Influence of apolipoprotein E genotype on the transmission of Alzheimer disease in a community-based sample.

The epsilon 4 allele of the apolipoprotein E locus (APOE) has been found to be an important predictor of Alzheimer disease (AD). However, linkage analysis has not clarified the role of APOE in the transmission of AD. The results of the current study provide evidence that the pattern of transmission of memory disorders differs in nuclear families in which the AD-affected proband did carry an epsilon 4 allele versus those families in which the AD-affected proband did not carry an epsilon allele. Further, risk of AD due to APOE genotype in the probands is modified by family history of memory disorders, suggesting gene-by-gene interactions. Family history remained a significant predictor of AD for affected probands with some, but not all, APOE genotypes in a logistic regression analysis. Though nonadditive in the prediction of AD, APOE genotype and family history acted additively in the prediction of age at AD onset. The results of complex segregation analysis were inconsistent with Mendelian segregation of memory disorders both in families of affected probands who did or did not carry an epsilon 4 allele, yet these two groups had significantly different parameter estimates for their transmission models. These results are consistent with gene-by-gene interactions, but also could result from common elements in the familial environment.     

A polymorphism in SOD2 is associated with development of Alzheimer's disease

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.     

Multiple etiologies for Alzheimer disease are revealed by segregation analysis.

We have evaluated several transmission models for Alzheimer disease (AD), using the logistic regressive approach in 401 nuclear families of consecutively ascertained and rigorously diagnosed probands. Models postulating no major gene effect, random environmental transmission, recessive inheritance, and sporadic occurrence were rejected under varied assumptions regarding the associations among sex, age, and major gene susceptibility. Transmission of the disorder was not fully explained by a single Mendelian model for all families. Stratification of families as early- and late-onset by using the median of family mean onset ages showed that, regardless of the model studied, two groups of families fit better than a single group. AD in early-onset families is transmitted as an autosomal dominant trait with full penetrance in both sexes and has a gene frequency of 1.5%. Dominant inheritance also gave the best fit of the data in late-onset families, but this hypothesis was rejected, suggesting the presence of heterogeneity within this subset. Our study also revealed that genetically nonsusceptible males and females develop AD, indicating the presence of phenocopies within early-onset and late-onset groups. Moreover, our results suggest that the higher risk to females is not solely due to their increased longevity.     

Fine mapping of the chromosome 12 late-onset Alzheimer disease locus: potential genetic and phenotypic heterogeneity

Apolipoprotein E (APOE) is the only confirmed susceptibility gene for late-onset Alzheimer disease (AD). In a recent genomic screen of 54 families with late-onset AD, we detected significant evidence for a second late-onset AD locus located on chromosome 12 between D12S373 and D12S390. Linkage to this region was strongest in 27 large families with at least one affected individual without an APOE-4 allele, suggesting that APOE and the chromosome 12 locus might have independent effects. We have since genotyped several additional markers across the region, to refine the linkage results. In analyzing these additional data, we have addressed the issue of heterogeneity in the data set by weighting results by clinical and neuropathologic features, sibship size, and APOE genotype. When considering all possible affected sib pairs (ASPs) per nuclear family, we obtained a peak maximum LOD score between D12S1057 and D12S1042. The magnitude and location of the maximum LOD score changed when different weighting schemes were used to control for the number of ASPs contributed by each nuclear family. Using the affected-relative-pair method implemented in GENEHUNTER-PLUS, we obtained a maximum LOD score between D12S398 and D12S1632, 25 cM from the original maximum LOD score. These results indicate that family size influences the location estimate for the chromosome 12 AD gene. The results of conditional linkage analysis by use of GENEHUNTER-PLUS indicated that evidence for linkage to chromosome 12 was stronger in families with affected individuals lacking an APOE-4 allele; much of this evidence came from families with affected individuals with neuropathologic diagnosis of dementia with Lewy bodies (DLB). Taken together, these results indicate that the chromosome 12 locus acts independently of APOE to increase the risk of late-onset familial AD and that it may be associated with the DLB variant of AD.     

Evidence for major gene inheritance of Alzheimer disease in families of patients with and without apolipoprotein E epsilon 4.

