Sequence variations in CREB1 cosegregate with depressive disorders in women.

Major depressive disorder (MDD) constitutes a major public health problem worldwide and affects women twice as frequently as men. Previous linkage studies have identified a 451 kb region of 2q33-35 that exhibited significant evidence of linkage to Mood Disorders among women (but not men) from families with recurrent, early-onset MDD (RE-MDD), a severe and strongly familial subtype of MDD. This 451 kb region includes CREB1, an attractive susceptibility gene for MDD and related disorders. Sequence variations in the CREB1 promoter and intron 8 have been detected that cosegregate with Mood Disorders, or their absence, in women from these families, identifying CREB1 as a sex-limited susceptibility gene for unipolar Mood Disorders. These findings implicate the cAMP signaling pathway in the pathophysiology of Mood Disorders and related conditions.

D2S2944 identifies a likely susceptibility locus for recurrent, early-onset, major depression in women.

Recurrent, early-onset, major depressive disorder (RE-MDD) is a strongly familial condition whose malignant effects have a significant negative impact on the health and longevity of patients and their family members. Sixteen of the 19 candidate susceptibility loci identified by a recent genome survey revealed allelic associations with RE-MDD in men or women, but not in both sexes. The association of D2S2944 alleles and genotypes with RE-MDD and related disorders was evaluated using a case-control study design employing 100 adults with RE-MDD and 100 adult controls who had no personal or family history of mental disorders. The results of the case-control study were subsequently evaluated in a sample of 81 families ascertained through probands with RE-MDD using the transmission/disequilibrium test. The frequency of the D2S2944 124-bp allele among women with RE-MDD was approximately three times that for female controls (P = 0.0003). Women who carried the D2S2944 124-bp allele revealed a significantly elevated risk of developing RE-MDD, as indicated by an odds ratio of 4.5 compared to female controls (P<0.001). In contrast, men with RE-MDD did not have an increased frequency of this allele compared to male controls, and men who were carriers did not exhibit an increased risk of developing RE-MDD or related disorders. Our findings also suggest that the D2S2944 124-bp allele increases the risk of alcohol and other substance use disorders among women with RE-MDD. The transmission/disequilibrium test provided confirmatory evidence of these sex-specific findings within families. The results of this study confirm the existence of sex-specific susceptibility loci for RE-MDD, and suggest that there may be important differences in the molecular pathophysiology of RE-MDD in men and women. Alternatively, our findings may reflect the existence of sex-specific differences in the molecular mechanisms that determine resilience to endogenous or environmental depressogenic stimuli. The identification and characterization of the D2S2944 susceptibility locus for RE-MDD and related substance use disorders is likely to provide important new insights into the clinical biology, treatment, and prevention of these disorders.

D10S1423 identifies a susceptibility locus for Alzheimer's disease in a prospective, longitudinal, double-blind study of asymptomatic individuals.

Typical, later-onset forms of Alzheimer's disease (AD) appear to be influenced by multiple susceptibility loci, combinations of which contribute to the development of this disorder. We previously reported the results of a systematic survey of the human genome for the identification of highly informative DNA polymorphisms (SSTRPs) that target new AD risk genes. In addition to the APOE locus, our survey detected five new candidate susceptibility loci for AD, including D10S1423. An association of the D10S1423 234-bp allele with AD has been reported in three independent samples of AD cases and controls (Boston, Pittsburgh, Bonn). Data from our case-control studies suggest a strong synergistic interaction between the D10S1423 234-bp and APOE E4 risk alleles (234-bp carrier: OR = 2.5, 95% CI = 1.4--4.5; E4 carrier: OR = 8.3, 95% CI = 4.3--15.8; both alleles: OR = 23.1, 95% CI = 5.3--99.5). This report describes the prospective, longitudinal, double-blind assessment of the age-specific risk of AD encountered by 325 asymptomatic first-degree relatives of AD probands who carried the D10S1423 234-bp allele, the APOE E4 allele, or both, after 11.5 years of systematic follow-up. A total of 18 incident cases of AD were detected during the first 3379 subject-years of this longitudinal study. The effects of carrying either or both of the D10S1423 234-bp and APOE E4 alleles on the age-specific risk of developing AD were determined using Kaplan-Meier survival analysis. The age-specific risk of developing AD was the greatest for individuals who carried both alleles (Mantel--Cox statistic = 20.12, df = 3, P = 0.0002; Breslow statistic = 13.36, df = 3, P = 0.004). Cox proportional hazards models were developed to estimate the risk ratios for each genotype, controlling for the potential effects of age at recruitment, sex, and years of education. In the resulting best fitting model, only individuals who carried both risk alleles exhibited a risk ratio that differed significantly from 1 (risk ratio = 16.2, P = 0.008, 95% CI = 2.1--128.3). After controlling for these genotypes, female gender was also significantly associated with increased risk of developing AD (risk ratio = 5.1, P = 0.02, 95% CI = 1.2--21.1). Neither age at recruitment nor years of education made significant contributions to the model.

