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Knowing the answers, we used the GAW11 data set to compare the power and efficiency of discordant versus concordant affected sib pairs for qualitative traits at different levels of penetrance. Samples of 200 concordant sib pairs outperformed discordant sib pairs for low penetrance (40%) and 70% penetrance models while at 90% penetrance they performed equally well. Increasing the sample size of discordant sib pairs to twice that of concordant pairs was not enough to reach the power of concordant sib pairs at the 40% and 70% penetrance models. For low penetrance using a combination of concordant and discordant sib pairs resulted in higher power than using discordant sib pairs alone. At 90% penetrance, the power of concordant and discordant sib pairs was similar in the region close to the gene while concordant sib pairs performed better at locations further from the gene.

Linkage analysis was performed on the GAW11 Problem 2 data set using stratification to explore the effects of the environmental risk factors and the differences between mild and severe phenotypes. Analysis of the four study populations stratified by the two risk factors identified regions on chromosomes 3 and 5 with significant evidence for linkage. Other loci were sought by removing families consistent with linkage to the chromosome 3 locus. Our studies identified a locus on chromosome 3 (markers 43-46) associated with the mild phenotype in the presence of risk factor 1 and with the severe phenotype independent of risk factor 1. This suggests that distinct allelic variants at the chromosome 3 locus may cause different forms of disease. The locus identified on chromosome 5 (markers 36-39) was linked to the severe phenotype, but exposure to factor 1 or 2 may have a protective effect. The regions on chromosomes 3 and 5 appeared to have independent roles in disease etiology. Evidence for two loci on chromosome 1 linked to the mild form was found. The methods successfully identified linkages and interaction consistent with the generating model.

A novel polymorphism (-491 A/T) within the regulatory region on the apolipoprotein E gene has recently been reported to be associated with risk for Alzheimer disease (AD). To test this association in an independent data set, we have examined this polymorphism in a sample of 88 well-characterized AD cases and compared the allele frequency and genotype frequencies for this polymorphism with those observed in 112 cognitively normal subjects drawn from the same ethnic group. These results suggest that in the current data set at least, the -491 A/T polymorphism is not associated with risk for AD, but may be in partial linkage disequilibrium with the APOE epsilon2/epsilon3/epsilon4 polymorphism.

Model-free sib-pair linkage analysis was used to screen the GAW9-Problem 1 data set for evidence of linkage of a rare disease to any of 360 highly polymorphic marker loci. Negative regressions nominally significant at the alpha = 0.05 level were obtained for 44 markers; however all of these proved to be Type I errors. None of the four disease loci were detected by sib-pair linkage, which was not surprising, given the particular model and sampling scheme used to generate these data. Neither deleting parental marker genotypic information nor misspecifying marker allele frequency estimates substantially increased the Type I error rate. A two-stage testing procedure using a 10 or 20 cM map and a liberal first stage significance level gave the same overall results as a one-stage 2 cM map but required only about 42% or 22% as many markers, respectively.

Background: Angiotensin-converting enzyme has been reported to show altered activity in patients with neurologic diseases. An insertion-deletion polymorphism in ACE has recently been linked to heart disease, cerebrovascular disease, and AD. Objective: To determine whether the angiotensinconverting enzyme (ACE) is associated with risk of Alzheimer disease (AD). Methods: We investigated the ACE polymorphism as a potential risk factor for AD in 151 patients with AD and 206 ethnically matched controls from Russia and in 236 patients with AD and 169 controls from North America by means of allele association methods and logistic regression. Results: None of the ACE genotypes was associated with increased susceptibility to AD in the total sample or in subsets stratified by apolipoprotein E gene (APOE) e4 status. However, the D allele was more frequent among AD cases between ages 66 and 70 years compared with controls in both the Russian (P = .02) and North American (P = .001) datasets. In this age group, the effect of D (odds ratio, 11.2; 95% confidence interval, 2.9-44.0) appeared to be independent of and equal or greater in magnitude to the effect of APOE e4 (odds ratio, 7.8; 95% confidence interval, 3.5-7.4). Conclusions: Our results suggest that APOE and ACE genotypes may be independent risk factors for lateonset AD, but the ACE association needs to be confirmed in independent samples in which the time and extent of vascular cofactors can be assessed. Arch Neurol. 2000;57:210-214

Alpha-2-macroglobulin (A2M) is a proteinase inhibitor that is present in senile plaques and may play a role in metabolism of amyloid beta (A β ) peptide. Recently it was reported that inheritance of the deletion allele (A2M-2) confers increased risk for late-onset Alzheimer disease (AD) with significance of this effect similar to the ϵ 4 allele of apolipoprotein E (APOE). We examined the distribution of A2M genotypes and alleles in a cohort of 146 AD patients and 160 age-matched non-demented individuals. There was no evidence for association in the total sample or in subsets stratified by age or APOE ϵ 4 status. These results suggest that this polymorphism is not a strong genetic risk factor for either early- or late-onset forms of the disorder. However, they do not exclude the possibility that an AD susceptibility allele is located elsewhere in A2M or a nearby gene.

