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.
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Introduction
Alzheimer’s disease (AD) is the most common neurodegenerative disease and represents a serious public health problem worldwide (Cacabelos et al. 2005; Defina et al. 2013). AD is categorized into two major groups, early-onset (EOAD) and late-onset Alzheimer’s disease (LOAD), differing in terms of their symptomatic, biological, genetic, and neurophysiological characteristics (Biagioni and Galvin 2011). EOAD corresponds to <1–6 % of all cases of Alzheimer disease (Avramopoulos 2009). This condition is inherited in an autosomal dominant pattern and caused by highly penetrant mutations in one of the three known genes (PSEN1, PSEN2, and APP). Affected people with this type of disease have the disease onset prior to age 65 (Goate et al. 1991; Levy-Lahad and Bird 1996; Sherrington et al. 1996).
In contrast to EOAD, sporadic or late-onset Alzheimer’s disease has heterogeneous etiology and affects individuals older than 65 years with modest or no familial clustering (Bird 2008; Cacabelos et al. 2005; Zetzsche et al. 2010).
Although LOAD patients exhibit no clear pattern of inheritance, twin and family-based studies have suggested a significant genetic component in the etiology of LOAD (Gatz et al. 2005, 2010). Results of scientific research have implicated complex interactions between different genetic variants, age, gender, and other environmental factors that modulate LOAD risk (Goldman et al. 2011; Reitz et al. 2011).
According to these studies, the estimated heritability in LOAD ranges from 25 to 75 % (Wilson et al. 2011). In addition to the ε4 allele of the apolipoprotein E gene (ApoE), which is the only genetic factor that unambiguously confers increased risk of LOAD, recent GWASs (genome-wide association studies) have implicated loci of other genes with more modest effects on this disease (Table 1).
Some of these loci are mapped to genes with established roles in Aβ metabolism [APOE, apolipoprotein J (clusterin), phosphatidylinositol-binding clathrin assembly protein], neuroinflammation (complement receptor 1, tumor necrosis factor-α, T cell receptor, CRR2, CRR5), calcium signaling (calcium homeostasis modulator 1), and hormonal regulation (estrogen receptor 1), and all are recognized as novel putative LOAD risk loci (www.alzgene.org).
APOE exerts its effect on the risk and age of onset distribution in a dose-related manner (Sando et al. 2008). APOE protein plays a critical role in Aβ (amyloid β) homeostasis, promotes the proteolytic clearance of amyloid β, and functions as a chaperone (Liu et al. 2009; Schellenberg and Montine 2012). Clusterin is a multifunctional glycoprotein. Both APOE and clusterin molecules are involved in Aβ metabolism and deposition and are protective agents against Aβ neurotoxicity (Koren et al. 2009). Both PICALM and BIN1 are ubiquitously expressed genes, most abundantly in the brain, and are involved in intracellular trafficking of proteins such as vesicle-associated membrane protein 2 (VAMP2) and neurotransmitters through clathrin-mediated endocytosis (CME) (Ando et al. 2013; Harel et al. 2008; Parikh et al. 2014; Xiao et al. 2012).
Neuroinflammation as a common feature of the brain pathology presents in Alzheimer’s disease is associated with immune mediators’s up-regulation. TNFα, a pro-inflammatory cytokine, a well-known immune mediator with modulating effects on memory and synaptic function, is up-regulated in AD patients and animal models of the disease (McAlpine et al. 2009; Tweedie et al. 2012).
CCR2, CCR5, and their related ligands are involved in the accumulation of microglia at sites affected by neuroinflammation (Galimberti et al. 2004; Navratilova 2006). CCR2 and its ligand CCL2 (MCP-1) is involved in the metabolism of Aβ, and CCR5 receptor has role in the regulation of brain immune responses in AD (Harries et al. 2012). A valine to isoleucine substitution at codon 64 within the first membrane region of CCR2, CCR2V64I, causes a controversial influence on the expression of CCR2 on the cell surface, while CCR5∆32 polymorphism creates a premature stop codon and has a protective effect toward inflammatory diseases such as AD (Sezgin et al. 2011).