Clinical and neurobiological correlates of D10S1423 genotype in Alzheimer's disease.

BACKGROUND: In a previous genome survey, we detected associations of alleles at six microsatellite loci with typical-onset AD, including the 234bp allele of the D10S1423 locus. The goal of the current study was to explore the clinical, neuropathological, and neurochemical correlates of the D10S1423 234bp allele in a group of 50 autopsy-confirmed cases of Alzheimer's disease (AD) who lacked other brain diseases. METHODS: Clinical assessments were performed as part of a longitudinal study of AD and related disorders. Autopsies were performed using standardized methods and diagnoses were made according to established criteria. Genotyping, morphometry, and neurochemical analyses were performed using postmortem brain tissue. RESULTS: Patients with AD who carried the D10S1423 234bp allele manifested substantial reductions in dopamine levels in all six cortical regions examined. In contrast, carriers tended to have higher concentrations of cortical norepinephrine and revealed a dosage effect of the D10S1423 234bp allele. CONCLUSIONS: These findings support the results of our genome survey and suggest that a novel susceptibility gene for AD resides near the D10S1423 locus. The characterization of biologically meaningful subtypes, including genotypic subtypes with particular neurobiological derangements, may be important for the advancement of experimental therapeutics in AD.

Clinical and neurobiological correlates of DXS1047 genotype in Alzheimer's disease.

BACKGROUND: The goal of the current study was to explore the clinical, neuropathological, and neurochemical correlates of the DXS1047 202 bp allele in a group of 50 autopsy-confirmed cases of Alzheimer's disease (AD) who lacked other concomitant brain diseases. We previously published the results of a genome survey for novel risk loci for typical-onset (> or = 60 years) AD conducted at 10 cM resolution (Zubenko et al 1998a, b). This survey detected associations of alleles at six microsatellite loci with AD, including the 202 bp allele of the DXS1047 locus that resides within Xq25 on the human cytogenetic map. METHODS: Clinical assessments were performed as part of a longitudinal study of AD and related disorders. Autopsies were performed using standardized methods and the resulting diagnoses were made according to established criteria. Genotyping, morphometry, and neurochemical analyses were performed using postmortem brain tissue. RESULTS: Patients with AD who carried the DXS1047 202 bp allele manifested cortical norepinephrine levels that ranged from 2.1 to 3.6 times the corresponding values for noncarriers (p = .002), controlling for the potential effects of gender, age at symptomatic onset or death, and postmortem interval. In contrast, carriers tended to have lower cortical levels of dopamine (p = .10). CONCLUSIONS: These findings support the results of our previous genome survey and suggest that the DXS1047 locus, or a locus in close proximity, modulates biological variables relevant to the pathophysiology of AD. In addition to providing insights into the clinical biology of AD, the characterization of biologically meaningful subtypes, including genotypic subtypes associated with particular neurobiological derangements, may be important to the advancement of experimental therapeutics in AD.

Reductions in brain phosphatidylinositol kinase activities in Alzheimer's disease.

BACKGROUND: Converging lines of evidence suggest that alterations in the intracellular trafficking of the amyloid precursor protein, its derivatives, and other relevant proteins may contribute to the pathophysiology of Alzheimer's disease (AD). Since phosphatidylinositol (PI) kinase plays a pivotal role in the sorting and transport of newly synthesized proteins to their final destinations, we explored the hypothesis that AD is associated with alterations in the specific activities of these enzymes in postmortem brain tissue. METHODS: The specific activities of soluble and particulate pools of PI 3-kinase and PI 4-kinase from the frontal cortex were compared between 11 cases with histopathologically confirmed AD and 11 nondemented controls matched for sex, race, age at death, and postmortem interval. Potential associations of these activities with sociodemographic and clinical features were also explored. RESULTS: AD was associated with 43-59% reductions in the specific activities of the soluble forms of both lipid kinases; but no significant change in the specific activities of the particulate species. Associations of these specific activities with sex, age at onset or death, duration of illness, postmortem interval, or densities of morphologic lesions in the frontal cortex were not observed among the 11 AD cases. CONCLUSIONS: In addition to regulating protein sorting and trafficking, PI kinases participate in a wide range of cellular processes including protection from apoptosis, differentiation and cell growth, regulation of the cytoskeleton, and glucose metabolism. The results of this study suggest that one or more of these alterations in AD may result from a common abnormality in PI kinase regulation.