A recent study showed modest evidence for an increased frequency of the bleomycin hydrolase (BH) V/V genotype in Alzheimer's disease (AD) patients compared with non-demented controls. To test this hypothesis, we examined this polymorphism in 621 rigorously evaluated patients and 502 control subjects (all caucasian) but were unable to detect an association between BH and AD even after controlling for age, gender, and apolipoprotein E (ApoE) genotype. We conclude that this polymorphism does not account for inherited susceptibility to AD in the populations represented in this sample.

The K-variant of butyrylcholinesterase (BCHE-K) recently has been reported to be associated with Alzheimer disease (AD) in carriers of the epsilon4 allele of the apolipoprotein E (APOE) gene. We have re-examined the frequency of the BCHE-K allele in a large data set of both sporadic and familial cases of AD disease, and we have also examined the segregation of three genetic markers on chromosome 3 near BCHE . Our data neither support an association of BCHE-K with sporadic or familial AD, nor do they suggest the existence of another gene nearby on chromosome 3 as a common cause of familial AD.

Blacker et al.1 reported an association between Alzheimer disease (AD) and the deletion allele (A2M*2) of an intronic polymorphism in the -2-macroglobulin gene (A2M; 2), which confers a risk for AD (OR=3.55, 95% CI=1.90-7.03) comparable with that of APOE*E4 (OR=3.54, 95% CI=1.76-7.12). We analysed two independent sets of AD families3, 4 using the same family-based association (sibship disequilibrium test1 (SDT) and sib transmission-disequilibrium test5 (S-TDT)) methods. Following the scheme of Blacker et al.1, we limited these analyses to nuclear families of European descent in which all affected individuals had AD onset over 50 years, marker information was available for at least one unaffected sib and, in the case of the S-TDT, two or more distinct genotypes were present in the sibship. We averaged P values for the S-TDT over 100 iterations (10,000 replicates per iteration) using a Monte-Carlo method6. Both data sets demonstrated the association of AD and APOE*E4 (SDT, Duke, P=0.000007; Toronto, P=0.0009), indicating sufficient power to detect associations of the magnitude reported for A2M*2 (1). Although prior evidence shows that these pedigrees are enriched for an AD locus on chromosome 12 near A2M (Refs 3,7), we were unable to detect an association with the A2M*2 polymorphism using either the SDT or S-TDT, even when the "stringent unaffecteds" method1 was applied (SDT, Duke, n = 60, P = 0.80, Toronto, n = 45, P = 0.82; S-TDT, Duke, n = 17, P = 0.64, Toronto, n = 21, P = 0.75). Furthermore, we did not detect an association in two independent series of sporadic AD cases of European descent after adjustment for APOE*E4 status (Table 1), despite the fact that each data set had more than 80% power to detect an odds ratio as low as 1.87 (an effect much smaller than reported for A2M*2; 1).

Context.—Alzheimer disease (AD) susceptibility genes have been identified on chromosomes 1, 14, 19, and 21, and a recent study has suggested a locus on chromosome 12.Objective.—To confirm or refute the existence of a familial AD susceptibility locus on chromosome 12 in an independent sample of familial AD cases.Design.—Retrospective cohort study. DNA data for 6 chromosome 12 genetic markers were evaluated using parametric lod score and nonparametric linkage methods and linkage heterogeneity tests. The latter include the admixture test of homogeneity in the total group of families and the predivided sample test in families stratified by the presence or absence of an apolipoprotein E (APOE) ∊4 allele among affected members. Parametric analyses were repeated assuming autosomal dominant inheritance of AD and either age- and sex-dependent penetrance or zero penetrance for the analysis of unaffected relatives.Setting.—Clinical populations in the continental United States, Canada, Argentina, and Italy.Patients.—Fifty-three white families composed of multiple members affected with AD, from whom DNA samples were obtained from 173 patients with AD whose conditions were diagnosed using established criteria and from 146 nondemented relatives.Main Outcome Measure.—Presence of an APOE ∊4 allele among affected family members.Results.—Using parametric methods, no evidence for linkage to the region spanned by the chromosome 12 markers could be detected if familial AD is assumed to arise from the same genetic locus in all 53 families. However, significant evidence for linkage was detected in the presence of locus heterogeneity using the admixture test (odds ratio, 15, 135:1). The estimated proportion of linked families within the 53 families examined varied between 0.40 and 0.65, depending on the genetic model assumed and APOE status. The precise location of the AD gene could not be determined, but includes the entire region suggested previously. Nonparametric linkage analysis confirmed linkage to chromosome 12 with the strongest evidence at D12S96 (P