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Author

Warren J. Strittmatter

Bio: Warren J. Strittmatter is a academic researcher from Duke University. The author has contributed to research in topic(s): Apolipoprotein E & Alzheimer's disease. The author has an hindex of 60, co-authored 160 publication(s) receiving 32220 citation(s). Previous affiliations of Warren J. Strittmatter include University of California & Harvard University.

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Papers
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Journal ArticleDOI: 10.1126/SCIENCE.8346443
13 Aug 1993-Science
Abstract: The apolipoprotein E type 4 allele (APOE-epsilon 4) is genetically associated with the common late onset familial and sporadic forms of Alzheimer9s disease (AD). Risk for AD increased from 20% to 90% and mean age at onset decreased from 84 to 68 years with increasing number of APOE-epsilon 4 alleles in 42 families with late onset AD. Thus APOE-epsilon 4 gene dose is a major risk factor for late onset AD and, in these families, homozygosity for APOE-epsilon 4 was virtually sufficient to cause AD by age 80.

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Topics: Late onset (69%), APOE*4 Allele (56%), SORL1 (54%) ...read more

8,099 Citations


Open accessJournal ArticleDOI: 10.1073/PNAS.90.5.1977
Abstract: Apolipoprotein E is immunochemically localized to the senile plaques, vascular amyloid, and neurofibrillary tangles of Alzheimer disease. In vitro, apolipoprotein E in cerebrospinal fluid binds to synthetic beta A4 peptide (the primary constituent of the senile plaque) with high avidity. Amino acids 12-28 of the beta A4 peptide are required. The gene for apolipoprotein E is located on chromosome 19q13.2, within the region previously associated with linkage of late-onset familial Alzheimer disease. Analysis of apolipoprotein E alleles in Alzheimer disease and controls demonstrated that there was a highly significant association of apolipoprotein E type 4 allele (APOE-epsilon 4) and late-onset familial Alzheimer disease. The allele frequency of the APOE-epsilon 4 in 30 random affected patients, each from a different Alzheimer disease family, was 0.50 +/- 0.06; the allele frequency of APOE-epsilon 4 in 91 age-matched unrelated controls was 0.16 +/- 0.03 (Z = 2.44, P = 0.014). A functional role of the apolipoprotein E-E4 isoform in the pathogenesis of late-onset familial Alzheimer disease is suggested.

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Topics: Apolipoprotein E (69%), SORL1 (65%), Senile plaques (63%) ...read more

4,008 Citations


Open accessJournal ArticleDOI: 10.1212/WNL.43.8.1467
01 Aug 1993-Neurology
Abstract: Apolipoprotein E, type epsilon 4 allele (APOE epsilon 4), is associated with late-onset familial Alzheimer's disease (AD). There is high avidity and specific binding of amyloid beta-peptide with the protein ApoE. To test the hypothesis that late-onset familial AD may represent the clustering of sporadic AD in families large enough to be studied, we extended the analyses of APOE alleles to several series of sporadic AD patients. APOE epsilon 4 is significantly associated with a series of probable sporadic AD patients (0.36 +/- 0.042, AD, versus 0.16 +/- 0.027, controls [allele frequency estimate +/- standard error], p = 0.00031). Spouse controls did not differ from CEPH grandparent controls from the Centre d'Etude du Polymorphisme Humain (CEPH) or from literature controls. A large combined series of autopsy-documented sporadic AD patients also demonstrated highly significant association with the APOE epsilon 4 allele (0.40 +/- 0.026, p < or = 0.00001). These data support the involvement of ApoE epsilon 4 in the pathogenesis of late-onset familial and sporadic AD. ApoE isoforms may play an important role in the metabolism of beta-peptide, and APOE epsilon 4 may operate as a susceptibility gene (risk factor) for the clinical expression of AD.

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Topics: Apolipoprotein E (58%), SORL1 (52%), Allele frequency (52%)

3,419 Citations


Journal ArticleDOI: 10.1038/NG0694-180
01 Jun 1994-Nature Genetics
Abstract: Gene dosage of the apolipoprotein E (APOE) epsilon 4 allele is a major risk factor for familial Alzheimer disease (AD) of late onset (after age 60). Here we studied a large series of 115 AD case subjects and 243 controls as well as 150 affected and 197 unaffected members of 66 AD families. Our data demonstrate a protective effect of the epsilon 2 allele, in addition to the dose effect of the epsilon 4 allele in sporadic AD. Although a substantial proportion (65%) of AD is attributable to the presence of epsilon 4 alleles, risk of AD is lowest in subjects with the epsilon 2/epsilon 3 genotype, with an additional 23% of AD attributable to the absence of an epsilon 2 allele. The opposite actions of the epsilon 2 and epsilon 4 alleles further support the direct involvement of APOE in the pathogenesis of AD.