Toll-like receptor 2 (TLR2), located in the Alzheimer dementia (AD) linkage region on 4q, is involved in the microglia-mediated inflammatory response (Blacker et al. 2003; Landreth and Reed-Geaghan 2009). TLR2 is a member of pattern recognition receptors in the innate immune system. TLR2 may also be essential for Aβ clearance and in that way provides neuroprotection in AD (Bsibsi et al. 2002; Richard et al. 2008). Calcium homeostasis modulator 1 (CALHM1), mainly expressed in the hippocampus, encodes a multipass transmembrane glycoprotein that controls cytosolic Ca2+ concentrations and Aβ levels (Shoji et al. 2005). A non-synonymous polymorphism, rs2986017 (p.P86L) in the CALHM1 gene, was reported to affect calcium homeostasis and promotes Aβ accumulation via a loss of CALHM1 control on Ca2+ permeability and cytosolic Ca2+ levels and increases the risk of AD (Dreses-Werringloer et al. 2008).
ESR1 is one of the receptors through which estrogen exerts its biological effects and mediates the effects of estrogen on AD (Sundermann et al. 2010). According to some reports, AD is more prevalent in women, and the use of estrogen by women after menopause is associated with a lower risk of AD or delayed disease (Ma et al. 2009). Numerous laboratory studies have demonstrated inhibitory effects of estrogen on Aβ plaque formation and its antioxidant and anti-apoptotic functions (Ba et al. 2004; Chiueh et al. 2003).
We aimed to examine the possible associations of 19 different risk factors for LOAD, identified recently by GWAS, in different genetic models, and their possible interaction with ApoE genotype conditions in LOAD within the Azeri Turkish population of Iran.
Materials and Methods
A total of 160 patients, 66 males and 94 females (age range between 65 and 99 and mean age 76.06 ± 7.75 years), with LOAD were recruited from northwest of Iran. The patients were screened by their physicians in the Neuroscience Research Center between February 2010 and July 2014 according to the DSM-IV diagnostic criteria (American Psychiatric Association 1994; Alberoni et al. 2000) and were referred to our laboratory for genotyping of candidate genes. The control group consisted of 163 ethnically, sex-matched 68 male and 95 female (age range between 65 and 89 and mean age 75.29 ± 6.75 years) participants. They underwent neurological and medical examinations, which showed that they were free of any symptoms suggestive of cognitive decline (Gharesouran et al. 2014). Among different racial or ethnic groups living in Iran, including Persian (51 %), Azeri Turk (24 %), Kurd (7 %), Arab (3 %), and other minorities, we limited our investigation to 15–24 million Azeri Turks in northwestern Iran.
Excluding patients with disease onset age before 65 years and from families with two or more affected people within more than one generation, ensured the sporadic form of the disease (Ray et al. 1998). Written informed consent was obtained from each participant, or their legally authorized representatives, who were accepted previously by the ethics committee of special clinics at the Tabriz University of Medical Sciences. This study was approved by the review board of the Neuroscience Research Center and Immunology Research Center at the Tabriz University of Medical Sciences.
Variants on CR1, PICALM, BIN1, and APOE genes were genotyped by PCR and direct sequencing. Genotypes related to polymorphisms on TNF α, CCR2, CLU, TLR1, and ESRα genes were determined by PCR–RFLP reaction, and the CCR5Δ32 genotype was determined by PCR without RFLP. The purified PCR products of these genes from AD cases and healthy controls were randomly sequenced bidirectionally (Gharesouran et al. 2014).
The Hardy–Weinberg equilibrium (HWE) was estimated using the Chi-square test. Differences in allele and genotype distribution between the LOAD patients and healthy controls were analyzed using the Chi-square and Fisher’s exact tests. We used the Bonferroni method to adjust for multiple statistical tests. A Bonferroni-corrected p value of 0.05 (based on the number of SNPs analyzed and genetic models) was regarded as statistically significant. The odds ratio (OR) was calculated at 95 % confidence interval (CI), whenever possible.
