  Google Scholar 

  • Farrer, L. A., Cupples, L. A., van Duijn, C. M., Kurz, A., Zimmer, R., et al. (1995). Apolipoprotein E genotype in patients with Alzheimer’s disease: Implications for the risk of dementia among relatives. Annals of Neurology, 38(5), 797–808.

    Article  PubMed  CAS  Google Scholar 

  • Galimberti, D., Fenoglio, C., Lovati, C., Gattia, A., Guidia, I., Venturellia, E., et al. (2004). CCR2-64I polymorphism and CCR5Δ32 deletion in patients with Alzheimer’s disease. Journal of the Neurological Sciences, 225(1), 79–83.

    Article  PubMed  CAS  Google Scholar 

  • Gatz, M., Fratiglioni, L., Johansson, B., Berg, S., Mortimer, J. A., Reynolds, C. A., et al. (2005). Complete ascertainment of dementia in the Swedish Twin Registry: The HARMONY study. Neurobiology of Aging, 26(4), 439–447.

    Article  PubMed  Google Scholar 

  • Gatz, M., Reynolds, C. A., Finkel, D., Pedersen, N. L., & Walters, E. (2010). Dementia in Swedish twins: Predicting incident cases. Behavior Genetics, 40(6), 768–775.

    Article  PubMed Central  PubMed  Google Scholar 

  • Gezen-Ak, D., Dursun, E., Hanağası, H., Bilgiç, B., Lohman, E., Araz, Ö. S., et al. (2013). BDNF, TNFα, HSP90, CFH, and IL-10 serum levels in patients with early or late onset Alzheimer’s disease or mild cognitive impairment. Journal of Alzheimer’s Disease, 37(1), 185–195.

    PubMed  CAS  Google Scholar 

  • Gharesouran, J., Rezazadeh, M., Khorrami, A., Ghojazadeh, M., Talebi, M., et al. (2014). Genetic evidence for the involvement of variants at APOE, BIN1, CR1, and PICALM loci in risk of late-onset Alzheimer’s disease and evaluation for interactions with APOE genotypes. Journal of Molecular Neuroscience, 54(4), 780–786.

    Article  PubMed  CAS  Google Scholar 

  • Gharesouran, J., Rezazadeh, M., & Mohaddes, S. M. (2013). Investigation of five polymorphic DNA markers associated with late onset Alzheimer disease. Genetika, 45(2), 503–514.

    Article  Google Scholar 

  • Giedraitis, V., Kilander, L., Degerman-Gunnarsson, M., Sundelöf, J., Axelsson, T., Syvänen, A. C., et al. (2009). Genetic analysis of Alzheimer’s disease in the Uppsala Longitudinal Study of Adult Men. Dementia and Geriatric Cognitive Disorders, 27(1), 59–68.

    Article  PubMed  Google Scholar 

  • Goate, A., Chartier-Harlin, M. C., Mullan, M., Brown, J., Crawford, F., Fidani, L., et al. (1991). Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature, 349(6311), 704–706.

    Article  PubMed  CAS  Google Scholar 

  • Goldman, J. S., Hahn, S. E., Catania, J. W., LaRusse-Eckert, S., Butson, M. B., Rumbaugh, M., et al. (2011). Genetic counseling and testing for Alzheimer disease: Joint practice guidelines of the American College of Medical Genetics and the National Society of Genetic Counselors. Genetics in Medicine, 13(6), 597–605.

    Article  PubMed Central  PubMed  Google Scholar 

  • Gozalpour, E., Kamali, K., Mohammd, K., Khorram Khorshid, H. R., Ohadi, M., Karimloo, M., et al. (2010). Association between Alzheimer’s disease and apolipoprotein E polymorphisms. Iranian Journal of Public Health, 39(2), 1–6.

    PubMed Central  PubMed  CAS  Google Scholar 

  • Gyungah, J., Adam, C. N., & Gary, W. B. (2010). Meta-analysis confirms CR1, CLU, and PICALM as Alzheimer disease risk loci and reveals interactions with APOE genotypes. Archives of Neurology, 67(12), 1473–1484.

    Article  Google Scholar 

  • Harel, A., Wu, F., Mattson, M. P., Morris, C. M., & Yao, P. J. (2008). Evidence for CALM in directing VAMP2 trafficking. Traffic, 9(3), 417–429.