Apolipoprotein E (APOE) genotype is the single most important determinant to the common form of Alzheimer disease (AD) yet identified. Several studies show that family history of AD is not entirely accounted for by APOE genotype. Also, there is evidence for an interaction between APOE genotype and gender. We carried out a complex segregation analysis in 636 nuclear families of consecutively ascertained and rigorously diagnosed probands in the Multi-Institutional Research in Alzheimer Genetic Epidemiology study in order to derive models of disease transmission which account for the influences of APOE genotype of the proband and gender. In the total group of families, models postulating sporadic occurrence, no major gene effect, random environmental transmission, and Mendelian inheritance were rejected. Transmission of AD in families of probands with at least one epsilon 4 allele best fit a dominant model. Moreover, single gene inheritance best explained clustering of the disorder in families of probands lacking epsilon 4, but a more complex genetic model or multiple genetic models may ultimately account for risk in this group of families. Our results also suggest that susceptibility to AD differs between men and women regardless of the proband's APOE status. Assuming a dominant model, AD appears to be completely penetrant in women, whereas only 62%-65% of men with predisposing genotypes develop AD. However, parameter estimates from the arbitrary major gene model suggests that AD is expressed dominantly in women and additively in men. These observations, taken together with epidemiologic data, are consistent with the hypothesis of an interaction between genes and other biological factors affecting disease susceptibility.     

Genome-wide association analysis reveals putative Alzheimer's disease susceptibility loci in addition to APOE

Alzheimer's disease (AD) is a genetically complex and heterogeneous disorder. To date four genes have been established to either cause early-onset autosomal-dominant AD (APP, PSEN1, and PSEN2(1-4)) or to increase susceptibility for late-onset AD (APOE5). However, the heritability of late-onset AD is as high as 80%, (6) and much of the phenotypic variance remains unexplained to date. We performed a genome-wide association (GWA) analysis using 484,522 single-nucleotide polymorphisms (SNPs) on a large (1,376 samples from 410 families) sample of AD families of self-reported European descent. We identified five SNPs showing either significant or marginally significant genome-wide association with a multivariate phenotype combining affection status and onset age. One of these signals (p = 5.7 x 10(-14)) was elicited by SNP rs4420638 and probably reflects APOE-epsilon4, which maps 11 kb proximal (r2 = 0.78). The other four signals were tested in three additional independent AD family samples composed of nearly 2700 individuals from almost 900 families. Two of these SNPs showed significant association in the replication samples (combined p values 0.007 and 0.00002). The SNP (rs11159647, on chromosome 14q31) with the strongest association signal also showed evidence of association with the same allele in GWA data generated in an independent sample of approximately 1,400 AD cases and controls (p = 0.04). Although the precise identity of the underlying locus(i) remains elusive, our study provides compelling evidence for the existence of at least one previously undescribed AD gene that, like APOE-epsilon4, primarily acts as a modifier of onset age.     

Phenotypical difference of Amyloid Precursor Protein (APP) V717L mutation in Japanese family

ABSTRACT: BACKGROUND: Alzheimer's disease (AD) is the most common form of dementia. Mutations in genes such as those encoding amyloid precursor protein (APP), presenilin 1 and presenilin 2, are responsible for early-onset familial AD.Case presentation In this study, we report a 275341 G > C (Val717Leu) mutation in the APP gene in a Japanese family with early onset AD by genetic screening. This mutation has previously been detected in European families. In the Japanese family we screened, the age at onset of AD was 47.1 +/- 3.1 years old (n = 9; range, 42-52). The symptoms in the affected members included psychiatric vulnerability and focal signs such as pyramidal signs, epileptic seizures, and myoclonic discharges. An MR imaging study showed relatively mild atrophic changes in the bilateral hippocampus and cerebral cortices in all affected members compared with their clinical presentations. CONCLUSION: We conclude that the clinical features of Alzheimer's disease can be different even when caused by the same mutation in the APP gene. Further clinical and genetic studies are required to clarify the relationship between phenotypes and genotypes.     

Detection of significant disease risks using a spatial conditional autoregressive model

SUMMARY: The conditional autoregressive (CAR) model is widely used to describe the geographical distribution of a specific disease risk in lattice mapping. Successful developments based on frequentist and Bayesian procedures have been extensively applied to obtain two-stage disease risk predictions at the subregional level. Bayesian procedures are preferred for making inferences, as the posterior standard errors (SE) of the two-stage prediction account for the variability in the variance component estimates; however, some recent work based on frequentist procedures and the use of bootstrap adjustments for the SE has been undertaken. In this article we investigate the suitability of an analytical adjustment for disease risk inference that provides accurate interval predictions by using the penalized quasilikelihood (PQL) technique to obtain model parameter estimates. The method is a first-order approximation of the naive SE based on a Taylor expansion and is interpreted as a conditional measure of variability providing conditional calibrated prediction intervals, given the data. We conduct a simulation study to demonstrate how the method can be used to estimate the specific subregion risk by interval. We evaluate the proposed methodology by analyzing the commonly used example data set of lip cancer incidence in the 56 counties of Scotland for the period 1975-1980. This evaluation reveals a close similarity between the solutions provided by the method proposed here and those of its fully Bayesian counterpart.     

