Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease.
Open accessAbstract
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.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
0 of 23 cited sources checked · 0 supported · 0 flagged
- Findingown data
In 30 randomly chosen affected individuals, one from each of 30 Alzheimer disease families, the APOE-e4 allele frequency was 0.50 ± 0.06.
“The alele frequency of the APOE-e4 in 30 random affected patients, each from a different Azheimer disease family, was 0.50 t 0.06;”
- Also stated in: § MATERIALS AND METHODS · plain
“the frequency of the APOE-e4 allele in the 30 patients (0.50 ± 0.06)”
Quote in the paperSubstantial claim - Also stated in: § MATERIALS AND METHODS · plain
- Findingcitation
The APOE-e4 allele frequency in the study's control group was similar to that in a larger population study.
“The allele frequency of APOE-E4 found in our control population was similar to that found in a larger population study (20).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [20] 20. Menzel, J., Kladetzky, K. G. & Assmann, G. (1983) Arterio- sclerosis 4, 310-315.
Not checked in the free run.
- Findingown data
The APOE-e4 allele frequency difference between the 30 patients and 91 controls was statistically significant (Z=2.44, P=0.014).
“the aUlele frequency of APOE-e4 in 91 age-matched unrelated controls was 0.16 ± 0.03 (Z = 2.44, P = 0.014).”
- Also stated in: § MATERIALS AND METHODS · plain
“differed significantly from the frequency found in the 91 controls (0.16 ± 0.03; Z = 2.44, P = 0.014).”
Quote in the paperSubstantial claim- Rests on an assumption: The 91 unrelated CEPH grandparents used as controls are genetically comparable to the familial Alzheimer disease cases, so the allele frequency difference is not due to population stratification.
- Rests on an assumption: The two early-onset families in the sample do not materially affect the association between APOE-e4 and late-onset familial Alzheimer disease.
- Also stated in: § MATERIALS AND METHODS · plain
- Findingown data
In 91 age-matched unrelated controls, the APOE-e4 allele frequency was 0.16 ± 0.03.
“the aUlele frequency of APOE-e4 in 91 age-matched unrelated controls was 0.16 ± 0.03 (Z = 2.44, P = 0.014).”
- Also stated in: § MATERIALS AND METHODS · plain
“the frequency found in the 91 controls (0.16 ± 0.03; Z = 2.44, P = 0.014).”
Quote in the paperSubstantial claim- Rests on an assumption: The 91 unrelated CEPH grandparents used as controls are genetically comparable to the familial Alzheimer disease cases, so the allele frequency difference is not due to population stratification.
- Also stated in: § MATERIALS AND METHODS · plain
- Findingown data
ApoE in CSF stayed bound to immobilized beta-A4-(1-40), beta-A4-(1-28), and beta-A4-(12-28) after PBS plus 5% SDS washing.
“ApoE in CSF remained bound to immobilized (A4-(1-40), fA4-(1-28), andj'A4-(12-28) after incubation and washing with phosphate-buffer saline plus 5% SDS.”
Quote in the paperSubstantial claim
- Findingown data
The contaminating beta-A4-binding protein was identified as ApoE by microsequencing.
“This contaminant protein was identified by protein microsequenc- ing to be ApoE.”
Quote in the paperSubstantial claim - Findingown data
ApoE immunoreactivity followed the distribution of beta-A4 amyloid, including near glial processes.
“ApoE immunoreactivity (Fig. 4B) closely imitated the distribution of 3A4 amyloid (Fig. 4C), even being observed near glial processes (Fig. 4 B and C, arrowheads).”
Quote in the paperNot a substantial claim - Findingown data
The 12-28 hydropathic mimic peptide bound ApoE after PBS plus 5% SDS washing.
“This peptide also bound ApoE after washing with phosphate- buffered saline plus 5% SDS (Fig. 2).”
Quote in the paperSubstantial claim - Findingown data
ApoE did not bind to the even-hydropathy peptide.
