Alzheimer Disease: Go RC

Perry RT, Collins JS, Wiener H, Acton R, Go RC. · Department of Epidemiology and International Health, University of Alabama at Birmingham, 35294, USA. · Neurobiol Aging. · Pubmed #11754994 No free full text.

Abstract: Tumor necrosis factor (TNF) is an important proinflammatory cytokine that is upregulated in Alzheimer disease (AD) patients and involved with AD genes. Several TNF promoter polymorphisms that increase expression are associated with inflammatory and infectious diseases. We previously reported results that detected a AD associated region near the TNF gene. Using family-based association tests we also reported an association between AD and a TNF haplotype in sibling-pair families, and a significant increase in the mean age of onset for a group of African-American AD patients carrying this same haplotype. Previous reports have shown that that the chromosome 1p and chromosome 12p regions are linked to late-onset AD. These two regions harbor TNF receptors (TNFR) 2 and 1, respectively, and binding to them mediates biological effects of TNF. We found a significant asssociation of a TNFR2 exon 6 polymorphism with late-onset AD in families with no individuals possessing the APOE E4E4 genotype under a dominant model. We found no significant association of three polymorphisms in the TNFR1 gene to AD. These results provide further evidence for the involvement of TNF in the pathogenesis of AD.

Baye TM, Perry RT, Wiener HW, Chen Z, Harrell LE, Go RC. · Section on Statistical Genetics, Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL 35294, USA. · Dis Markers. · Pubmed #18688078 No free full text.

Abstract: The objective of this research was to develop a procedure to identify candidate genes under linkage peaks confirmed in a follow-up of candidate regions of interests (CRIs) identified in our original genome scan in the NIMH Alzheimer's diseases (AD) Initiative families (Blacker et al. [1]). There were six CRIs identified that met the threshold of multipoint lod score (MLS) of >or= 2.0 from the original scan. The most significant peak (MLS = 7.7) was at 19q13, which was attributed to APOE. The remaining CRIs with 'suggestive' evidence for linkage were identified at 9q22, 6q27, 14q22, 11q25, and 3p26. We have followed up and narrowed the 9q22 CRI signal using simple tandem repeat (STR) markers (Perry et al. [2]). In this confirmatory project, we have followed up the 6q27, 14q22, 11q25, and 3p26 CRIs with a total of 24 additional flanking STRs, reducing the mean interval marker distance (MID) in each CRI, and substantially increase in the information content (IC). The linkage signals at 6q27, 14q22 and 11q25 remain 'suggestive', indicating that these CRIs are promising and worthy of detailed fine mapping and assessment of candidate genes associated with AD. We have developed a bioinformatics approach for identifying candidate genes in these confirmed regions based on the Gene Ontology terms that are annotated and enriched among the systematic meta-analyzed genes, confirmed by at least three case-control samples, and cataloged in the "AlzGene database" as potential Alzheimer disease susceptibility genes (http://www.alzgene.org).

Dickson MR, Li J, Wiener HW, Perry RT, Blacker D, Bassett SS, Go RC. · Department of Epidemiology and International Health, The University of Alabama at Birmingham, Birmingham, Alabama 35294-0001, USA. · Am J Med Genet B Neuropsychiatr Genet. · Pubmed #18189239 links to  free full text

Abstract: We performed linkage analysis for age at onset (AAO) in the total Alzheimer's disease (AD) NIMH sample (N = 437 families). Families were subset as late-onset (320 families, AAO > or = 65) and early/mixed (117 families, at least 1 member with 50 < AAO < 65). Treating AAO as a censored trait, we obtained the gender and APOE adjusted residuals in a parametric survival model and analyzed the residuals as the quantitative trait (QT) in variance-component linkage analysis. For comparison, AAO-age at exam (AAE) was analyzed as the QT adjusting for affection status, gender, and APOE. Heritabilities for residual and AAO-AAE outcomes were 66.3% and 74.0%, respectively for the total sample, 56.0% and 57.0% in the late-onset sample, and 33.0% for both models in the early/mixed sample. The residual model yielded the largest peaks on chromosome 1 with LOD = 2.0 at 190 cM in the total set, LOD = 1.7 at 116 cM on chromosome 3 in the early/mixed subset, and LOD = 1.4 at 71 and 86 cM, respectively, on chromosome 6 in the late-onset subset. For the AAO-AAE outcome model the largest peaks were identified on chromosome 1 at 137 cM (LOD = 2.8) and chromosome 6 at 69 cM (LOD = 2.3) and 86 cM (LOD = 2.2) all in the late-onset subset. Additional peaks with LOD > or = 1 were identified on chromosomes 1, 2, 3, 6, 8, 9, 10, and 12 for the total sample and each subset. Results replicate previous findings, but identify additional suggestive peaks indicating the genetics of AAO in AD is complex with many chromosomal regions potentially containing modifying genes.