Family‐based genome scan for age at onset of late‐onset Alzheimer's disease in whole exome sequencing data

Alzheimer's disease (AD) is a common and complex neurodegenerative disease. Age at onset (AAO) of AD is an important component phenotype with a genetic basis, and identification of genes in which variation affects AAO would contribute to identification of factors that affect timing of onset. Increase in AAO through prevention or therapeutic measures would have enormous benefits by delaying AD and its associated morbidities. In this paper, we performed a family‐based genome‐wide association study for AAO of late‐onset AD in whole exome sequence data generated in multigenerational families with multiple AD cases. We conducted single marker and gene‐based burden tests for common and rare variants, respectively. We combined association analyses with variance component linkage analysis, and with reference to prior studies, in order to enhance evidence of the identified genes. For variants and genes implicated by the association study, we performed a gene‐set enrichment analysis to identify potential novel pathways associated with AAO of AD. We found statistically significant association with AAO for three genes (WRN, NTN4 and LAMC3) with common associated variants, and for four genes (SLC8A3, SLC19A3, MADD and LRRK2) with multiple rare‐associated variants that have a plausible biological function related to AD. The genes we have identified are in pathways that are strong candidates for involvement in the development of AD pathology and may lead to a better understanding of AD pathogenesis.     

The amyloid precursor protein locus and very-late-onset Alzheimer disease

Although mutations in the amyloid-beta precursor protein (APP) gene are known to confer high risk of Alzheimer disease (AD) to a small percentage of families in which it has early onset, convincing evidence of a major role for the APP locus in late-onset AD has not been forthcoming. In this report, we have used a covariate-based affected-sib-pair linkage method to analyze the chromosome 21 clinical and genetic data obtained on affected sibships by the National Institute of Mental Health Alzheimer Disease Genetics Initiative. The baseline model (without covariates) gave a LOD score of 0.02, which increases to 1.43 when covariates representing the additive effects of E2 and E4 are added. Larger increases in LOD scores were found when age at last examination/death (LOD score 5.54; P=.000002) or age at onset plus disease duration (LOD score 5.63; P=.000006) were included in the linkage model. We conclude that the APP locus may predispose to AD in the very elderly.     

A population-based study of familial Alzheimer disease: linkage to chromosomes 14, 19, and 21.

Linkage of Alzheimer disease (AD) to DNA markers on chromosomes 14, 19, and 21 was studied in 10 families in which the disease was apparently inherited as an autosomal dominant trait. Families were derived from a Dutch population-based epidemiologic study of early-onset AD. Although in all probands the onset of AD was at or before age 65 years, the mean age at onset was after age 65 years in four families (referred to as "LOAD"). Among the six families with early-onset AD (referred to as "EOAD," i.e., mean age of onset of AD of relatives was at or before age 65 years), conclusive linkage to 14q24.3 was found in one family with a very early onset (around 47 years), while linkage to the same region was excluded in two other families. For the LOAD families, predominantly negative lod scores were obtained, and the overall lod score excluded linkage to chromosome 14. The results with markers on chromosome 19 and chromosome 21 were not conclusive for EOAD and LOAD. The findings of our study confirm genetic heterogeneity within familial EOAD.     

Genetic study of familial cases of Alzheimer's disease

A small number (1-5%) of Alzheimer's disease (AD) cases associated with the early-onset form of the disease (EOAD) appears to be transmitted as a pure genetic, autosomal dominant trait. To date, three genes responsible for familial EOAD have been identified in the human genome: amyloid precursor protein (APP), presenilin 1 (PS1), and presenilin 2 (PS2). Mutations in these genes account for a significant fraction (18 to 50%) of familial cases of early onset AD. The mutations affect APP processing causing increased production of the toxic Abeta42 peptide. According to the "amyloid cascade hypothesis", aggregation of the Abeta42 peptide in brain is a primary event in AD pathogenesis. In our study of twenty AD patients with a positive family history of dementia, 15% (3 of 20) of the cases could be explained by coding sequence mutations in the PS1 gene. Although a frequency of PS1 mutations is less than 2% in the whole population of AD patients, their detection has a significant diagnostic value for both genetic counseling and treatment in families with AD.     

