Alzheimer Disease: Bassett SS

Su SC, Caffo B, Garrett-Mayer E, Bassett SS. · Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, 615 North Wolfe Street, Baltimore, MD 21205-2179, USA. · Biostatistics. · Pubmed #18723853 No free full text.

Abstract: Functional magnetic resonance imaging (f MRI) is a noninvasive technique which is commonly used to quantify changes in blood oxygenation and flow coupled to neuronal activation. One of the primary goals of f MRI studies is to identify localized brain regions where neuronal activation levels vary between groups. Single voxel t-tests have been commonly used to determine whether activation related to the protocol differs across groups. Due to the generally limited number of subjects within each study, accurate estimation of variance at each voxel is difficult. Thus, combining information across voxels is desirable in order to improve efficiency. Here, we construct a hierarchical model and apply an empirical Bayesian framework for the analysis of group f MRI data, employing techniques used in high-throughput genomic studies. The key idea is to shrink residual variances by combining information across voxels and subsequently to construct an improved test statistic. This hierarchical model results in a shrinkage of voxel-wise residual sample variances toward a common value. The shrunken estimator for voxel-specific variance components on the group analyses outperforms the classical residual error estimator in terms of mean-squared error. Moreover, the shrunken test statistic decreases false-positive rates when testing differences in brain contrast maps across a wide range of simulation studies. This methodology was also applied to experimental data regarding a cognitive activation task.

Yassa MA, Verduzco G, Cristinzio C, Bassett SS. · Department of Psychiatry and Behavioral Sciences, Johns Hopkins Medical Institutions, Johns Hopkins Hospital, Phipps 300, 600 North Wolfe Street, Baltimore, MD 21287, USA. · Neurology. · Pubmed #18474845 links to  free full text

Abstract: OBJECTIVE: This study was undertaken to examine differential functional MRI patterns in those at genetic risk for Alzheimer disease (AD), specifically investigating parietal lobe activation, a brain region with changes noted in the early stages of AD. METHODS: This study uses functional MRI to investigate blood oxygenation level dependent changes in the parietal lobe in a high-risk sample of 18 asymptomatic offspring of autopsy-confirmed AD cases, compared to 15 matched controls. The cognitive activation paradigm was a mental rotation task, which requires individuals to rotate three-dimensional cube stimuli to judge their similarity. RESULTS: We found no differences in either reaction time or performance accuracy between groups. However, the at-risk individuals showed increases in activation in the right superior parietal lobule (BA 7), the right insula (BA 13), the right middle frontal gyrus (BA 10), and the right inferior frontal gyrus (BA 47). CONCLUSIONS: We present evidence for a compensatory mechanism for those at increased risk for Alzheimer disease (AD). This study examines and confirms parietal changes with increased risk for late-onset AD, despite normal cognitive performance. Added to the previous findings from this group, these results demonstrate the sensitivity of functional imaging measures to brain changes that are not yet reflected in cognitive performance, which may ultimately serve as an important indicator of disease.

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.

Hamshere ML, Holmans PA, Avramopoulos D, Bassett SS, Blacker D, Bertram L, Wiener H, Rochberg N, Tanzi RE, Myers A, Wavrant-De Vrièze F, Go R, Fallin D, Lovestone S, Hardy J, Goate A, O'Donovan M, Williams J, Owen MJ. · Biostatistics and Bioinformatics Unit, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK. · Hum Mol Genet. · Pubmed #17725986 links to  free full text

Abstract: Previous attempts to identify genetic loci conferring risk for late-onset Alzheimer's disease (LOAD) through linkage analysis have observed some regions of linkage in common. However, due to the sometimes-considerable overlap between the samples, some of these reports cannot be considered to be independent replications. In order to assess the strength of the evidence for linkage and to obtain the best indication of the location of susceptibility genes, we have amalgamated three large samples to give a total of 723 affected relative pairs (ARPs). Multipoint, model-free ARP linkage analysis was performed. Genome-wide significant evidence for linkage was observed on 10q21.2 (LOD=3.3) and genome-wide suggestive evidence was observed on 9q22.33 (LOD=2.5) and 19q13.32 (LOD=2.0). One further region on 9p21.3 was identified with an LOD score>1. We observe no evidence to suggest that more than one locus is responsible for the linkage to 10q21.2, although this linked region may harbour more than one susceptibility gene. Evidence of allele-sharing heterogeneity between the original collection sites was observed on chromosome 9 but not on chromosome 10 or 19. Evidence for an interaction was observed between loci on chromosomes 10 and 19. Where samples overlapped, the genotyping consistency was high, estimated to average at 97.3%. Our large-scale linkage analysis consolidates clear evidence for a susceptibility locus for LOAD on 10q21.2.