    Article  PubMed  CAS  Google Scholar 

  • Harold, D., Abraham, R., Hollingworth, P., Sims, R., Gerrish, A., Hamshere, M., et al. (2009). Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer’s disease, and shows evidence for additional susceptibility genes. Nature Genetics, 41(10), 1088–1093.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Harries, L. W., Bradley-smith, R. M., Llewellyn, D. J., Pilling, L. C., Fellows, A., Henley, W., et al. (2012). Leukocyte CCR2 expression is associated with mini-mental state examination score in older adults. Rejuvenation Research, 15(4), 395–404.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Hatters, D. M., Peters-Libeu, C. A., & Weisgraber, K. H. (2006). Apolipoprotein E structure: Insights into function. Trends in Biochemical Sciences, 31(8), 445–454.

    Article  PubMed  CAS  Google Scholar 

  • Hollingworth, P., Harold, D., Sims, R., Gerrish, A., Lambert, J. C., Carrasquillo, M. M., et al. (2011). Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer’s disease. Nature Genetics, 43(5), 429–435.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Hostage, C. A., Roy Choudhury, K., Doraiswamy, P. M., & Petrella, J. R. (2013). Dissecting the gene dose-effects of the APOE ε4 and ε2 alleles on hippocampal volumes in aging and Alzheimer’s disease. PLoS ONE, 8(2), e54483.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Houlden, H., Crook, R., Hardy, J., Roques, P., Collinge, J., & Rossor, M. (1994). Confirmation that familial clustering and age of onset in late onset Alzheimer’s disease are determined at the apolipoprotein E locus. Neuroscience Letters, 174(2), 222–224.

    Article  PubMed  CAS  Google Scholar 

  • Hu, X., Pickering, E., Liu, Y. C., Hall, S., Fournier, H., Katz, E., et al. (2011). Meta-analysis for genome-wide association study identifies multiple variants at the BIN1 locus associated with late-onset Alzheimer’s disease. PLoS One, 6(2), e16616.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Huerta, C., Alvarez, V., Mata, I. F., Coto, E., Ribacoba, R., Martínez, C., et al. (2004). Chemokines (RANTES and MCP-1) and chemokine-receptors (CCR2 and CCR5) gene polymorphisms in Alzheimer’s and Parkinson’s disease. Neuroscience Letters, 370(2–3), 151–154.

    Article  PubMed  CAS  Google Scholar 

  • Inoue, K., Tanaka, N., Yamashita, F., Sawano, Y., Asada, T., & Goto, Y. (2010). The P86L common allele of CALHM1 does not influence risk for Alzheimer disease in Japanese cohorts. American Journal of Medical Genetics: Part B Neuropsychiatric Genetics, 153B(2), 532–535.

    CAS  Google Scholar 

  • Ji, Y., Urakami, K., Wada-Isoe, K., Adachi, Y., & Nakashima, K. (2000). Estrogen receptor gene polymorphisms in patients with Alzheimer’s disease, vascular dementia and alcohol-associated dementia. Dementia and Geriatric Cognitive Disorders, 11(3), 119–122.

    Article  PubMed  CAS  Google Scholar 

  • Jones, L., Holmans, P. A., Hamshere, M. L., Harold, D., Moskvina, V., Ivanov, D., et al. (2010). Genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of Alzheimer’s disease. PLoS One, 5(11), e13950.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Jun, G., Naj, A. C., Beecham, G. W., Wang, L. S., Buros, J., Gallins, P. J., et al. (2010). Meta-analysis confirms CR1, CLU, and PICALM as alzheimer disease risk loci and reveals interactions with APOE genotypes. Archives of Neurology, 67(12), 1473–1484.

    Article  PubMed Central  PubMed  Google Scholar 

  • Kamboh, M. I., Minster, R. L., Demirci, F. Y., Ganguli, M., Dekosky, S. T., Lopez, O. L., et al. (2012). Association of CLU and PICALM variants with Alzheimer’s disease. Neurobiology of Aging, 33(3), 518–521.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Karch, C. M., Jeng, A. T., Nowotny, P., Cady, J., Cruchaga, C., & Goate, A. M. (2012). Expression of novel Alzheimer’s disease risk genes in control and Alzheimer’s disease brains. PLoS One, 7(11), e50976.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Kok, E. H., Luoto, T., Haikonen, S., Goebeler, S., Haapasalo, H., & Karhunen, P. J. (2011). CLU, CR1 and PICALM genes associate with Alzheimer’s-related senile plaques. Alzheimer’s Research & Therapy, 3(2), 12–15.