Neurobiological correlates of a putative risk allele for Alzheimer's disease on chromosome 12q.

OBJECTIVE: To explore the clinical, neuropathologic, and neurochemical correlates of the D12S1045 91 base pair (bp) allele in a group of 50 autopsy-confirmed cases of AD who lacked other concomitant brain diseases. BACKGROUND: In a previous genome survey for novel risk loci for typical-onset (> or =60 years) AD conducted at 10 cM resolution, we detected associations of alleles at six microsatellite loci with AD. These included the 91bp allele of the D12S1045 locus that resides in the telomeric region of 12q. METHODS: Clinical assessment was performed as part of a longitudinal study of AD and related disorders. Standardized pathologic methods, genotyping, morphometry, and neurochemical analyses were performed with postmortem brain tissue. RESULTS: Patients with AD who carried the D12S1045 91bp allele manifested earlier ages at symptomatic onset and death, greater densities of cortical neurofibrillary tangles, and substantially greater reductions in cortical dopamine levels compared to noncarriers. A dosage effect of the number of D12S1045 91bp alleles on cortical dopamine levels was also observed. CONCLUSIONS: Carrying the D12S1045 91bp allele was associated with greater clinical, neuropathologic, and neurochemical severity independent of sex and APOE genotype. These findings suggest that a novel susceptibility gene for AD resides at or in close proximity to the D12S1045 locus.

Prospective study of risk factors for Alzheimer's disease: results at 7.5 years.

OBJECTIVE: The primary goal of this study was to evaluate increased platelet membrane fluidity as a putative risk factor for Alzheimer's disease and its relationship to the APOE epsilon4 genotype. METHOD: This report describes the results of a prospective, longitudinal study of 330 initially asymptomatic, first-degree relatives of probands with Alzheimer's disease. RESULTS: Nine incident cases of Alzheimer's disease were detected during the first 2,220 subject-years of the follow-up period. Age, increased platelet membrane fluidity, and the APOE epsilon4 allele made significant independent contributions to the risk of developing Alzheimer's disease, while sex and years of education did not. Increased platelet membrane fluidity was associated with incident Alzheimer's disease cases between the ages of 64 and 71, while the epsilon4 allele was associated with incident Alzheimer's disease cases from age 64 until at least age 80. CONCLUSIONS: These results indicate that increased platelet membrane fluidity is not produced by the APOE epsilon4 allele. Instead, increased platelet membrane fluidity and the epsilon4 allele appear to make significant independent contributions to the risk of developing Alzheimer's disease among the first-degree relatives of patients with this disorder. Moreover, the age ranges over which these risk factors operate appear to be different.

A genome survey for novel Alzheimer disease risk loci: results at 10-cM resolution.

We completed a systematic survey of the human genome, conducted at an average resolution of 10 cM, for the identification of simple sequence tandem repeat polymorphisms (SSTRPs) that target new risk genes for Alzheimer disease (AD) by virtue of linkage disequilibrium. The efficiency of our association study was enhanced by genotyping pools of DNA from autopsy-confirmed cases with AD and matched controls. Allelic associations with AD were observed for 6 of the 391 SSTRPs in the CHLC Human Screening Set/Weber Version 6 (Research Genetics, Inc., Huntsville, AL): D1S518, D1S547, D10S1423, D12S1045, D19S178, and DXS1047. These allelic associations were replicated in an independent sample of autopsied AD cases and controls recruited from a geographically disparate site. The association of the large D19S178 alleles with AD appeared to arise from linkage disequilibrium with the APOE epsilon 4 allele, whose effect on increasing the risk of AD has been established. None of the remaining SSTRPs was in close proximity to loci previously reported to influence the risk of developing AD. Instead, they may identify five novel AD susceptibility loci.

Initial results of a genome survey for novel Alzheimer's disease risk genes: association with a locus on the X chromosome.

