Familial alzheimer's disease in american descendants of the volga germans: Probable genetic founder effect

Bird, Thomas D.; Lampe, Thomas H.; Nemens, Ellen; Miner, Gary W.; Sumi, S. M.; Schellenberg, Gerard D.

doi:10.1002/ana.410230106

Cited by 127 publications

(58 citation statements)

References 11 publications

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“…Evidence for an additional early-onset locus comes from studies of the VG kindreds. These families come from a group of Germans who, in the 1760s, emigrated to the Volga river region of Russia (80,91 Linkage analysis of the VG families with chromosome 21 markers has yielded negative results (23,24,29) and no mutations have been identified in theAPP gene (29). Similarly, linkage analysis with chromosome 14 markers nearAD3 (63,71) and with the chromosome 19 APOCII STRP locus gave negative results (68,92).…”

Section: The Vg Kindredsmentioning

confidence: 99%

Genetic dissection of Alzheimer disease, a heterogeneous disorder.

Schellenberg

1995

Proc. Natl. Acad. Sci. U.S.A.

166

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The genetics of Alzheimer disease (AD) are complex and not completely understood. Mutations in the amyloid precursor protein gene (APP) can cause early-onset autosomal dominant AD. In vitro studies indicate that cells expressing mutant APPs overproduce pathogenic forms of the A beta peptide, the major component of AD amyloid. However, mutations in the APP gene are responsible for 5% or less of all early-onset familial AD. A locus on chromosome 14 is responsible for AD in other early-onset AD families and represents the most severe form of the disease in terms of age of onset and rate of decline. Attempts to identify the AD3 gene by positional cloning methods are underway. At least one additional early-onset AD locus remains to be located. In late-onset AD, the apolipoprotein E gene allele epsilon 4 is a risk factor for AD. This allele appears to act as a dose-dependent age-of-onset modifier. The epsilon 2 allele of this gene may be protective. Other late-onset susceptibility factors remain to be identified.

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Section: The Vg Kindredsmentioning

confidence: 99%

Genetic dissection of Alzheimer disease, a heterogeneous disorder.

Schellenberg

1995

Proc. Natl. Acad. Sci. U.S.A.

166

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“…Additional pedigree data were collected from 3 international studies: the Dominantly Inherited Alzheimer Network (DIAN) Study, 9 a large Colombian kindred carrying the PSEN1 E280A mutation, 14 and a set of 11 extended families of Volga German ancestry carrying an identical PSEN2 N141I mutation due to a genetic founder effect. 5,15 Updated findings from a previously published multigenerational PSEN1 L286V kindred were provided by the investigator. 16 To avoid potential double reporting, pedigrees for each mutation type were manually examined for possible duplicates, and these were removed where identified.…”

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confidence: 99%

Symptom onset in autosomal dominant Alzheimer disease

et al. 2014

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Objective: To identify factors influencing age at symptom onset and disease course in autosomal dominant Alzheimer disease (ADAD), and develop evidence-based criteria for predicting symptom onset in ADAD.Methods: We have collected individual-level data on ages at symptom onset and death from 387 ADAD pedigrees, compiled from 137 peer-reviewed publications, the Dominantly Inherited Alzheimer Network (DIAN) database, and 2 large kindreds of Colombian (PSEN1 E280A) and Volga German (PSEN2 N141I) ancestry. Our combined dataset includes 3,275 individuals, of whom 1,307 were affected by ADAD with known age at symptom onset. We assessed the relative contributions of several factors in influencing age at onset, including parental age at onset, age at onset by mutation type and family, and APOE genotype and sex. We additionally performed survival analysis using data on symptom onset collected from 183 ADAD mutation carriers followed longitudinally in the DIAN Study.Results: We report summary statistics on age at onset and disease course for 174 ADAD mutations, and discover strong and highly significant (p , 10 216 , r 2 . 0.38) correlations between individual age at symptom onset and predicted values based on parental age at onset and mean ages at onset by mutation type and family, which persist after controlling for APOE genotype and sex.Conclusions: Significant proportions of the observed variance in age at symptom onset in ADAD can be explained by family history and mutation type, providing empirical support for use of these data to estimate onset in clinical research. Researchers have identified more than 230 different autosomal dominant Alzheimer disease (ADAD) mutations located in the genes for amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2), including the canonical case discovered by Alois Alzheimer.1 There are significant differences between mutation types in age at symptom onset, and many result in onset as early as the third or fourth decade of life.2,3 Some families carrying an identical ADAD mutation can have significantly different ages at onset, suggesting the presence of other genetic or environmental modifiers of the disease process.4,5 APOE genotype was found to slightly modify age at onset in 2 ADAD kindreds, 5,6 although it is not yet clear whether this is the case for ADAD in general. The factors influencing symptom onset and progression in From the

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“…Familial forms of this disor der have been repeatedly demonstrated in large pedigrees of families with multiple affected members [2][3][4][5][6][7][8] and family history studies have shown increased risk of de mentia to relatives of AD probands in comparison to AD probands. This represents the first report of morbid risk estimates based on a sample with prospective clinical as well as neuropathologic diagnoses.…”

Section: Introductionmentioning

confidence: 99%

Morbid Risk to First Degree Relatives of Neuropathologically Confirmed Cases of Alzheimer's Disease

Bierer

Silverman

Mohs

et al. 1992

Dement Geriatr Cogn Disord

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One source of variance in familial aggregation studies in Alzheimer''s disease (AD) is proband diagnosis. In this study, the morbid risk of primary progressive dementia (PPD) was assessed in first degree relatives of 32 patients with clinically diagnosed AD (mean onset = 59.9 ± 7.2 years) whose diagnoses were confirmed at autopsy. The Alzheimer''s Disease Risk Questionnaire and the Dementia Questionnaire were administered to multiple family informants by trained raters blind to the probands'' clinical and neuropathologic diagnoses. Morbid risk for PPD was analyzed using the Kaplan-Meier life-table method. The estimated cumulative risk of PPD in first degree relatives (n = 159; age ≧: 45) was estimated to be 48.8 ± 11.3% by age 86. The risk estimate for affected siblings (n = 96; age ≧ 45) reached 54.9 ± 20.7 % by age 78. These figures are consistent with those calculated for most cohorts of relatives of clinically selected AD probands lacking autopsy confirmation of diagnosis. Although based on a relatively small sample, this series is the first morbid risk analysis to employ clinically diagnosed probands with neuropathologic confirmation of AD.

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Familial alzheimer's disease in american descendants of the volga germans: Probable genetic founder effect

Cited by 127 publications

References 11 publications

Genetic dissection of Alzheimer disease, a heterogeneous disorder.

Genetic dissection of Alzheimer disease, a heterogeneous disorder.

Symptom onset in autosomal dominant Alzheimer disease

Morbid Risk to First Degree Relatives of Neuropathologically Confirmed Cases of Alzheimer's Disease

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