    Article  CAS  Google Scholar 

  • Koren, J., Jinwal, U. K., Lee, D. C., Jones, J. R., Shults, C. L., Johnson, A. G., et al. (2009). Chaperone signalling complexes in Alzheimer’s disease. Journal of Cellular and Molecular Medicine, 13(4), 619–630.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Lambert, J. C., Harris, J. M., Mann, D., Lemmon, H., Coates, J., Cumming, A., et al. (2001). Are the estrogen receptors involved in Alzheimer’s disease? Neuroscience Letters, 306(3), 193–197.

    Article  PubMed  CAS  Google Scholar 

  • Lambert, J. C., Heath, S., Even, G., Campion, D., Sleegers, K., Hiltunen, M., et al. (2009). Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer’s disease. Nature Genetics, 41(10), 1094–1099.

    Article  PubMed  CAS  Google Scholar 

  • Lambert, J. C., Zelenika, D., Hiltunen, M., Chouraki, V., Combarros, O., Bullido, M. J., et al. (2011). Evidence of the association of BIN1 and PICALM with the AD risk in contrasting European populations. Neurobiology of Aging, 32(4), 756.e11-5.

    Article  PubMed  CAS  Google Scholar 

  • Landreth, G. E., & Reed-Geaghan, E. G. (2009). TLRs in Alzheimer’s disease. Current Topics in Microbiology and Immunology, 336, 137–153.

    PubMed Central  PubMed  CAS  Google Scholar 

  • Lee, J. H., Cheng, R., Barral, S., Reitz, C., Medrano, M., Lantigua, R., et al. (2011). Identification of novel loci for Alzheimer disease and replication of CLU, PICALM, and BIN1 in Caribbean Hispanic individuals. Archives of Neurology, 3, 320–328.

    Google Scholar 

  • Levy-Lahad, E., & Bird, T. D. (1996). Genetic factors in Alzheimer’s disease: A review of recent advances. Annals of Neurology., 40(6), 829–840.

    Article  PubMed  CAS  Google Scholar 

  • Li, H., Wetten, S., Li, L., St Jean, P. L., Upmanyu, R., Surh, L., et al. (2008). Candidate single-nucleotide polymorphisms from a genomewide association study of Alzheimer disease. Archives of Neurology, 65(1), 45–53.

    Article  PubMed  Google Scholar 

  • Lin, G. F., Ma, Q. W., Zhang, D. S., Zha, Y. L., Lou, K. J., & Shen, J. H. (2003). Polymorphism of alpha-estrogen receptor and aryl hydrocarbon receptor genes in dementia patients in Shanghai suburb. Acta Pharmacologica Sinica, 24(7), 651–656.

    PubMed  CAS  Google Scholar 

  • Liu, C., Kanekiyo, T., Xu, H., & Bu, G. (2009). Apolipoprotein E and Alzheimer disease: Risk, mechanisms and therapy. Nature Reviews Neurology, 9(2), 106–118.

    Article  CAS  Google Scholar 

  • Ma, S. L., Tang, N. L., Tam, C. W., Lui, V. W., Lau, E. S., Zhang, Y. P., et al. (2009). Polymorphisms of the estrogen receptor alpha (ESR1) gene and the risk of Alzheimer’s disease in a southern Chinese community. International Psychogeriatrics, 21(5), 977–986.

    Article  PubMed  Google Scholar 

  • Mahley, R. W., & Huang, Y. (2006). Apolipoprotein (apo) E4 and Alzheimer’s disease: Unique conformational and biophysical properties of apoE4 can modulate neuropathology. Acta Neurologica Scandinavica. Supplementum, l, 185, 8–14.

    Article  CAS  Google Scholar 

  • Marambaud, P., Dreses-Werringloer, U., & Vingtdeux, V. (2009). Calcium signaling in neurodegeneration. Molecular Neurodegeneration, 4, 20–24.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Masoodi, T. A., Al Shammari, S. A., Al-Muammar, M. N., Alhamdan, A. A., & Talluri, V. R. (2013). Exploration of deleterious single nucleotide polymorphisms in late-onset Alzheimer disease susceptibility genes. Gene, 512(2), 429–437.