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Topics: Allele frequency (55%), Apolipoprotein E (54%), Allele (50%)

1,694 Citations


Open accessJournal ArticleDOI: 10.1073/PNAS.90.20.9649
Abstract: Amyloid beta-peptide (A beta) deposition in senile plaques and cerebral vessels is a neuropathological feature of Alzheimer disease (AD). We examined the possibility that commonly observed variability in A beta deposition in late-onset AD might be related to apolipoprotein E genotype (APOE gene; the two most common alleles are 3 and 4), since APOE4 is a susceptibility gene for late-onset AD and apolipoprotein E interacts strongly with A beta in vitro. In an autopsy series of brains of late-onset AD patients, we found a strong association of APOE4 allele with increased vascular and plaque A beta deposits. Late-onset AD patients with one or two APOE4 alleles have a distinct neuropathological phenotype compared with patients homozygous for APOE3.

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Topics: Senile plaques (64%), Apolipoprotein E (61%), Amyloid beta (59%) ...read more

1,421 Citations


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Journal ArticleDOI: 10.1126/SCIENCE.1072994
John Hardy1, Dennis J. Selkoe2Institutions (2)
19 Jul 2002-Science
Abstract: It has been more than 10 years since it was first proposed that the neurodegeneration in Alzheimer9s disease (AD) may be caused by deposition of amyloid β-peptide (Aβ) in plaques in brain tissue. According to the amyloid hypothesis, accumulation of Aβ in the brain is the primary influence driving AD pathogenesis. The rest of the disease process, including formation of neurofibrillary tangles containing tau protein, is proposed to result from an imbalance between Aβ production and Aβ clearance.

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Topics: Amyloid beta (67%), Biochemistry of Alzheimer's disease (66%), Senile plaques (65%) ...read more

11,721 Citations


Journal ArticleDOI: 10.1126/SCIENCE.8346443
13 Aug 1993-Science
Abstract: The apolipoprotein E type 4 allele (APOE-epsilon 4) is genetically associated with the common late onset familial and sporadic forms of Alzheimer9s disease (AD). Risk for AD increased from 20% to 90% and mean age at onset decreased from 84 to 68 years with increasing number of APOE-epsilon 4 alleles in 42 families with late onset AD. Thus APOE-epsilon 4 gene dose is a major risk factor for late onset AD and, in these families, homozygosity for APOE-epsilon 4 was virtually sufficient to cause AD by age 80.

...read more

Topics: Late onset (69%), APOE*4 Allele (56%), SORL1 (54%) ...read more

8,099 Citations


Open accessJournal ArticleDOI: 10.1038/NATURE08494
Teri A. Manolio1, Francis S. Collins1, Nancy J. Cox2, David Goldstein3  +24 moreInstitutions (21)
08 Oct 2009-Nature
Abstract: Genome-wide association studies have identified hundreds of genetic variants associated with complex human diseases and traits, and have provided valuable insights into their genetic architecture. Most variants identified so far confer relatively small increments in risk, and explain only a small proportion of familial clustering, leading many to question how the remaining, 'missing' heritability can be explained. Here we examine potential sources of missing heritability and propose research strategies, including and extending beyond current genome-wide association approaches, to illuminate the genetics of complex diseases and enhance its potential to enable effective disease prevention or treatment.

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7,195 Citations


Journal ArticleDOI: 10.1038/NATURE02168
John W. Belmont1, Paul Hardenbol, Thomas D. Willis, Fuli Yu1  +142 moreInstitutions (50)
18 Dec 2003-Nature
Abstract: The goal of the International HapMap Project is to determine the common patterns of DNA sequence variation in the human genome and to make this information freely available in the public domain. An international consortium is developing a map of these patterns across the genome by determining the genotypes of one million or more sequence variants, their frequencies and the degree of association between them, in DNA samples from populations with ancestry from parts of Africa, Asia and Europe. The HapMap will allow the discovery of sequence variants that affect common disease, will facilitate development of diagnostic tools, and will enhance our ability to choose targets for therapeutic intervention.

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Topics: International HapMap Project (67%), Imputation (genetics) (64%), Haplotype estimation (58%) ...read more

5,704 Citations


Journal ArticleDOI: 10.1152/PHYSREV.2001.81.2.741
Dennis J. Selkoe1Institutions (1)
Abstract: Rapid progress in deciphering the biological mechanism of Alzheimer's disease (AD) has arisen from the application of molecular and cell biology to this complex disorder of the limbic and association cortices. In turn, new insights into fundamental aspects of protein biology have resulted from research on the disease. This beneficial interplay between basic and applied cell biology is well illustrated by advances in understanding the genotype-to-phenotype relationships of familial Alzheimer's disease. All four genes definitively linked to inherited forms of the disease to date have been shown to increase the production and/or deposition of amyloid β-protein in the brain. In particular, evidence that the presenilin proteins, mutations in which cause the most aggressive form of inherited AD, lead to altered intramembranous cleavage of the β-amyloid precursor protein by the protease called γ-secretase has spurred progress toward novel therapeutics. The finding that presenilin itself may be the long-sought γ-...

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Topics: Presenilin (64%), APH-1 (56%), Amyloid precursor protein secretase (53%) ...read more

5,644 Citations


Performance
Metrics

Author's H-index: 60

No. of papers from the Author in previous years
YearPapers
20202
20132
20122
20111
20101
20092

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