Chen Z, Simmons MS, Perry RT, Wiener HW, Harrell LE, Go RC. · Department of Epidemiology, University of Alabama at Birmingham School of Public Health, Birmingham, Alabama 35294, USA. · Am J Med Genet B Neuropsychiatr Genet. · Pubmed #17918233 No free full text.

Abstract: Brain-derived neurotrophic factor (BDNF)/tyrosine receptor kinase (TRK) signaling pathway activates a wide range of downstream intracellular cascades, regulating neuronal development and plasticity, long-term potentiation, and apoptosis. The NTRK family encodes the receptors TRKA, TRKB, and TRKC, to which the neurotrophins, nerve growth factor (NGF), BDNF and neurotrophin-3 (NT-3) bind, respectively, with high affinity. Signaling through these receptors appears to be compromised in Alzheimer's disease (AD). This study is the most comprehensive investigation of genetic variants of NTRK2, and the first to show significant association between NTRK2 with AD. Fourteen single nucleotide polymorphisms (SNPs), located in 8 of 18 linkage disequilibrium (LD) blocks, were genotyped in 203 families with at least two AD affected siblings with mean age of onset (MAO) of 70.9 +/- 7.4 years and one unaffected sibling from the NIMH-ADGJ dataset. Family based association testing found no single SNP association, however, significant associations were found for two and three locus haplotypes (P = 0.012, P = 0.009, respectively) containing SNPs rsl624327, rsl443445, and rs378645. These SNPs are located in areas of the gene containing sequences that could be involved in alternative splicing and/or regulation of NTRK2. Our results suggest that NTRK2 may be a genetic susceptibility gene contributing to AD pathology.

Li J, Cowden LG, King JD, Briles DA, Schroeder HW, Stevens AB, Perry RT, Chen Z, Simmons MS, Wiener HW, Tiwari HK, Harrell LE, Go RC. · Department of Epidemiology and International Health, School of Public Health, University of Alabama at Birmingham, Birmingham, Alabama, USA. · Psychosom Med. · Pubmed #17634568 links to  free full text

Abstract: OBJECTIVE: To assess the effects of psychological stress on the antibody response to tetanus vaccine adjusting for cytokine gene polymorphisms and other nongenetic factors in caregivers of patients with Alzheimer's disease (AD). METHODS: A family-based follow-up study was conducted in 119 spouses and offspring of community-dwelling patients with AD. Psychological stress was measured by the Perceived Stress Scale (PSS) and the Center for Epidemiologic Studies Depression (CES-D) scale at baseline and 1 month after the vaccination. Nutritional status, health behaviors, comorbidity, and stress-buffering factors were assessed by self-administered questionnaires, 10 single nucleotide polymorphisms (SNP) from six selected cytokines genotyped, and anti-tetanus toxoid immunoglobulin G (IgG) concentrations tested using enzyme-linked immunosorbent assays. The effects of stress and other potential confounders were assessed by mixed models that account for familial correlations. RESULTS: The baseline PSS score, the baseline CES-D score, the interleukin-10-1082 A>G SNP GG genotype, and the baseline anti-tetanus IgG were inversely associated with antibody fold increase. CONCLUSION: Both psychological stress and cytokine gene polymorphisms affected antibody fold increase. The study provided additional support for the detrimental effects of psychological stress on the antibody response to tetanus vaccine.