    Article  PubMed  CAS  Google Scholar 

  • Mattila, K. M., Axelman, K., Rinne, J. O., Blomberg, M., Lehtimäki, T., Laippala, P., et al. (2000). Interaction between estrogen receptor 1 and the epsilon4 allele of apolipoprotein E increases the risk of familial Alzheimer’s disease in women. Neuroscience Letters, 282(1–2), 45–48.

    Article  PubMed  CAS  Google Scholar 

  • McAlpine, F. E., Lee, J., Harms, A. S., Ruhn, K. A., Blurton-Jones, M., Hong, J., et al. (2009). Inhibition of soluble TNF signaling in a mouse model of Alzheimer’s disease prevents pre-plaque amyloid-associated neuropathology. Neurobiology of Disease, 34(1), 163–177.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Melesie, G., & Dinsa, H. (2013). A literature review on: pathogenesis and management of dementia due to Alzheimer disease. Bio-Genetics Journal, 1(1), 18–31.

    Google Scholar 

  • Minster, R. L., Demirci, F. Y., Dekosky, S. T., & Kamboh, M. I. (2009). No association between CALHM1 variation and risk of Alzheimer disease. Human Mutation, 30(4), E566–E569.

    Article  PubMed Central  PubMed  Google Scholar 

  • Naj, A. C., Jun, G., Beecham, G. W., Wang, L. S., Vardarajan, B. N., Buros, J., et al. (2011). Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer’s disease. Nature Genetics, 43(5), 436–441.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Navratilova, Z. (2006). Polymorphisms in CCL2 & CCL5 chemokines/chemokine receptors genes and their association with diseases. Biomedical papers of the Medical Faculty of the University Palacky, Olomouc Czech Republic, 150(2), 191–204.

    Article  CAS  Google Scholar 

  • Nishimura, M., Kuno, S., Mizuta, I., Ohta, M., Maruyama, H., Kaji, R., et al. (2003). Influence of monocyte chemoattractant protein 1 gene polymorphism on age at onset of sporadic Parkinson’s disease. Movement Disorders, 18(8), 953–955.

    Article  PubMed  Google Scholar 

  • Parikh, I., Fardo, D. W., & Estus, S. (2014). Genetics of PICALM expression and Alzheimer’s disease. PLoS One, 9(3), e91242.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Piaceri, I., Bagnoli, S., Lucenteforte, E., Mancuso, M., Tedde, A., & Siciliano, G. (2011). Implication of a genetic variant at PICALM in Alzheimer’s disease patients and centenarians. Journal of Alzheimer’s Disease, 24(3), 409–413.

    PubMed  Google Scholar 

  • Porrello, E., Monti, M. C., Sinforiani, E., Cairati, M., Guaita, A., Montomoli, C., et al. (2006). Estrogen receptor alpha and APOEepsilon4 polymorphisms interact to increase risk for sporadic AD in Italian females. European Journal of Neurology, 13(6), 639–644.

    Article  PubMed  CAS  Google Scholar 

  • Randall, C. N., Strasburger, D., Prozonic, J., Morris, S. N., Winkie, A. D., Parker, G. R., et al. (2009). Cluster analysis of risk factor genetic polymorphisms in Alzheimer’s disease. Neurochemical Research, 34(1), 23–28.

    Article  PubMed  CAS  Google Scholar 

  • Ray, W. J., Ashall, F., & Goate, A. M. (1998). Molecular pathogenesis of sporadic and familial forms of Alzheimer’s disease. Molecular Medicine Today, 4(4), 151–157.

    Article  PubMed  CAS  Google Scholar 

  • Reitz, C., Brayne, C., & Mayeux, R. (2011). Epidemiology of Alzheimer disease. Nature Reviews Neurology, 7(3), 137–152.

    Article  PubMed Central  PubMed  Google Scholar 

  • Richard, K. L., Filali, M., Préfontaine, P., & Rivest, S. (2008). Toll-like receptor 2 acts as a natural innate immune receptor to clear amyloid beta 1–42 and delay the cognitive decline in a mouse model of Alzheimer’s disease. Journal of Neuroscience, 22, 5784–5793.

    Article  CAS  Google Scholar 

  • Ripke, S., O’Dushlaine, C., Chambert, K., Moran, J. L., Kähler, A. K., Akterin, S., et al. (2013). Genome-wide association analysis identifies 13 new risk loci for schizophrenia. Nature Genetics, 45(10), 1150–1159.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Sambamurti, K., Greig, N. H., & Lahiri, D. K. (2002). Advances in the cellular and molecular biology of the beta-amyloid protein in Alzheimer’s disease. NeuroMolecular Medicine, 1(1), 1–31.