Avramopoulos D, Wang R, Valle D, Fallin MD, Bassett SS. · Department of Psychiatry, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA. · Neurogenetics. · Pubmed #17334805 No free full text.

Abstract: Alzheimer's disease (AD) is a disabling neurodegenerative disorder with onset commonly in late life. Three genes have been identified causing earlier onset AD, and a fourth has been shown to be a risk factor for late onset AD (LOAD), while many more yet unrecognized genes are thought to contribute to susceptibility. Many studies have reported linkage to LOAD on human chromosome 10, where we have identified a parent of origin effect [Bassett SS, Avramopoulos D, Perry RT, Wiener H, Watson B Jr, Go RC, Fallin MD. Am J Med Genet B Neuropsychiatr Genet 141:537-540, (2006), Bassett SS, Avramopoulos D, Fallin D. Am J Med Genet 114:679-686, (2002)]. In this paper, we report on a gene in this region that shows reduced expression with increasing age, reduced expression in females across ages, and further reduction in LOAD patients. In concordance with the observed parent of origin effect on the linkage, this reduction is more pronounced in patients with an affected mother. We discovered this gene while studying the alkaline ceramidase gene (ASAH2); it is a partial paralog of ASAH2, and we call it ASAH2L. It is the result of a partial duplication of ASAH2 on chromosome 10q11.23, just downstream from the sequence with promoter activity. ASAH2L has a polymorphic start codon with a single nucleotide change of the original ASAH2 sequence plus other putative translation start sites that might produce novel proteins. It is expressed in all the tissues we tested including the brain and is an interesting example of the generation of a new gene. Comparison of primate and other mammal genomes suggests that ASAH2L is human specific. Further research would be necessary to determine the function of the ASAH2L transcript and explore any possible involvement in neurodegeneration.

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.

Avramopoulos D, Zandi P, Gherman A, Fallin MD, Bassett SS. · Department of Psychiatry, The Johns Hopkins University, School of Medicine, Broadway Research Building 509, 733 North Broadway, Baltimore, MD 21205, USA. · Hum Genomics. · Pubmed #16848972 No free full text.

Abstract: Genes for complex disorders have proven hard to find using linkage analysis. The results rarely reach the desired level of significance and researchers often have failed to replicate positive findings. There is, however, a wealth of information from other scientific approaches which enables the formation of hypotheses on groups of genes or genomic regions likely to be enriched in disease loci. Examples include genes belonging to specific pathways or producing proteins interacting with known risk factors, genes that show altered expression levels in patients or even the group of top scoring locations in a linkage study. We show here that this hypothesis of enrichment for disease loci can be tested using genome-wide linkage data, provided that these data are independent from the data used to generate the hypothesis. Our method is based on the fact that non-parametric linkage analyses are expected to show increased scores at each one of the disease loci, although this increase might not rise above the noise of stochastic variation. By using a summary statistic and calculating its empirical significance, we show that enrichment hypotheses can be tested with power higher than the power of the linkage scan data to identify individual loci. Via simulated linkage scans for a number of different models, we gain insight in the interpretation of genome scan results and test the power of our proposed method. We present an application of the method to real data from a late-onset Alzheimer's disease linkage scan as a proof of principle.

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.