“ApoE did not bind to this immobilized peptide (Fig. 2 Lower).”
Quote in the paperSubstantial claim - Findingown data
ApoE from cerebrospinal fluid binds with high avidity to synthetic beta-A4 peptide in vitro.
“In vitro, apolipoprotein E in cerebrospinal fluid binds to synthetic 13A4 peptide (the primary constituent of the senile plaque) with high avidity.”
- Also stated in: § MATERIALS AND METHODS · boosted
“Using this technique, we have demonstrated high-avidity binding of ApoE in CSF to ,BA4 peptide.”
Quote in the paperSubstantial claim - Also stated in: § MATERIALS AND METHODS · boosted
- Findingown data
The APOE-e4 allele occurs more frequently in late-onset familial Alzheimer disease patients than in age-matched unrelated controls.
“Analysis of apolipoprotein E alleles in Alzhei- mer disease and controls demonstrated that there was a highiy significant assocition of apolipoprotein E type 4 alele (APOE- e4) and late-onset familil Alzheimer disea.”
- Also stated in: § MATERIALS AND METHODS · plain
“Association studies ofAPOE alleles using DNA samples from one randomly selected familial Alzheimer disease patient from each of 30 families and from 91 age-matched unrelated controls showed that the frequency of the APOE-e4 allele in the 30 patients (0.50 ± 0.06) differed significantly from the frequency found in the 91 controls (0.16 ± 0.03; Z = 2.44, P = 0.014).”
- Also stated in: § MATERIALS AND METHODS · plain
“The association of the APOE-e4 allele with familial Alzheimer disease was significantly increased compared to the population controls and is consistent with prior analyses.”
Quote in the paperSubstantial claim- Rests on an assumption: The 91 unrelated CEPH grandparents used as controls are genetically comparable to the familial Alzheimer disease cases, so the allele frequency difference is not due to population stratification.
- Rests on an assumption: The two early-onset families in the sample do not materially affect the association between APOE-e4 and late-onset familial Alzheimer disease.
- Also stated in: § MATERIALS AND METHODS · plain
- Findingown data
The 12-28 amino acid segment of beta-A4 peptide is necessary for ApoE binding.
“Amino acids 12-28 of the flA4 peptide are required.”
- Also stated in: § MATERIALS AND METHODS · plain
“ApoE in CSF remained bound to immobilized (A4-(1-40), fA4-(1-28), andj'A4-(12-28) after incubation and washing with phosphate-buffer saline plus 5% SDS.”
Quote in the paperSubstantial claim - Also stated in: § MATERIALS AND METHODS · plain
- Interpretationown data
The combined peptide binding, immunochemistry, and allele association results suggest a more integrated role for ApoE in beta-A4 metabolism and targeting in Alzheimer disease.
“Our combined peptide binding data, immunochemistry, and allele association analyses suggest a more integrated role of ApoE in (3A4 metabolism and targeting in Alzheimer disease.”
Quote in the paperSubstantial claim- Rests on an assumption: In vitro binding of ApoE to synthetic beta-A4 peptides reflects a biologically relevant interaction that occurs in vivo.
- Interpretationown data
ApoE binding to beta-A4, the hydropathic mimic peptide, and prion protein plaque may depend on hydrophobic domains in those peptides.
“Binding of ApoE to PA4, to the hydropathic mimic peptide, and to the prion protein plaque may require the hydrophobic domains of each of these peptides.”
Quote in the paperSubstantial claim - Interpretationown data
The ApoE-E4 isoform may have a functional role in the pathogenesis of late-onset familial Alzheimer disease.
“A functional role of the apolipoprotein E-E4 isoform in the pathogenesis of late-onset familial Alzheimer dise is suggested.”
Quote in the paperSubstantial claim- Rests on an assumption: In vitro binding of ApoE to synthetic beta-A4 peptides reflects a biologically relevant interaction that occurs in vivo.
- Rests on an assumption: Localization of ApoE to Alzheimer disease lesions indicates a functional pathogenetic role rather than a secondary or incidental association.