    Article  PubMed  CAS  Google Scholar 

  • Sando, S. B., Melquist, S., Cannon, A., Hutton, L. M., Sletvold, O., Saltvedt, I., et al. (2008). APOE ε4 lowers age at onset and is a high risk factor for Alzheimer’s disease; A case control study from central Norway. BMC Neurology, 8, 9.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Schellenberg, G. D., & Montine, T. J. (2012). The genetics and neuropathology of Alzheimer’s disease. Acta Neuropathologica, 124(3), 305–323.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Seshadri, S., Fitzpatrick, A. L., Ikram, M. A., DeStefano, A. L., Gudnason, V., Boada, M., et al. (2010). Genome-wide analysis of genetic loci associated with Alzheimer disease. The Journal of American Medical Association, 303(18), 1832–1840.

    Article  CAS  Google Scholar 

  • Sezgin, I., Koksal, B., Bagci, G., Kurtulgan, H. K., & Ozdemir, O. (2011). CCR2 polymorphism in chronic renal failure patients requiring long-term hemodialysis. Internal Medicine, 21, 2457–2461.

    Article  CAS  Google Scholar 

  • Sherrington, R., Froelich, S., Sorbi, S., Chi, H., Rogaeva, E. A., Levesque, G., et al. (1996). Alzheimer’s disease associated with mutations in presenilin 2 is rare and variably penetrant. Human Molecular Genetics, 5(7), 985–988.

    Article  PubMed  CAS  Google Scholar 

  • Shi, H., Belbin, O., Medway, C., Brown, K., Kalsheker, N., Carrasquillo, M., et al. (2012). Genetic variants influencing human aging from late-onset Alzheimer’s disease (LOAD) genome-wide association studies (GWAS). Neurobiology of Aging, 33(8), 1849.e5-18.

    Article  PubMed  CAS  Google Scholar 

  • Shibata, N., Kuerban, B., Komatsu, M., Ohnuma, T., Baba, H., & Arai, H. (2010). Genetic association between CALHM1, 2, and 3 polymorphisms and Alzheimer’s disease in a Japanese population. Journal of Alzheimer’s Disease, 20(2), 417–421.

    PubMed  CAS  Google Scholar 

  • Shoji, M., Kuwano, R., Asada, T., Imagawa, M., Higuchi, S., Urakami, K., et al. (2005). A proposal for diagnostic and clinical assessment criteria for Alzheimer’s disease. Rinshō shinkeigaku, 45(2), 128–137.

    PubMed  Google Scholar 

  • Sundermann, E. E., Maki, P. M., & Bishop, J. R. (2010). A review of estrogen receptor α gene (ESR1) polymorphisms, mood, and cognition. Menopause, 17(4), 874–886.

    Article  PubMed Central  PubMed  Google Scholar 

  • Tan, E. K., Ho, P., Cheng, S. Y., Yih, Y., Li, H. H., Fook-Chong, S., et al. (2011). CALHM1 variant is not associated with Alzheimer’s disease among Asians. Neurobiology of Aging, 32(3), 546.

    Article  PubMed  CAS  Google Scholar 

  • Tan, M. S., Yu, J. T., & Tan, L. (2013). Bridging integrator 1 (BIN1): Form function, and Alzheimer’s disease. Trends in Molecular Medicine, 19(10), 594–603.

    Article  PubMed  CAS  Google Scholar 

  • Tweedie, D., Ferguson, R. A., Fishman, K., Frankola, K. A., Van Praag, H., Holloway, H. W., et al. (2012). Tumor necrosis factor-α synthesis inhibitor 3, 6′-dithiothalidomide attenuates markers of inflammation, Alzheimer pathology and behavioral deficits in animal models of neuroinflammation and Alzheimer’s disease. Journal of Neuroinflammation, 9, 106–108.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Vande, I. B., Asosingh, K., Vanderkerken, K., Straetmans, N., Van Camp, B., & Van Riet, I. (2003). Chemokine receptor CCR2 is expressed by human multiple myeloma cells and mediates migration to bone marrow stromal cell-produced monocyte chemotactic proteins MCP-1, -2 and -3. British Journal of Cancer, 88(6), 855–862.