Causes of Alzheimer's disease

It is now understood that genetic factors play a crucial role in the risk of developing Alzheimer''s disease (AD). Rare mutations in at least 3 genes are responsible for early-onset familial AD. A common polymorphism in the apolipoprotein E gene is the major determinant of risk in families with late-onset AD, as well as in the general population. Advanced age, however, remains the major established risk factor for AD, although environmental variables may also have some role in disease expression. Some pathogenic factors directly associated with aging include oxidative damage and mutations in messenger RNA. Other factors unrelated to the aging process may, in the future, be amenable to therapeutic intervention by way of estrogen replacement therapy for postmenopausal women, anti-inflammatory drug therapy and reducing vascular risk factors. Older theories, such as aluminum playing a role in the pathogenesis of AD, have been mostly discarded as our understanding of pathogenic mechanisms of AD has advanced.     

Analysis of melanoma onset: assessing familial aggregation by using estimating equations and fitting variance components via Bayesian random effects models.

We investigate whether relative contributions of genetic and shared environmental factors are associated with an increased risk in melanoma. Data from the Queensland Familial Melanoma Project comprising 15,907 subjects arising from 1912 families were analyzed to estimate the additive genetic, common and unique environmental contributions to variation in the age at onset of melanoma. Two complementary approaches for analyzing correlated time-to-onset family data were considered: the generalized estimating equations (GEE) method in which one can estimate relationship-specific dependence simultaneously with regression coefficients that describe the average population response to changing covariates; and a subject-specific Bayesian mixed model in which heterogeneity in regression parameters is explicitly modeled and the different components of variation may be estimated directly. The proportional hazards and Weibull models were utilized, as both produce natural frameworks for estimating relative risks while adjusting for simultaneous effects of other covariates. A simple Markov Chain Monte Carlo method for covariate imputation of missing data was used and the actual implementation of the Bayesian model was based on Gibbs sampling using the free ware package BUGS. In addition, we also used a Bayesian model to investigate the relative contribution of genetic and environmental effects on the expression of naevi and freckles, which are known risk factors for melanoma.     

A Frailty‐Model‐Based Approach to Estimating the Age‐Dependent Penetrance Function of Candidate Genes Using Population‐Based Case‐Control Study Designs: An Application to Data on the BRCA1 Gene

Summary The population‐based case–control study design is perhaps one of, if not the most, commonly used designs for investigating the genetic and environmental contributions to disease risk in epidemiological studies. Ages at onset and disease status of family members are routinely and systematically collected from the participants in this design. Considering age at onset in relatives as an outcome, this article is focused on using the family history information to obtain the hazard function, i.e., age‐dependent penetrance function, of candidate genes from case–control studies. A frailty‐model‐based approach is proposed to accommodate the shared risk among family members that is not accounted for by observed risk factors. This approach is further extended to accommodate missing genotypes in family members and a two‐phase case–control sampling design. Simulation results show that the proposed method performs well in realistic settings. Finally, a population‐based two‐phase case–control breast cancer study of the BRCA1 gene is used to illustrate the method.     

Regulation of Alzheimer beta-amyloid precursor trafficking and metabolism

Alzheimer's disease (AD) is characterized by the intracranial accumulation of the 4 kDa amyloid-beta peptide (Abeta), following proteolysis of a approximately 700-amino acid, integral membrane precursor, the Alzheimer amyloid precursor protein (APP). The best evidence causally linking APP to AD has been provided by the discovery of mutations within the APP coding sequence that segregate with disease phenotypes in autosomal dominant forms of familial AD (FAD). Though FAD is rare ( < 10% of all AD), the hallmark features (amyloid plaques, neurofibrillary tangles, synaptic and neuronal loss, neurotransmitter deficits and dementia) are indistinguishable when FAD is compared with typical, common, 'non-familial', or sporadic, AD (SAD). Studies of some clinically relevant mutant APP molecules from FAD families have yielded evidence that APP mutations can lead to the enhanced generation or aggregability of Abeta, consistent with a pathogenic role in AD. Other genetic loci for FAD have been discovered which are distinct from the immediate regulatory and coding regions of the APP gene, indicating that defects in molecules other than APP can also specify cerebral amyloidogenesis and FAD. To date, all APP and non-APP FAD mutations can be demonstrated to have the common feature of promoting amyloidogenesis of Abeta. Epidemiological studies indicate that postmenopausal women on estrogen replacement therapy (ERT) have their relative risk of developing SAD diminished by about one third as compared with age-matched women not receiving ERT [M.X. Tang, D. Jacobs, Y. Stern, K. Marder, P. Schofield, B. Gurland, H. Andrews, R. Mayeux, Effect of estrogen during menopause on risk and age at onset of Alzheimer's disease, Lancet 348 (2000) 429432]. Because of the key role of cerebral Abeta accumulation in initiating AD pathology, it is most attractive that estradiol might modulate SAD risk or age-at-onset by inhibiting Abeta accumulation. A possible mechanistic basis for such a scenario is reviewed here.     