To assess the role of interaction of the APOE ɛ4 allele with these polymorphisms, the stratified analysis was performed regarding the existing of ApoE ɛ4 allele. To adjust case and control for APOE ε4 status, subjects were divided into the APOE ε4-positive and APOE ε4-negative subgroups. In addition, the significance of the SNPs association with LOAD was tested in the dominant, additive, and recessive models for SNPs with minor allele homozygote counts of more than 14.
Results
Allele and genotype distribution of the investigated SNPs is shown in Table 2. The distributions of investigated markers were in HWE for both AD patients and controls (p > 0.05, corrected p = 0.003). Allele distributions in CCR2 (rs1799864), TNF α (rs1800629), PICALM (rs541458), BIN1 (rs744373), APOE, TLR2 (−196 to −174 Del), ESRα (PvuII), and ESRα (XbaI) (8 of the 19 investigated polymorphisms) were significantly different between the LOAD and control groups. However, CALHM1 (rs2986017) showed nominally significant association with an increased risk of LOAD, but missed criteria for significance after Bonferroni correction (p = 0.01, corrected p = 0.19).
Significant differences were revealed in genotype distribution of CCR2 (rs1799864), CALHM1 (rs2986017), TNF α (rs1800629), PICALM (rs541458), APOE, CLU (rs11136000), and TLR2 (−196 to −174del) polymorphisms among the LOAD and control groups in this ethnic group (Table 2). CALHM1 (rs2986017), CLU (rs11136000), BIN1 (rs744373), ESRα (PvuII), and ESRα (XbaI) genotype distributions among the LOAD and control groups were only significant before Bonferroni correction (Table 2).
As shown in Table 3, seven markers, CCR2 (rs1799864), CLU (rs11136000), ESRα (PvuII), ESRα (XbaI), TLR2 (−196 to −174 del), TNF α (rs1800629), and APOE had minor allele homozygote counts more than 14, and the significance of their associations with LOAD was tested in a dominant, additive, and recessive model.
Among them, CCR2 (rs1799864), ESRα (PvuII), ESRα (XbaI), TNF α (rs1800629), and APOE were correlated with the LOAD in three different statistical models. However, ESRα (PvuII) in dominant model and ESRα (XbaI) in dominant and recessive models missed their correlations with the LOAD after Bonferroni correction (corrected significant p = 0.002).
TLR2 (−196 to −174 del) was associated with the risk of LOAD only in the additive and dominant models (recessive model p = 0.073), and CLU (rs11136000) showed no association with LOAD in additive and dominant models (p = 0.27 and p = 0.16, respectively). CLU (rs11136000) association with LOAD in recessive model (p = 0.0329) missed after Bonferroni correction (Table 3).
After adjusting for APOE, statistical analysis of the allelic distribution showed an association with PICALM (rs541458), BIN1 (rs744373), CCR2 (rs1799864), TNF α (rs1800629), TLR2 (−196 to −174 del), and ESRα (PvuII) only among subjects without the APOE ε4 allele. The association with CCR5, ESR α (XbaI), and TNF α (rs1800630) was evident only among subjects with the APOE ε4 allele.
Among them PICALM (rs541458), CCR5 (rs333), and ESR α (XbaI) missed their association after Bonferroni correction (corrected significant p = 0.003).
The interactions of other SNPs with the APOE ε4 allele were not statistically significant. The genotype distribution of the investigated SNPs after adjusting for APOE is shown in Table 4.
Discussion
Alzheimer’s disease is clinically characterized by a progressive decline of memory with pathogenic features including amyloid plaques, oxidative stress, dysfunctional calcium homeostasis, hormonal dysregulation, and decline in immune system function (Melesie and Dinsa 2013; Wuwongse et al. 2010). AD, particularly multifactorial type, LOAD, is immensely complex on the molecular level (Bertram and Tanzi 2012).