Moscarillo TJ, Holt H, Perman M, Goldberg S, Cortellini L, Stoler JM, DeJong W, Miles BJ, Albert MS, Go RC, Blacker D. · Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, Mass., USA. · Community Genet. · Pubmed #17380059 No free full text.

Abstract: OBJECTIVES: In preparation for the development of an educational intervention on Alzheimer disease (AD) genetics, we undertook a pilot survey of knowledge in this area and attitudes toward genetic testing for AD among individuals with a family history of AD. METHODS: For the pilot study, we administered a 30-min questionnaire to 57 unaffected individuals from a genetic linkage study. For the focus groups, we interviewed two groups of subjects, ages 44-70 years, with a family history of AD, one of 10 Caucasians and the other of 6 African-Americans. RESULTS: The pilot study showed that there was limited knowledge of genetics overall and AD genetics in particular, considerable concern about personal risk, and little knowledge of or interest in genetic testing for the disease. The focus groups reinforced and fleshed out these impressions and highlighted the importance of caregiving experience in the attitudes toward personal risk for AD. CONCLUSIONS: These results underscore the value of genetics education for this and other complex diseases and suggest specific foci for educational interventions.

Wiener HW, Perry RT, Chen Z, Harrell LE, Go RC. · Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, AL 35294-0022, USA. · Genes Brain Behav. · Pubmed #17376152 No free full text.

Abstract: Genes involved in cellular mechanisms to repair oxidative damage are strong candidates as etiologic factors for Alzheimer's disease (AD). One important enzyme involved in this mechanism is superoxide dismutase 2 (SOD2). The gene for this enzyme lies within a single haplotype block at 6q25.3, a region showing evidence for linkage to AD in a genome scan. We genotyped four single nucleotide polymorphisms (SNPs) in SOD2 in families of the National Institute of Mental Health-AD Genetics Initiative (ADGI): rs2758346 in the 5' untranslated region (UTR), rs4880 in exon 2, rs2855116 in intron 3 and rs5746136 in the 3'UTR. Under a dominant model, family-based association tests showed significant evidence for association of AD with the first three loci in a candidate gene set of families with individuals having age of onset of at least 50 years and two affected and one unaffected sibling, and in a late-onset subset of families (families with all affected individuals having age of onset of at least 65 years) from the full ADGI sample. The alleles transmitted more frequently to cases than expected under the null hypothesis were T, C, G, and G. Global tests of the transmission of haplotypes indicate that the first two loci have the most consistent association with risk of AD. Because of the high linkage disequilibrium in this small (14 kb) gene, and the presence of 100 SNPs in this gene, 26 of which may have functional significance, additional genotyping and sequencing are needed to identify the functionally relevant SNP. We discuss the importance of our findings and the relevance of SOD2 to AD risk.

Perry RT, Gearhart DA, Wiener HW, Harrell LE, Barton JC, Kutlar A, Kutlar F, Ozcan O, Go RC, Hill WD. · Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL 35294-0022, USA. · Neurobiol Aging. · Pubmed #17157413 links to  free full text

Abstract: From a normal human brain phage display library screen we identified the gamma (A)-globin chain of fetal hemoglobin (Hb F) as a protein that bound strongly to A beta1-42. We showed the oxidized form of adult Hb (metHb A) binds with greater affinity to A beta1-42 than metHb F. MetHb is more toxic than oxyhemoglobin because it loses its heme group more readily. Free Hb and heme readily damage vascular endothelial cells similar to Alzheimer's disease (AD) vascular pathology. The XmnI polymorphism (C-->T) at -158 of the gamma (G)-globin promoter region can contribute to increased Hb F expression. Using family-based association testing, we found a significant protective association of this polymorphism in the NIMH sibling dataset (n=489) in families, with at least two affected and one unaffected sibling (p=0.006), with an age of onset >50 years (p=0.010) and >65 years (p=0.013), and families not homozygous for the APOE4 allele (p=0.041). We hypothesize that Hb F may be less toxic than adult Hb in its interaction with A beta and may protect against the development of AD.