As the initial step in a systematic genome survey, 16 simple sequence tandem repeat polymorphisms that span the X chromosome at an average spacing of 10 cM were examined for allelic associations with typical-onset Alzheimer's disease (AD). The efficiency of this survey was substantially enhanced by genotyping pools of genomic DNA from 50 autopsy-confirmed AD cases and 50 autopsied controls who were similar in sex ratio, race, and age at death. The frequency of the DXS1047 202-bp allele was twice as common among AD cases (0.45 +/- S.E. 0.06) than controls (0.22 +/- S.E. 0.05), a finding that was reproduced in an independent and geographically disparate sample. Consistent with Hardy-Weinberg equilibrium, the proportion of women with AD who carried the 202-bp allele, 73% was nearly double that observed for men with AD, 38%. However, the frequency of the 202-bp allele was similar for men and women and the presence of this allele did not affect the age at onset of dementia in either sex. Furthermore, the frequency of the DXS1047 202-bp allele in AD cases and controls was unaffected by the APOE genotype, indicating that these two loci modulate AD risk independently. Finally, the frequency of the 202-bp allele among 50 autopsy-confirmed cases of Parkinson's disease (0.29 +/- S.E. 0.06) was indistinguishable from the control value, reflecting relative specificity for this allelic association with AD.

Initial results of a genome survey for novel Alzheimer's disease risk genes: association with a locus on the X chromosome.

As the initial step in a systematic genome survey, 16 simple sequence tandem repeat polymorphisms that span the X chromosome at an average spacing of 10 cM were examined for allelic associations with typical-onset Alzheimer's disease (AD). The efficiency of this survey was substantially enhanced by genotyping pools of genomic DNA from 50 autopsy-confirmed AD cases and 50 autopsied controls who were similar in sex ratio, race, and age at death. The frequency of the DXS1047 202-bp allele was twice as common among AD cases (0.45+/-S.E. 0.06) than controls (0.22+/-S.E. 0.05), a finding that was reproduced in an independent and geographically disparate sample. Consistent with Hardy-Weinberg equilibrium, the proportion of women with AD who carried the 202-bp allele, 73% was nearly double that observed for men with AD, 38%. However, the frequency of the 202-bp allele was similar for men and women and the presence of this allele did not affect the age at onset of dementia in either sex. Furthermore, the frequency of the DXS1047 202-bp allele in AD cases and controls was unaffected by the APOE genotype, indicating that these two loci modulate AD risk independently. Finally, the frequency of the 202-bp allele among 50 autopsy-confirmed cases of Parkinson's disease (0.29+/-S.E. 0.06) was indistinguishable from the control value, reflecting relative specificity for this allelic association with AD.

Association of the APOE epsilon 4 allele with clinical subtypes of late life depression.

The APOE genotypes of 45 elderly inpatients with major depression were determined to investigate the relationship of this disorder to irreversible dementia in late life. We specifically tested the hypothesis that the frequency of the APOE epsilon 4 allele is elevated in depressed elders with cognitive impairment or psychotic features, subtypes that have been reported to be at increased risk of developing Alzheimer's disease (AD). The frequency of epsilon 4 allele was not elevated in the overall group of 45 inpatients and, contrary to our expectation, was not associated with cognitive impairment in this group. In contrast, the epsilon 4 allele frequency for the patients with psychotic features was nearly four times that for the patients without psychotic features and nearly double that of elderly controls. These data suggest that elderly depressed inpatients with cognitive impairment are at risk for developing AD by an epsilon 4-independent pathway, while those with psychotic features are at risk for developing AD by an epsilon 4-dependent pathway. These findings suggest that subtypes of idiopathic major depression in late life may serve as landmarks that distinguish separable pathogenetic pathways to AD.

Clinically-silent mutation in the putative iron-responsive element in exon 17 of the beta-amyloid precursor protein gene.

Three missense mutations in exon 17 of the beta-amyloid precursor protein (APP) gene have been reported to cosegregate in families with early onset Alzheimer's disease (AD). All three mutations result in amino acid substitutions at codon 717 and may produce AD by altering the structure of the transmembrane domain of APP. Alternatively, the mutations may destabilize the stem of a putative iron-responsive element (IRE) in which they lie and confer pathogenicity by inactivating this negative regulatory element. We have detected a clinically-silent mutation in codon 716 that would also be expected to disrupt the putative IRE but results in no amino acid substitution. This result strongly suggests that the missense mutations at codon 717 produce AD by altering the amino acid sequence of APP rather than the IRE. Furthermore, the identification of a clinically-silent mutation among four point mutations that span only three nucleotides of exon 17 suggests that this region may be a mutational "hot" spot.