    Article  CAS  Google Scholar 

  • Wang, L. Z., Tian, Y., Yu, J. T., Chen, W., Wu, Z. C., Zhang, Q., et al. (2011). Association between late-onset Alzheimer’s disease and microsatellite polymorphisms in intron II of the human toll-like receptor 2 gene. Neuroscience Letters, 489(3), 164–167.

    Article  PubMed  CAS  Google Scholar 

  • Wijsman, E. M., Pankratz, N. D., Choi, Y., Rothstein, J. H., Faber, K. M., Cheng, R., et al. (2011). Genome-wide association of familial late-onset Alzheimer’s disease replicates BIN1 and CLU and nominates CUGBP2 in interaction with APOE. PLoS Genetics, 7(2), e1001308.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Wilson, R. S., Barral, S., Lee, J. H., Leurgans, S. E., Foroud, T. M., Sweet, R. A., et al. (2011). Heritability of different forms of memory in the Late Onset Alzheimer’s Disease Family Study. Journal of Alzheimer’s Disease, 23(2), 249–255.

    PubMed Central  PubMed  Google Scholar 

  • Wuwongse, S., Chang, R. C., & Law, A. C. K. (2010). The putative neurodegenerative links between depression and Alzheimer’s disease. Progress in Neurobiology, 91(4), 362–375.

    Article  PubMed  CAS  Google Scholar 

  • www.alzgene.org

  • Xiao, Q., Gil, S., Yan, P., Wang, Y., Han, S., Gonzales, E., et al. (2012). Role of phosphatidylinositol clathrin assembly lymphoid-myeloid leukemia (PICALM) in intracellular amyloid precursor protein (APP) processing and amyloid plaque pathogenesis. Journal of Biological Chemistry, 287(25), 21279–21289.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Xing, X., Jia, J. P., Ji, X. J., & Tian, T. (2013). Estrogen associated gene polymorphisms and their interactions in the progress of Alzheimer’s disease. Progress in Neurobiology, 111, 53–74.

    Article  PubMed  CAS  Google Scholar 

  • Yu, J. T., Li, L., Zhu, Q. X., Zhang, Q., Zhang, W., Wu, Z. C., et al. (2010). Implication of CLU gene polymorphisms in Chinese patients with Alzheimer’s disease. Clinica Chimica Acta, 411(19–20), 1516–1519.

    Article  CAS  Google Scholar 

  • Yu, J. T., Mou, S., Wang, L., Mao, C., & Tan, L. (2011). Toll-like receptor 2 −196 to −174 del polymorphism influences the susceptibility of Han Chinese people to Alzheimer’ s disease. Journal of Neuroinflammation, 8, 136.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Zetzsche, T., Rujescu, D., Hardy, J., & Hampel, H. (2010). Advances and perspectives from genetic research: Development of biological markers in Alzheimer’s disease. Expert Review of Molecular Diagnostics, 10(5), 667–690.

    Article  PubMed  CAS  Google Scholar 

  • Zhang, Q., Yu, J. T., Zhu, Q. X., Zhang, W., Wu, Z. C., Miao, D., et al. (2010). Complement receptor 1 polymorphisms and risk of late-onset Alzheimer’s disease. Brain Research, 1348, 216–221.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The authors are appreciative to all of the subjects who kindly agreed to participate in this study. This project was supported by the Neuroscience Research Center and Immunology Research Center at the Tabriz University of Medical Sciences.

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Authors and Affiliations

  1. Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran

    Maryam Rezazadeh, Aziz Khorrami, Tarlan Yeghaneh & Jalal Gharesouran

  2. Neuroscience Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

    Mahnaz Talebi

  3. Virology Department, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran

    Seyed Jalal Kiani

  4. Department of Medicine, Huddinge, H7, Karolinska Institutet, Stockholm, Sweden

    Yaser Heshmati

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  1. Maryam Rezazadeh
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  2. Aziz Khorrami
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  7. Jalal Gharesouran
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Correspondence to Jalal Gharesouran.

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Rezazadeh, M., Khorrami, A., Yeghaneh, T. et al. Genetic Factors Affecting Late-Onset Alzheimer’s Disease Susceptibility. Neuromol Med 18, 37–49 (2016). https://doi.org/10.1007/s12017-015-8376-4

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  • DOI: https://doi.org/10.1007/s12017-015-8376-4

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