SNPing away at complex diseases: analysis of single-nucleotide polymorphisms around APOE in Alzheimer disease

There has been great interest in the prospects of using single-nucleotide polymorphisms (SNPs) in the search for complex disease genes, and several initiatives devoted to the identification and mapping of SNPs throughout the human genome are currently underway. However, actual data investigating the use of SNPs for identification of complex disease genes are scarce. To begin to look at issues surrounding the use of SNPs in complex disease studies, we have initiated a collaborative SNP mapping study around APOE, the well-established susceptibility gene for late-onset Alzheimer disease (AD). Sixty SNPs in a 1.5-Mb region surrounding APOE were genotyped in samples of unrelated cases of AD, in controls, and in families with AD. Standard tests were conducted to look for association of SNP alleles with AD, in cases and controls. We also used family-based association analyses, including recently developed methods to look for haplotype association. Evidence of association (P相似文献   

Relation between nicotine intake and Alzheimer's disease.

OBJECTIVE--To study the association between Alzheimer''s disease and nicotine intake through smoking. DESIGN--Population based case-control study. SETTING--City of Rotterdam and four northern provinces of The Netherlands. SUBJECTS--198 patients with early onset Alzheimer''s disease, 198 controls matched for age and sex, and families of 17 patients in whom Alzheimer''s disease was apparently inherited as an autosomal dominant disorder. MAIN OUTCOME MEASURES--Age of onset of dementia, relative risk of Alzheimer''s disease. RESULTS--89 of 193 patients with Alzheimer''s disease had a history of smoking compared with 102 of 195 controls. Among the patients and controls with a family history of dementia, smoking was significantly less common in those with dementia (40/95 with dementia v 55/96 controls; relative risk 0.35; 95% confidence interval 0.16 to 0.78). The risk of Alzheimer''s disease decreased with increasing daily number of cigarettes smoked before onset of disease (relative risk 0.3 in those smoking greater than 21/day v 1 in non-smokers). In six families in which the disease was apparently inherited as an autosomal dominant disorder, the mean age of onset was 4.17 years later in smoking patients than in non-smoking patients from the same family (p = 0.03). CONCLUSIONS--These findings suggest an inverse association between smoking and Alzheimer''s disease, although smoking cannot be advocated for other health reasons. We speculate that nicotine may have a role in the aetiology of both Alzheimer''s disease and Parkinson''s disease.     

Genetic epidemiology of rheumatoid arthritis.

We conducted family studies and segregation analyses of rheumatoid arthritis (RA) that were based on consecutive patients with RA ascertained without regard to family history or known risk factors. First-degree relatives from 135 simplex and 30 multiplex families were included in the analyses. A highly penetrant recessive major gene, with a mutant allele frequency of .005, was identified as the most parsimonious genetic risk factor. Significant evidence for heterogeneity in risk for RA was observed for proband gender but not for proband age at onset. Kaplan-Meier risk analysis demonstrated significant evidence for differences in the distribution of risk among first-degree relatives. These analyses demonstrated that both proband gender and age at onset are important risk factors but that proband gender appears to be the more important determinant of risk, with relatives of male probands having the greatest cumulative risk for RA. In addition, log-linear modeling identified proband gender, familiality (multiplex or simplex), and an interaction term between these two variables as being adequate to define the distribution of risk in families. The pattern of risk for RA among susceptible individuals and its inheritance is thus heterogeneous. For future genetic analyses, families with an excess of affected males having a young age at onset may be the most informative in identifying the putative recessive gene and its modifiers.