Perry RT, Wiener H, Harrell LE, Blacker D, Tanzi RE, Bertram L, Bassett SS, Go RC. · Department of Epidemiology and International Health, University of Alabama at Birmingham, Birmingham, Alabama 35294-0022, USA. · Am J Med Genet B Neuropsychiatr Genet. · Pubmed #17034007 No free full text.

Abstract: Other than the APOE peak at 19q13, the 9q22 region was identified in our original genomic scan as the candidate region with the highest multipoint lod score (MLS) in the subset of late onset Alzheimer's Disease (AD) families (MLS = 2.9 at 101 cM) from the NIMH Genetics Initiative sample. We have now genotyped an additional 12 short tandem repeats (STR) in this region. Multipoint analysis shows the region remains significant with an increase in the peak MLS from 2.9 to 3.8 at 95 cM near marker D9S1815, and the 1 LOD interval narrows from 21.5 to 11 cM. HLOD scores also provide evidence for significant linkage (4.5 with an alpha = 31%) with a further narrowing of the region to 6.6 cM (92.2-98.8 cM). Single nucleotide polymorphisms (SNPs) in the Ubiquilin1 gene (UBQLN1), located at 83.3 cM, have been reported to be significantly associated to AD, accounting for a substantial portion of the original linkage signal [Bertram et al., 2005]. Our analyses of the higher resolution genotype data generated here provide further support for the existence of a least one additional locus on chromosome 9q22. In an effort to pinpoint this putative AD susceptibility gene, we have begun to analyze SNPs in other candidate genes in and around this narrowed region to test for additional associations to AD.

Bassett SS, Avramopoulos D, Perry RT, Wiener H, Watson B, Go RC, Fallin MD. · Department of Psychiatry, Johns Hopkins University, Baltimore, Maryland, USA. · Am J Med Genet B Neuropsychiatr Genet. · Pubmed #16741936 links to  free full text

Abstract: The chromosome 10q region has recently received a great deal of attention in late-onset Alzheimer's disease (LOAD), given the growing evidence of linkage to LOAD, or to A-beta levels, reported by several groups. In a recent paper we reported evidence of linkage in this region in our subset of the NIMH AD genetics initiative pedigrees, approaching genome-wide significance (non-parametric LOD score = 3.27), when only families with maternal disease origin were analyzed [Bassett et al. (2002); Am J Med Genet 114:679-686]. We have now extended this work, using an independent subset of NIMH AD pedigrees from the University of Alabama at Birmingham (UAB), and show further evidence of linkage using parent-of-origin information. As in our Hopkins sample, maternal but not paternal pedigrees show significantly increased linkage in the chromosome 10q region compared to the unstratified sample. Combining data from our previous fine-mapping work on this region and five new markers genotyped in all pedigrees results in a non-parametric LOD score of 3.73 in the same region, a value that reaches genome wide significance for linkage, with an empirical P value = 0.003. These results support our earlier findings and narrow the region of interest. In combination with findings from other groups, these results provide further evidence that this chromosome 10 region harbors a gene implicated in LOAD, and our use of parent-of-origin information has been useful in further narrowing the region of interest.

Dickson MR, Perry RT, Wiener H, Go RC. · Department of Epidemiology and International Health, University of Alabama at Birmingham, Birmingham, AL 35294-0022, USA. · Am J Med Genet B Neuropsychiatr Genet. · Pubmed #16082716 No free full text.

Abstract: Substantial laboratory evidence suggests Transforming Growth Factor-beta1 (TGFB1) is linked to Alzheimer's Disease (AD) pathology. The purpose of the study was to estimate the genetic association of TGFB1 with AD while controlling for apolipoprotein E4 allele (APOE4) status, the only well-established genetic risk factor for AD. Two study populations were genotyped for the TGFB1-509 and +869 single nucleotide polymorphisms (SNPs) that have been associated with TGFB1 levels. Constituting these populations were 203 families from the NIMH AD Genetic Initiative with at least two affected siblings and a normal sibling, and a population of 126 African-American (AA) AD cases versus 93 age matched controls. Results from family-based analyses showed a significant association between the TGFB1 -509 SNP and AD for the entire set of 203 families (P = 0.007), and a subset of these families without a homozygous APOE4 family member (P = 0.026). Results from family-based analyses on the TGFB1 +869 SNP were not significant in the 203 families. While associations for the main effects of the TGFB1 +869 and -509 SNP with AD in the AA case-control study were also not significant, results did indicate that TGFB1 may function as an effect modifier of APOE4 risk. Specifically, the odds of AD associated with having at least one APOE4 allele increased in an additive fashion with one or two copies of the higher producer allele when stratified by TGFB1 -509 genotype and by TGFB1 +869 genotype. Results support a role for TGFB1 in AD pathogenesis.