In this article, we report the results of case–control investigations of potential risk factors for LOAD in northwestern Iran of patients with Azeri Turkish origin (Gharesouran et al. 2013). We also re-examined the SNPs association with LOAD in different genetic models. We then compared allele and genotype distribution of the variants after adjustment for APOE status. Overall in the present study, 19 of the most replicated markers association with LOAD were assessed (Table 2).
The ε4 allele of apolipoprotein E accounts for 20–70 % of the LOAD risk and offers odds ratios (ORs) ranging from 6 to 30 in the APOE ε4/ε4 genotype carriers for disease association (Ertekin-Taner 2007, 2010; Corneveaux et al. 2010). APOE ε4, compared with APOE ε3 and APOE ε2, has less three-dimensional folding stability (Koren et al., 2009; Mahley and Huang 2006; Hatters et al. 2006). APOE ε4 is also not as efficient at repairing neuronal damage, transporting cholesterol, and delivery of cholesterol to neurons as ApoE ε3 (Liu et al. 2009; Kok et al. 2011).
According to our statistical results, APOE ε4 is a LOAD risk factor in the additive model (OR 8.430; 95 % CI 4.784–14.854), dominant model (OR 6.619; 95 % CI 3.617–12.109), and recessive model (OR 17.821; 95 % CI 4.175–76.075). In a previous study in Iran, the difference between individuals with and without a ε4 allele regarding the susceptibility to LOAD was a risk factor of 6.5 (Gozalpour et al. 2010). In the Gyungah et al. study on 7070 cases with AD and 8169 cognitively normal controls (13 cohorts), including white, African-American, and Caribbean Hispanic individuals, a APOE ε4 significant association with AD was revealed (ORs 1.80–9.05) in all groups except the Amish and Arabs (Gyungah et al. 2010). Although the contribution of APOE allele is known to make the strongest association with LOAD susceptibility, much remains to be learned about the contributions of loci with more modest effects identified by genome-wide association studies (GWASs).
Failing in localize additional highly penetrant LOAD susceptibility genes and regarding to pathogenic features of AD, it seems that multiple low penetrate alleles, with modest effects and related to genes with roles in calcium homeostasis, in hormonal regulation, and in the immune system, can be considered to be possible risk factors for LOAD.
CALHM1 plays a role in controlling cytosolic Ca2+ levels and APP processing (Marambaud et al. 2009). The P86L polymorphism minor allele in this gene was reported to be a predisposing factor in LOAD. Unlike the Japanese, the T allele distribution was increased in AD cases as compared to controls with ORs ranging from 1.29 to 1.99 in the combined population from USA, France, UK, and Italy (Dreses-Werringloer et al. 2008; Inoue et al. 2010). Although the minor allele (A) at SNP rs2986017 within CALHM1 showed a nominally significant association with an increased risk of LOAD (nominal p = 0.011; OR 2.232; 95 % CI 1.223–4.073) suggesting that the A allele is the risk allele, this did not remain significant after Bonferroni correction.
Some studies propose a gender- and race-specific pattern for ESR1-mediated hormonal effects on clinical outcomes in LOAD (Sundermann et al. 2010; Xing et al. 2013). The recent reports demonstrate a protective effect of the x and p alleles in addition to the px haplotype of the Xbal and PvuII SNPs against LOAD in the Italian and Caucasian population (Becherini et al. 2000; Corbo et al. 2006; Lambert et al. 2001). In a case–control study involving Japanese individuals, a greater prevalence of the X and P alleles in patients versus controls was revealed. Our results present evidence that indicates the risk of dementia associated with X and P alleles and their related genotypes and haplotypes. The association was also replicated in three different genetic models, although not all of these associations were statistically significant after adjustment for multiple comparisons (Table 3). A significant association was observed between increased risk of LOAD and X allele in participants who carried the APOE ε4 without Bonferroni correction (p = 0.0279), whereas the risk of LOAD regarding PP genotype and P allele was significant for participants who did not carry the APOE ε4 allele (p = 0.002 and p = 0.0005 for allelic and genotypic distribution, respectively) (Table 4).