- Interpretationreasoning
The presence of ApoE in the defining pathological lesions of Alzheimer disease suggests a functional pathogenetic role for ApoE.
“The ldcalization of ApoE to the defining pathological lesions of Alzheimer disease suggests a functional pathogenetic role for ApoE.”
Quote in the paperSubstantial claim- Rests on an assumption: Localization of ApoE to Alzheimer disease lesions indicates a functional pathogenetic role rather than a secondary or incidental association.
- Interpretationreasoning
ApoE binding to beta-A4 or other hydrophobic peptides may be a required step in targeting those peptides for their final intra- or extracellular metabolism.
“Binding of ApoE to .3A4peptide, or to other hydrophobic peptides, may be a requisite step in targeting these peptides for their final intra-or extracellular metabolism.”
Quote in the paperSubstantial claim- Rests on an assumption: In vitro binding of ApoE to synthetic beta-A4 peptides reflects a biologically relevant interaction that occurs in vivo.
- Interpretationreasoning
The APOE-e4 association with familial Alzheimer disease implies that allele-specific functions may contribute to the molecular mechanism of disease expression.
“The finding that the APOE-e4 allele is associated with familial Alzheimer disease patients has two major implications.First, there may be allele-specific functions that con- tribute to the molecular mechanism ofthe disease expression.”
Quote in the paperSubstantial claim - Premisecitation
The APOE locus falls in a chromosome 19 region previously linked to late-onset familial Alzheimer disease.
“The gene for apolipo- protein E is located on chromosome 19q13.2,within the region previously associated with linkage of late-onset familial Alz- heimer diseas.”
- Also stated in: § MATERIALS AND METHODS · hedged
“With nonparametric linkage analysis methods (15), genetic markers from chromosome 19q13.1-q13.3had previously suggested linkage to late-onset familial Alzheimer disease.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [15] 15. Pericak-Vance, M. A., Bebout, J. L., Gaskell, P. C., Jr., Ya- maoka, L. H., Hung, W. Y., Alberts, M. J., Walker, A. P., Bartlett, R. J., Haynes, C. A., Welsh, K. A., Earl, N. L., Heyman, A., Clark, C. M. & Roses, A. D. (1991) Am. J. Hum. Genet. 48, 1034-1050.
Not checked in the free run.
- Also stated in: § MATERIALS AND METHODS · hedged
- Interpretationreasoning
ApoE may be a shared factor in the pathogenesis or cellular response of several dementing diseases.
“ApoE may be a common denominator in either the pathogenesis or the cellular response of several dementing dis-Table 1.”
Quote in the paperSubstantial claim
- May combine two claims. 12
- Classified as probably not a substantial claim. 19
May combine two claims.
Findingown dataApoE protein is present in senile plaques, vascular amyloid, and neurofibrillary tangles in Alzheimer disease brain tissue.
“Apolipoprotein E is immunochemically local- ized to the senile plaques, vascular amyloid, and neuroflbrillary tangles of Alzheimer diwase.”
- Also stated in: § MATERIALS AND METHODS · plain
“Antiserum to ApoE stained amyloid plaques in tissues from Alzheimer disease patients and an aged lemur (Fig. 4 B and E).”
- Also stated in: § MATERIALS AND METHODS · plain
“ApoE is found in senile plaques, in neurofibrillary tangles, and-at the sites of congophilic angiopathy of Alzhei- mer disease”
Quote in the paperSubstantial claim- Also stated in: § MATERIALS AND METHODS · plain
May combine two claims.
Findingown dataAnti-ApoE antiserum stained amyloid plaques in Alzheimer disease patient tissue and in an aged lemur.
“Antiserum to ApoE stained amyloid plaques in tissues from Alzheimer disease patients and an aged lemur (Fig. 4 B and E).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAntithrombin did not bind beta-A4 peptide, but a contaminating protein did.