Go RC, Perry RT, Wiener H, Bassett SS, Blacker D, Devlin B, Sweet RA. · University of Alabama at Birmingham, Birmingham, AL 35294, USA. · Am J Med Genet B Neuropsychiatr Genet. · Pubmed #16082692 No free full text.

Abstract: Probands with late onset Alzheimer's disease (LOAD) exhibit positive symptoms of psychosis, 30-60% of the time. Positive symptoms of psychosis have been shown to appear prior to the onset of dementia to be accompanied by greater cognitive deficits, and to predict a more rapid decline. A study of the distribution of AD with psychosis (ADP) in families from the NIMH Alzheimer's Disease Genetic Initiative sample indicates that the trait is heritable, and linkage studies of multiplex ADP families have found suggestive peaks on 2p, 6q, 8p, and 21q. A genome scan of idiopathic psychosis, schizophrenia, in the Icelandic population identified a risk haplotype within the 5' region of neuregulin-1 (NRG1) on 8p12. Associations with NRG1 SNPs have also been found in other schizophrenia populations from Scotland, Ireland, and China. Here, we report results demonstrating a significant linkage peak for ADP on 8p12 in the NIMH AD dataset, encompassing the NRG1 region. We also demonstrate that there is a significant association with a NRG1 SNP (single nucleotide polymorphism), rs392499, with ADP, chi2 = 7.0, P = 0.008. This same SNP is part of a 3-SNP haplotype preferentially transmitted to individuals with this phenotype. Our results suggest that NRG1 plays a role in increasing the genetic risk to positive symptoms of psychosis in a proportion of LOAD families.

Saunders AJ, Bertram L, Mullin K, Sampson AJ, Latifzai K, Basu S, Jones J, Kinney D, MacKenzie-Ingano L, Yu S, Albert MS, Moscarillo TJ, Go RC, Bassett SS, Daly MJ, Laird NM, Wang X, Velicelebi G, Wagner SL, Becker DK, Tanzi RE, Blacker D. · Genetics and Aging Research Unit, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. · Hum Mol Genet. · Pubmed #12966032 links to  free full text

Abstract: Alpha-2-Macroglobulin (A2M) is a highly plausible candidate gene for Alzheimer's disease (AD) in a region of chromosome 12 that has numerous independent reports of genetic linkage. We previously reported that a 5 bp deletion in A2M was associated with AD in a subset of the National Institute of Health (NIMH) Genetics Initiative AD family sample. Efforts to replicate this association finding in case - control samples have been largely negative, while those in family samples have been more positive. We hypothesized that variable findings regarding this deletion, along with variable reports of association with V1000I, another polymorphism in the gene, result from linkage disequilibrium in the area as well as ascertainment differences between family-based and case-control studies. Thus, we resequenced the A2M locus to identify novel polymorphisms to test for genetic association with AD. We identified seven novel polymorphisms and tested them in the full NIMH sample of 1439 individuals in 437 families. We found significant genetic association of the 5 bp deletion and two novel polymorphisms with AD. Substantial linkage disequilibrium was detected across the gene as a whole, and haplotype analysis also showed significant association between AD and groups of A2M polymorphisms. Several of these polymorphisms and haplotypes remain significantly associated with AD even after correction for multiple testing. Taken together, these findings, and the positive reports in other family-based studies, continue to support a potential role for A2M or a nearby gene in AD. However, the negative case - control studies suggest that any underlying pathogenic polymorphisms have a modest effect, and may operate primarily among individuals with a family history of AD.