TNFα, CCR2, TLR2, BIN1, and PICALM contribute to the LOAD pathogenesis in different ways, especially with their role in the immune system. Among different polymorphisms in the promoter of the TNFα gene with effects on the transcription rate and susceptibility to different diseases, rs1800629 associates with an elevated transcriptional activity. Significant elevated serum concentrations of TNFα have been reported in Alzheimer patients compared to controls (Gezen-Ak et al. 2013). In southern China, Spain, and US populations, the effect of this variant was revealed on the age of onset of LOAD (Randall et al. 2009; Alvarez et al. 2002). Similarly, the allele and genotypic distribution between case and control groups provided an evidence of the possible role of rs1800629 in LOAD pathogenesis in the Azeri Turkish population (p < 0.001; OR 0.12.36; 95 % CI 7.473–20.44). Allelic but not genotypic distribution in the APOE ε4 adjusted subgroups revealed a negative interaction between this marker and the ε4 allele of APOE (Table 4).
TLR2 is essential for Aβ clearance, activation of microglia, and induction of phagocytosis. TLR2 deficiency in transgenic AD mice could increase Aβ deposition and accelerate cognitive decline (Bsibsi et al. 2002; Richard et al. 2008). Assessing the involvement of −196 to −174 Del in TLR2 in developing LOAD suggests a significant association between this variant and the risk of LOAD in our investigation as in the Chinese population (Yu et al. 2011).
Considering adjustment for multiple comparisons, this association was confirmed in additive and dominant models. After adjustment for APOE ε4, frequency distribution of −196 to −174 Del genotypes but not alleles differed significantly between patient and control groups among non-APOE ε4 carriers (Tables 3, 4).
CCR2 is believed to mediate blood monocyte extravasation for sites of inflammation and be involved in macrophage recruitment to the injured peripheral system (Vande et al. 2003). In our study population, the occurrence of rs1799864 CCR2-64I allele polymorphism is decreased in LOAD patients (p < 0.001; OR 0.222, 95 % CI 0.142–0.347) and also a low frequency of the genotype 64I/64I in AD patients proved a real protective effect of this polymorphism on AD (2.5 vs 12.8 %) (p < 0.001). Our finding about this polymorphism is in agreement with the results of Galimberti et al. carried out on the Italian population (p = 0.037; OR 0.65; 95 % CI 0.41–1.03) (Galimberti et al. 2004). Our findings showed the association in dominant, recessive, and additive models. After adjustment for APOE, and considering Bonferroni correction, the association limited only in the group without carrying the APOE allele (Table 4).
BIN1 has a key role in regulating endocytosis and endolysosomal trafficking pathways that, through which APP, Aβ, and ApoE are all internalized, suggests a potential association with AD pathology (Tan et al. 2013). Higher levels of BIN1 expression have recently been reported to be associated with later age at onset and shorter disease duration in AD patients (Karch et al. 2012). In Seshadri et al. study, three-stage meta-analysis (8,371 LOAD cases and 26,965 controls) on variant rs744373 offered the strongest association with LOAD after ApoE, CLU, and PICALM (p = 1.6 × 10−11, OR 1.15) (Seshadri et al. 2010). Lambert et al. replicated the association of the BIN1 rs744373 variant with the risk of AD in three European populations (p = 2.9 × 10−7; OR 1.26; 95 % CI 1.15–1.38) (Lambert et al. 2010). In our research, only BIN1 rs744373 marker allelic association was replicated in the investigation of possible associations among three selected SNPs on BIN1 and LOAD (allelic distribution: p < 0.0001, OR 95 % CI 2.847 (1.562–5.187); genotypic distribution p = 0.006). After adjustment for APOE status, both allelic and genotypic distribution of this variant showed association, only among APOE ε4 non-carriers, with LOAD.