“Using the in vitro assay described here, we found that antithrombin, a related protein, did not bind the fA4 peptide but a contaminant protein did.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataGuanidine hydrochloride failed to elute ApoE from beta-A4-(12-28) peptide but eluted nearly all ApoE from the even-hydropathy control peptide.
“Guanidine hydrochloride did not elute ApoE from the 3A4-(12-28) peptide but did elute virtually all the ApoE bound to the even-hydropathy control peptide (Fig. 1 Lower, lanes 4).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationApoE has three major isoforms identified by amino acid sequencing: E3, E4, and E2.
“There are three major isoforms of ApoE identified by amino acid sequencing, designated ApoE-E3, ApoE-E4, and ApoE-E2.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [1] 1. Mahley, R. W. (1988) Science 240, 622-628.
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationAPOE mRNA is increased severalfold in Alzheimer disease brain and in scrapie-infected animal brain.
“APOE mRNA is increased severalfold in the brain of patients with Alzheimer disease and in the brain of animals with scrapie (10), a transmissible disease in animals that is similar to Creutzfeld-Jakob disease in humans and also exhibits prion protein plaques (9).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [10] 10. Diedrich, J. F., Minnigan, H., Carp, R. I., Whitaker, J. N., Race, R., Frey, W., II, & Haase, A. T. (1991) J. Virol. 65, 4759-4768.
Not checked in the free run.
- cites [9] 9. Prusiner, S. B., Hsiao, K. K., Bredesen, D. E. & DeArmond, S. J. (1989) in Handbook of Clinical Neurology, ed.
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationApoE is also bound in amyloid plaques of Creutzfeld-Jakob disease.
“ApoE is also bound in the amyloid plaques of another dementing degenerative disease, Creutzfeld-Jakob disease (8).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [8] 8. Namba, Y., Tomonaga, M., Kawasaki, H., Otomo, E. & Ikeda, K. (1991) Brain Res. 541, 163-166.
Not checked in the free run.
Probably not a substantial claim: may not pass S2 (checkable).
InterpretationcitationGiven that beta-A4 amyloid is a normal extracellular product in many cell types, specific ApoE-beta-A4 interactions could define additional mechanisms of Alzheimer disease pathogenesis.
“With the recent appreciation that 3A4 amyloid is a normal extracellular product in many cell types (26), the discovery of specific interactions between ApoE and ,SA4 could define additional mechanisms of Alz- heimer disease pathogenesis.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [26] 26. Haass, C., Schlossmacher, M. G., Hung, A. Y., Vigo-Pelfey, C., Mellon, A., Ostaszewski, B. L., Lieberburg, I., Koo, E. H., Schenk, D., Teplow, D. B. & Selkoe, D. J. (1992) Science 359, 322-325.
Not checked in the free run.
- Rests on an assumption: In vitro binding of ApoE to synthetic beta-A4 peptides reflects a biologically relevant interaction that occurs in vivo.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationApoE-E4 has arginine at residue 112, while E3 has cysteine.
“ApoE-E4 contains an arginine at residue 112, whereas E3 has a cysteine.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [1] 1. Mahley, R. W. (1988) Science 240, 622-628.
Not checked in the free run.
May combine two claims.
Study design and conductown dataAPOE-e4 allele frequency was similar across all 83 tested Alzheimer disease patients in the 30 families, supporting that the 30-patient random sample represented the families' e4 frequency.
“APOE-e4 frequency was similar for all 83 tested Alzheimer disease patients in the 30 families, indicating that the random sample used in the association analysis accurately represented the e4 allele frequency in the families (Table 1).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
InterpretationreasoningThe APOE-e4 association with familial Alzheimer disease implies that another intragenic polymorphism on an APOE-e4 background could confer susceptibility to Alzheimer disease.
“Second, there could also be another intragenic polymorphism on an APOE-e4 background that confers susceptibility to Alzheimer disease.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
PremisecitationThe APOE gene maps to chromosome 19q13.2.
“The gene for apolipo- protein E is located on chromosome 19q13.2,within the region previously associated with linkage of late-onset familial Alz- heimer diseas.”