Bassett SS, Yousem DM, Cristinzio C, Kusevic I, Yassa MA, Caffo BS, Zeger SL. · Department of Psychiatry, School of Medicine, Johns Hopkins University, Baltimore, MD, USA. · Brain. · Pubmed #16627465 links to  free full text

Abstract: Alzheimer's disease poses a looming crisis for the health care system as well as society in general. The low efficacy of current treatments for those already affected with this disease has prompted the suggestion that interventions might be more successful if they were applied before the development of significant pathology, that is, when individuals are clinically asymptomatic. Currently, the field requires a sensitive and specific diagnostic tool for identifying those individuals destined to develop this disease. As a first step, we present here an analysis of cross-sectional data for 95 asymptomatic offspring (50-75 years of age) of autopsy-confirmed late-onset familial Alzheimer's disease cases and 90 age-matched controls, studied with functional magnetic resonance imaging (fMRI) to investigate brain activation patterns. Analysis of activation in response to a paired-associates memory paradigm found significantly different patterns in these groups. At-risk individuals showed more intense and extensive activation in the frontal and temporal lobes including the hippocampus during memory encoding, an increase unrelated to the APOE epsilon4 allele. They also showed decreased activation particularly in the cingulum and thalamus during both the encoding and recall phases of the task. These results demonstrate that asymptomatic individuals, at genetic risk for development of late-onset Alzheimer's disease by virtue of familial clustering, show functional activation patterns distinct from those without such risk more than a decade before their parent's onset age. While longitudinal study is needed to determine whether these patterns, or a subset of them, are predictive of disease onset, these findings suggest that functional neuroimaging holds promise as a method of identifying pre-clinical Alzheimer's disease.

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.

Bassett SS, Kusevic I, Cristinzio C, Yassa MA, Avramopoulos D, Yousem DM, Fallin MD. · Department of Psychiatry, School of Medicine, Johns Hopkins University, Baltimore, MD 21287, USA. · Ann Neurol. · Pubmed #15984011 links to  free full text

Abstract: Previously, we reported evidence of genetic heterogeneity in late-onset familial Alzheimer's disease, based on sex of affected parent, demonstrating linkage to chromosome 10q, a region identified by other groups and implicated as a quantitative trait loci for Abeta levels, in families with an affected mother. Using functional magnetic resonance imaging and a memory encoding task, we now show differential brain activation patterns among asymptomatic offspring which correspond to the previous linkage finding. These results suggest the possibility that activation patterns may prove useful as a preclinical quantitative trait related to the putative familial late-onset AD gene in this chromosome 10 region.

Avramopoulos D, Fallin MD, Bassett SS. · The Johns Hopkins University, Department of Psychiatry, School of Medicine, Meyer 4 Room 139, 600 N. Wolfe St, Baltimore, MD 21287, USA. · Am J Med Genet B Neuropsychiatr Genet. · Pubmed #15389761 No free full text.

Abstract: Cases of early onset AD have been attributed to three genes, PSEN1, PSEN2, and APP, while the only gene consistently associated with late onset AD (LOAD) is APOE. Several genome scans have now been performed for LOAD with inconsistent findings in several genomic regions, possibly reflecting the underlying genetic heterogeneity. Many lines of evidence suggest that the absence or presence of psychotic symptoms, common in AD, might delineate distinct etiologic disease subtypes. We have performed a genome scan of 148 AD pedigrees (ages of onset more than 50 years) including the presence or absence of delusions and hallucinations as covariates. This approach identified linkage to a locus on chromosome 14q24.3, close to the PSEN1 locus (LOD score 3.91; genome-wide empirical P = 0.052), derived from individuals that do not have co-morbid hallucinations. The finding appears stronger (LOD score 5.74; genome-wide empirical P = 0.048) in families that include younger affected members (AAO between 50 and 65 years), however it is not present without the inclusion of the covariate and we observe no correlation between the presence of hallucinations and the age of onset. A mutation screen of PSEN1 did not detect any coding region or splice site mutations. This linkage finding suggests the presence of a gene causing AD without co-morbid hallucinations and with an earlier (yet not early) age at onset (AAO) in the 14q24 region. This region requires further study to replicate the finding and identify the genetic variant responsible for the linkage.

Bassett SS, Havstad SL, Chase GA. · Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. · Genet Test. · Pubmed #15345108 No free full text.