Significant associations between LOAD and several SNPs close to PICALM have been demonstrated, including rs12800974, rs17159904, and rs541458 (www.alzgene.org). Harold et al. reported the first significant evidence for these SNPs association (rs541458: p = 8.3 × 10−10; OR 0.86) with LOAD (Harold et al. 2009; Piaceri et al. 2011). In our study, among three variants on PICALM, rs541458 was associated with an increased risk for LOAD occurrence.
After adjustment for APOE status, both the allelic and genotypic association observed for this variant limited only in APOE ε4 non-carriers. This association did not remain significant after Bonferroni correction (p = 0.0265; p = 0.0366 for allelic and genotypic distribution, respectively).
Similar to other multifactorial diseases, the absence of the risk genes decreased the likelihood but does not completely rule out the disease occurrence. However, finding the LOAD associated markers in an individual raises the chances of disease from a priori risk for the general population to higher risk and increases the odds with the age of presentation. In conclusion, we have replicated CCR2 (rs1799864), ESRα (PvuII), ESR1α (XbaI), TNFα (rs1800629) as well as APOE, associations with LOAD susceptibility in Azeri Turk ancestry populations in dominant, recessive, and additive models.
Our results reveal after adjusting for APOE and considering Bonferroni adjustment for multiple testing, the association with TNFα (rs1800630) (regarding allelic distribution) was evident only among subjects with the APOE ε4 allele, whereas TNFα (rs1800629) (allelic distribution), TLR2 (genotypic distribution) and CCR2, ESR1α (PvuII), and BIN1 (rs744373) (both allelic and genotypic distribution) differences between case and control groups were restricted to non-APOE ε4 carriers. It seems that the genetic effect of these variants is relevant in predisposing to LOAD only in the absence of the APOE ε4 allele, while in ε4 carriers the genetic effect is determined by this robust susceptibility factor.
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.
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.
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.
American Psychiatric Association. (1994). Diagnostic and statistical manual of mental disorders (4th ed.). Washington, DC: American Psychological Association.
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.
Avramopoulos, D. (2009). Genetics of Alzheimer’s disease: Recent advances. Genome Medicine, 1(3), 34.
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.
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.
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.
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.
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.
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).
Bertram, L., & Tanzi, R. E. (2012). The genetics of Alzheimer’s disease. Progress in Molecular Biology and Translational Science, 107, 79–100.
Biagioni, M. C., & Galvin, J. E. (2011). Using biomarkers to improve detection of Alzheimer’s disease. Neurodegenerative Disease Management, 1(2), 127–139.
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.
Bird, T. D. (2008). Genetic aspects of Alzheimer disease. Genetics in Medicine, 10(4), 231–239.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Ertekin-Taner, N. (2007). Genetics of Alzheimer’s disease: A centennial review. Neurologic Clinics, 25(3), 611–667.
Ertekin-Taner, N. (2010). Genetics of Alzheimer disease in the pre- and post-GWAS era. Alzheimer’s Research & Therapy, 2(1), 3.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Landreth, G. E., & Reed-Geaghan, E. G. (2009). TLRs in Alzheimer’s disease. Current Topics in Microbiology and Immunology, 336, 137–153.
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.
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.
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.
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.
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.
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.
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.
Marambaud, P., Dreses-Werringloer, U., & Vingtdeux, V. (2009). Calcium signaling in neurodegeneration. Molecular Neurodegeneration, 4, 20–24.
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.
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.
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.
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.
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.
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.
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.
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.
Parikh, I., Fardo, D. W., & Estus, S. (2014). Genetics of PICALM expression and Alzheimer’s disease. PLoS One, 9(3), e91242.
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.
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.
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.
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.
Reitz, C., Brayne, C., & Mayeux, R. (2011). Epidemiology of Alzheimer disease. Nature Reviews Neurology, 7(3), 137–152.
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.
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.
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.
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.
Schellenberg, G. D., & Montine, T. J. (2012). The genetics and neuropathology of Alzheimer’s disease. Acta Neuropathologica, 124(3), 305–323.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12017-015-8376-4