Blacker D, Bertram L, Saunders AJ, Moscarillo TJ, Albert MS, Wiener H, Perry RT, Collins JS, Harrell LE, Go RC, Mahoney A, Beaty T, Fallin MD, Avramopoulos D, Chase GA, Folstein MF, McInnis MG, Bassett SS, Doheny KJ, Pugh EW, Tanzi RE, Anonymous00039. · Massachusetts General Hospital, Charlestown, MA, USA. · Hum Mol Genet. · Pubmed #12490529 links to  free full text

Abstract: Alzheimer's disease (AD) is a devastating neurodegenerative disorder of late life with complex inheritance. Mutations in three known genes lead to the rare early-onset autosomal dominant form of AD, while a common polymorphism (epsilon 4) in the gene encoding apolipoprotein E (APOE ) is a risk factor for more typical late-onset (>60 years) AD. A recent study concluded that there are up to four additional genes with an equal or greater contribution to the disease. We performed a 9 cM genome screen of 437 families with AD, the full National Institute of Mental Health (NIMH) sample, which has been carefully ascertained, evaluated and followed by our group over the last decade. Performing standard parametric and non-parametric linkage analyses, we observed a 'highly significant' linkage peak by Lander and Kruglyak criteria on chromosome 19q13, which probably represents APOE. Twelve additional locations-on 1q23, 3p26, 4q32, 5p14, 6p21, 6q27, 9q22, 10q24, 11q25, 14q22, 15q26 and 21q22-met criteria for 'suggestive' linkage [i.e. two-point lod score (TLS) >/=1.9 and/or multipoint lod score (MLS) >/=2.2] in at least one of our analyses. Although some of these will surely prove to be false positives, these linkage signals should provide a valuable framework for future studies aimed at identifying additional susceptibility genes for late-onset AD.

Graff-Radford NR, Green RC, Go RC, Hutton ML, Edeki T, Bachman D, Adamson JL, Griffith P, Willis FB, Williams M, Hipps Y, Haines JL, Cupples LA, Farrer LA. · Genetics Program L-320, Boston University School of Medicine, 715 Albany St, Boston, MA 02118, USA. · Arch Neurol. · Pubmed #11939894 links to  free full text

Abstract: BACKGROUND: The association between Alzheimer disease (AD) and genotypes at the apolipoprotein E (APOE) locus has been confirmed in numerous populations worldwide, but appears to be inconsistent in African American subjects. OBJECTIVE: To investigate the association between APOE genotypes and AD in elderly African American subjects. DESIGN: Clinic-based, multicenter case-control study and a family study. PARTICIPANTS: A total of 338 African American probands meeting criteria for probable or definite AD, 301 cognitively healthy, elderly unrelated control subjects (spouses and community volunteers), and 108 siblings of 88 AD probands. MAIN OUTCOME MEASURES: Odds of AD according to APOE genotype. RESULTS: Compared with individuals with the APOEepsilon3/epsilon3, the odds of having AD were significantly increased among those with 1 or more copies of the epsilon4 allele; the odds ratio (OR) for the epsilon3/epsilon4 genotype was 2.6 (95% confidence interval [CI], 1.8-3.7), and the OR for the epsilon4/epsilon4 genotype was 10.5 (95% CI, 5.1-21.8). These risks decreased substantially after 68 years of age. The risk for AD was lower among individuals with the epsilon2/epsilon3 genotype (OR, 0.41; 95% CI, 0.22-0.79). The patterns of association were similar in men and women. These results obtained from comparisons of unrelated AD patients and controls were bolstered by results of analysis of family data that showed preferential transmission of the epsilon4 allele to demented siblings (P<<.001) and of the epsilon2 allele to nondemented siblings (P=.005). CONCLUSIONS: The presence of 1 or 2 epsilon4 alleles is a determinant of AD risk in African American subjects. The age-related risk for decline associated with the epsilon4 allele and the apparent protective effect of the epsilon2 allele are similar to patterns observed in white subjects.