- Also stated in: § MATERIALS AND METHODS · plain
“APOE is on the proximal long arm of chromosome 19, at 19q13.2 (1).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [1] 1. Mahley, R. W. (1988) Science 240, 622-628.
Not checked in the free run.
- Also stated in: § MATERIALS AND METHODS · plain
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationCreutzfeld-Jakob disease amyloid deposits contain prion protein, not the beta-A4 peptide found in Alzheimer disease.
“The amyloid deposits in Creutzfeld-Jakob disease contain the prion protein, not the 3A4 peptide in Alzheimer disease (9).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [9] 9. Prusiner, S. B., Hsiao, K. K., Bredesen, D. E. & DeArmond, S. J. (1989) in Handbook of Clinical Neurology, ed.
Not checked in the free run.
Classified as probably not a substantial claim. May combine two claims.
InterpretationreasoningA function involving binding, transport, and targeting of beta-A4 or other peptides may link the diagnostic lesions and genetic susceptibility, suggesting a functional role for ApoE isoforms in Alzheimer disease pathogenesis.
“A function involving the binding, transport, and targeting of 83A4 (or other peptides) may link the diagnostic lesions and genetic susceptibility, suggesting a functional role for ApoE isoforms in the mechanism of Alzheimer disease pathogenesis.”
Quote in the paperSubstantial claim- Rests on an assumption: In vitro binding of ApoE to synthetic beta-A4 peptides reflects a biologically relevant interaction that occurs in vivo.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
InterpretationcitationIntraneuronal ApoE staining may represent neurofibrillary tangles or early neuronal degeneration.
“In addition, intraneuronal staining was observed, which may represent staining of neurofibrillary tangles (8) or early degeneration of neurons (Fig. 4 D-F).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [8] 8. Namba, Y., Tomonaga, M., Kawasaki, H., Otomo, E. & Ikeda, K. (1991) Brain Res. 541, 163-166.
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationPCR-based restriction isotyping of APOE alleles has been developed for population studies.
“PCR-based restriction isotyping ofAPOE alleles has been developed for use in population'studies (13, 14).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [13] 13. Wenham, P. R., Price, W. H. & Blundell, G. (1991) Lancet 337, 1158-1159.
Not checked in the free run.
- cites [14] 14. Hixson, J. E. & Vernier, D. T. (1990)J. LipidRes. 31, 545-548.
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationBrain contains large amounts of APOE mRNA, second only to liver.
“Brain contains large quantities ofAPOE mRNA, second only to the liver (5).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [5] 5. Elshourbagy, N. A., Liao, W. S., Mahley, R. W. & Taylor, J. M. (1985) Proc. Natl. Acad. Sci. USA 82, 203-207.
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationSeveral proteins, including ApoE, APP, alpha1-antichymotrypsin, complement factors, and immunoglobulins, are associated with beta-A4.
“Several additional proteins are asso- ciated with 13A4, including ApoE, APP, a1-antichymotrypsin, complement factors, and immunoglobulins (12).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [12] 12. Beyreuther, K. & Masters, C. L. (1991) Brain Pathol. 1, 241-251.
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationApoE-E2 has cysteine at residue 158, while E3 has arginine.
“ApoE-E2 contains a cysteine at residue 158, whereas E3 has an arginine.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [1] 1. Mahley, R. W. (1988) Science 240, 622-628.
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Interpretationown dataThe association of APOE-e4 with familial Alzheimer disease is consistent with prior analyses.
“The association of the APOE-e4 allele with familial Alzheimer disease was significantly increased compared to the population controls and is consistent with prior analyses.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationAfter optic nerve crush in the central nervous system, ApoE binds to degenerating optic tracts and to retino-recipient layers of the lateral geniculate nucleus and superior colliculus.