Abstract: A survey questionnaire regarding perceptions of risk and genetic susceptibility to Alzheimer's disease (AD) was completed by 518 offspring of AD cases from families with multiple affected, ascertained as part of a genetic linkage study of late onset AD. The questionnaire focused on respondents' perceptions of their own risk for AD as well as on the properties of real and hypothetical susceptibility tests, including error rates for false-positive and false-negative test results. Our findings showed that about 20% of the sample would refuse a susceptibility test with zero error rates, about 40% would accept tests with very high error rates in both directions, and the remainder would exercise some discrimination. Acceptance of high test error rates was significantly associated with male gender, low education, and high perceived lifetime risk of AD. In a previous paper related to this work, we showed that physicians caring for these families exercised much more discrimination in judging the acceptability of genetic tests they would offer to these same respondents. The findings show that there is a pressing need to educate the public, particularly those with relatives affected by a complex disease, to expect standards of accuracy for genetic tests comparable to those that prevail in other diagnostic and prognostic testing efforts in the broad field of clinical medicine.

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.

Bassett SS, Avramopoulos D, Fallin D. · Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Am J Med Genet. · Pubmed #12210287 No free full text.

Abstract: Evidence for a parent of origin effect in Alzheimer disease was obtained from a sample of 148 sibships on which affection status of the parents was sought using family history interviews. The parent study recruited families with two or more affected sibs for late onset AD utilizing rigorous diagnostic criteria. In 74 families, there was evidence of an affected parent, 49 maternal and 25 paternal. Genome scan data were analyzed for the sample as a whole and for the maternal and paternal families separately, using Genehunter-ASM. Seven regions with Z(lr) scores >or=2 were identified, four in maternal families (chr. 10,12,19,20) and three in paternal families (chr. 1,7,13). With the exception of the chromosome 10 finding, analysis by parent of origin greatly increased evidence of linkage in areas showing no linkage in the overall analyses. For example, a chr. 12 region reached a LOD = 2.29 among maternal families whereas the same region showed a LOD = 0.3 when all families were analyzed together. The strongest findings among maternal families (chr. 10 and 12) were followed up with fine mapping that resulted in an increase in maximum LOD scores from 2.7-3.2 on chr. 10, and 2.29-2.42 on chr. 12. These analyses highlight the importance of parent of origin effects in late-onset AD families and identify several genomic regions that may include genes linked to late-onset AD specific to disease transmission from the mother and require further investigation.

Chase GA, Geller G, Havstad SL, Holtzman NA, Bassett SS. · Department of Biostatistics and Research Epidemiology, Henry Ford Health Sciences Center, Johns Hopkins University School of Mediicne, Baltimore, MD, USA. · Genet Med. · Pubmed #12172396 No free full text.

Abstract: PURPOSE: Examine physician knowledge, preferences, and use of genetic tests for Alzheimer's disease (AD). METHODS: Survey of 426 community-based physicians treating AD patients. RESULTS: Majority gave inaccurate estimates of AD risk. Medical specialty predicted appropriate use of current tests. Recommending substances to prevent memory loss was related to acceptance of error-free tests. High patient loads and familiarity with genetic tests predicted lower tolerance for test error. CONCLUSION: Physicians do not endorse indiscriminate genetic susceptibility testing for AD. However, insufficient knowledge of disease risk, etiology, genetic susceptibility, and use of existing tests indicated a need for further physician education in this area.

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.

Bassett SS. · Department of Psychiatry, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21287-5371, USA. · J Geriatr Psychiatry Neurol. · Pubmed #10616868 No free full text.

Abstract: This study was undertaken to examine the relationship between two different competencies, financial and medical decision making, and explore whether neuropsychological testing can identify a common underlying cognitive operation impaired in patients with AD. The objective was to examine the neuropsychological predictors of financial and medical decision-making competencies in patients with Alzheimer's disease (AD). Twenty individuals with mild to moderate AD and 20 control subjects matched for age and education were evaluated at a university medical center. All participants were administered a financial competency questionnaire, a competency test for medical decision making, and a set of standardized neuropsychological tests selected to reflect cognitive processes theoretically related to competency. In addition, an informant provided information regarding banking history for each participant. AD patients performed more poorly on all measures, including both measures of competency, which were highly related (R = .718, P < .001). Two tests, Trails A and Word List Recall, were significantly correlated with both competency measures, with Trails A predicting over 85% of the variance in competency scores. Trails A discriminated competent from not competent participants with an accuracy ranging from 77% to 82%. Measures of financial and medical decision-making competency were significantly correlated among patients with AD. One brief neuropsychological test of attention, Trails A, proved to be highly predictive of performance on both competency measures and useful in the discrimination of competent performance on these measures and by informant report.