Perry RT, Collins JS, Harrell LE, Acton RT, Go RC. · Department of Epidemiology and International Health, University of Alabama at Birmingham, 35294, USA. · Am J Med Genet. · Pubmed #11378846 No free full text.

Abstract: Alzheimer disease (AD) is an emotionally devastating and exceptionally costly disease. Apolipoprotein E (APOE) is a major risk factor gene for AD regardless of age of onset or family history. However, this association may not be as strong or consistent in ethnic groups such as African Americans, raising the possibility of other modifier gene(s). In a group of African American AD patients, a significantly increased risk of AD was associated with two E4 alleles (OR = 5.6; 95% CI = 1.5-21.0) or one E4 allele (OR = 2.5; 95% CI = 1.3-5.0) when compared to E3/E3 genotype, and there was a significant lowering of age of onset for affecteds with E4/E4 genotype as compared to one E2 allele (P = 0.02) or all others (P = 0.03). We also found a significant increase in age of onset with the -308 #2 (A) allele of TNF when compared to AD cases with no #2 allele. A significant increase in age was also demonstrated with the #2 allele (99 base pairs) of the microsatellite TNFa, located approximately 10.5 kb upstream of TNF. When these two alleles were combined with the TNF -238G (#1) allele to give a haplotype, the significant increase in age was still demonstrated. Polymorphisms in the APOE promoter and six other candidate genes did not appear to demonstrate any significant association with our African American AD patients. Our results confirm the established association of APOE4 to AD observed in several ethnic groups, including African Americans. In addition, TNF appears to have some modifying effect in AD, primarily on age of onset, or it could be in linkage disequilibrium with a modifier locus nearby.

Bertram L, Blacker D, Mullin K, Keeney D, Jones J, Basu S, Yhu S, McInnis MG, Go RC, Vekrellis K, Selkoe DJ, Saunders AJ, Tanzi RE. · Genetics and Aging Unit, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. · Science. · Pubmed #11125142 links to  free full text

Abstract: Recent studies suggest that insulin-degrading enzyme (IDE) in neurons and microglia degrades Abeta, the principal component of beta-amyloid and one of the neuropathological hallmarks of Alzheimer's disease (AD). We performed parametric and nonparametric linkage analyses of seven genetic markers on chromosome 10q, six of which map near the IDE gene, in 435 multiplex AD families. These analyses revealed significant evidence of linkage for adjacent markers (D10S1671, D10S583, D10S1710, and D10S566), which was most pronounced in late-onset families. Furthermore, we found evidence for allele-specific association between the putative disease locus and marker D10S583, which has recently been located within 195 kilobases of the IDE gene.

Collins JS, Perry RT, Watson B, Harrell LE, Acton RT, Blacker D, Albert MS, Tanzi RE, Bassett SS, McInnis MG, Campbell RD, Go RC. · Department of Epidemiology and International Health, University of Alabama at Birmingham, Birmingham, Alabama 35294-0022, USA. · Am J Med Genet. · Pubmed #11121190 No free full text.

Abstract: Tumor necrosis factor (TNF), a proinflammatory cytokine, may be involved in the pathogenesis of Alzheimer disease (AD) based on observations that senile plaques have been found to upregulate proinflammatory cytokines. Additionally, nonsteroidal anti-inflammatory drugs have been found to delay and prevent the onset of AD. A collaborative genome-wide scan for AD genes in 266 late-onset families implicated a 20 centimorgan region at chromosome 6p21.3 that includes the TNF gene. Three TNF polymorphisms, a -308 TNF promoter polymorphism, whose TNF2 allele is associated with autoimmune inflammatory diseases and strong transcriptional activity, the -238 TNF promoter polymorphism, and the microsatellite TNFa, whose 2 allele is associated with a high TNF secretion, were typed in 145 families consisting of 562 affected and unaffected siblings. These polymorphisms formed a haplotype, 2-1-2, respectively, that was significantly associated with AD (P = 0.005) using the sibling disequilibrium test. Singly, the TNFa2 allele was also significantly associated (P = 0.04) with AD in these 145 families. This TNF association with AD lends further support for an inflammatory process in the pathogenesis of AD. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:823-830, 2000.

Buxbaum JD, Lilliehook C, Chan JY, Go RC, Bassett SS, Tanzi RE, Wasco W, Blacker D. · Department of Psychiatry, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1230, New York, NY 10029, USA. · Neurosci Lett. · Pubmed #11072133 No free full text.

Abstract: Calsenilin is a recently-identified member of the neuronal calcium sensor family. Like other members of this family, it is found in the brain and binds calcium. Calsenilin was discovered by virtue of its interaction with both presenilin-1 and -2, proteins that are involved in the etiology of Alzheimer's disease. Because calsenilin may play a role in Alzheimer's disease and other disease with alterations in calcium homeostasis, we characterized the human gene. The gene, which we localized to chromosome 2, extends over a region of at least 74 kb and includes nine exons. Interestingly, the ninth exon of calsenilin contains a highly polymorphic CA repeat, adjacent to the stop codon. In a study of Alzheimer patients and their unaffected siblings, there was no evidence of association of AD with any calsenilin allele. This CA repeat will be useful for linkage and linkage disequilibrium studies to determine whether calsenilin variants contribute to risk in other diseases.

Guo Z, Cupples LA, Kurz A, Auerbach SH, Volicer L, Chui H, Green RC, Sadovnick AD, Duara R, DeCarli C, Johnson K, Go RC, Growdon JH, Haines JL, Kukull WA, Farrer LA. · Department of Medicine, Boston University School of Medicine, MA 02118, USA. · Neurology. · Pubmed #10746604 No free full text.

Abstract: OBJECTIVES: It has been suggested in some studies that head injury is a risk factor for AD, and that this risk is heightened among carriers of the APOE-epsilon4 allele. We examined the effects of head injury and APOE genotype on AD risk in a large family study. SUBJECTS: A total of 2,233 probands who met criteria for probable or definite AD and their 14,668 first-degree family members (4,465 parents, 7,694 siblings, and 2,509 spouses) were ascertained at 13 centers in the United States, Canada, and Germany participating in the MIRAGE (Multi-Institutional Research in Alzheimer Genetic Epidemiology) project. Information on head injury was collected by interview of multiple informants and review of medical records. Nondemented relatives and spouses served as control subjects for this study. METHODS: Odds of AD for head trauma with or without loss of consciousness were computed by comparing probands with unaffected spouses using conditional logistic regression analysis. To account for the unique biologic relationship between probands and their parents and siblings, odds of AD were computed using a generalized estimating equation (GEE) Poisson regression approach. GEE logistic regression was used to examine the joint effects of APOE genotype and head injury on the odds of AD in probands and a control group comprised of unaffected siblings and spouses. RESULTS: Comparison of probands with their unaffected spouses yielded odds ratios for AD of 9.9 (95% CI, 6.5 to 15.1) for head injury with loss of consciousness and 3.1 (2.3 to 4.0) for head injury without loss of consciousness. The corresponding odds derived from the comparison of probands with their parents and sibs were 4.0 (2.9 to 5.5) for head injury with loss of consciousness and 2.0 (1.5 to 2.7) for head injury without loss of consciousness. Head injury without loss of consciousness did not significantly increase the risk of AD in spouses (OR = 1.3; 95% CI, 0.4 to 4.1). The joint effects of head injury and APOE genotype were evaluated in a subsample of 942 probands and 327 controls (spouses and siblings). Head injury increased the odds of AD to a greater extent among those lacking epsilon4 (OR = 3.3) than among epsilon4 heterozygotes (OR = 1.8) or homozygotes (OR = 1.3). CONCLUSION: Head injury is a risk factor for AD. The magnitude of the risk is proportional to severity and heightened among first-degree relatives of AD patients. The influence of head injury on the risk of AD appears to be greater among persons lacking APOE-epsilon4 compared with those having one or two epsilon4 alleles, suggesting that these risk factors may have a common biologic underpinning.

Bertram L, Saunders AJ, Mullin K, Sampson A, Moscarillo TJ, Basset SS, Go RC, Blacker D, Tanzi RE. · No affiliation provided · Mol Psychiatry. · Pubmed #12851634 No free full text.

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