“After crush injury to the central nervous system optic nerve, ApoE is bound to the degenerating optic tracts and to the retino-recipient layers of the lateral geniculate nucleus and the superior colliculus (7).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [7] 7. Snipes, G. J., McGuire, C. B., Norden, J. J. & Freeman, J. A. (1986) Proc. Nat!. Acad. Sci. USA 83, 1130-1134.
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationApoE is produced and secreted in the central nervous system by astrocytes.
“ApoE is pro- duced and secreted in the central nervous systram by astro- cytes (2-4).”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [2] 2. Ignatius, M. J., Gebicke-Harter, P. J., Skene, J. H. P., Schill- ing, J. W., Weisgraber, K. H., Mahley, R. W. & Shooter, E. M. (1986) Proc. Natl. Acad. Sci. USA 83, 1125-1129.
Not checked in the free run.
- cites [3] 3. Boyles, J., Pitas, R. E., Wilson, E., Mahley, R. W. & Taylor, J. M. (1985) J. Clin. Invest. 76, 1501-1513.
Not checked in the free run.
- cites [4] 4. Pitas, R. E., Boyles, J. K., Lee, S. H., Foss, D. & Mahley, R. W. (1987) Biochim. Biophys. Acta 917, 148-161.
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationIn the peripheral nervous system, ApoE synthesis increases 250- to 350-fold within 3 weeks after sciatic nerve crush, and ApoE makes up 5% of total soluble extracellular protein.
“In the peripheral nervous system, the synthesis of ApoE increases 250-to 350-fold within 3 weeks of sciatic nerve crush, and ApoE constitutes 5% of the total soluble extracellular protein (2, 6).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [2] 2. Ignatius, M. J., Gebicke-Harter, P. J., Skene, J. H. P., Schill- ing, J. W., Weisgraber, K. H., Mahley, R. W. & Shooter, E. M. (1986) Proc. Natl. Acad. Sci. USA 83, 1125-1129.
Not checked in the free run.
- cites [6] 6. Boyles, J. K., Zoellner, C. D., Anderson, L. J., Kosik, L. M., Pitas, R. E., Weisgraber, K. H., Hui, D. Y., Mahley, R. W., Gebicke-Haerter, P. J., Ignatius, M. J. & Shooter, E. M. (1989) J. Clin. Invest. 83, 1015-1031.
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationThese proteins and beta-A4 amyloid peptide are found around cerebral vessels in Alzheimer disease, producing congophilic angiopathy.
“These pro- teins, as well as the ,BA4 amyloid peptide, are also found surrounding cerebral vessels in Alzheimer disease, producing the”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [12] 12. Beyreuther, K. & Masters, C. L. (1991) Brain Pathol. 1, 241-251.
Not checked in the free run.
The paper relies on this without support.
In vitro binding of ApoE to synthetic beta-A4 peptides reflects a biologically relevant interaction that occurs in vivo.
“Using this technique, we have demonstrated high-avidity binding of ApoE in CSF to ,BA4 peptide.”
The paper relies on this without support.
The 91 unrelated CEPH grandparents used as controls are genetically comparable to the familial Alzheimer disease cases, so the allele frequency difference is not due to population stratification.
“Controls used in the study were 91 unrelated grandparents from the Centre d'Etude du Polymorphisme Humain (16).”
The paper relies on this without support.
The two early-onset families in the sample do not materially affect the association between APOE-e4 and late-onset familial Alzheimer disease.
“In 28 of the families the disease was of the late-onset type (mean age of onset >60 years of age), and in 2 of the families, early onset (mean age of onset < 60 years of age).”
The paper relies on this without support.
Localization of ApoE to Alzheimer disease lesions indicates a functional pathogenetic role rather than a secondary or incidental association.
“The ldcalization of ApoE to the defining pathological lesions of Alzheimer disease suggests a functional pathogenetic role for ApoE.”
The paper relies on this without support.
The synthetic beta-A4 peptide fragments used in the binding assay reproduce the relevant structural features of native beta-A4 in senile plaques.
“Preparation of Immobilized Peptides.fA4 peptides (Bachem) and other peptides were covalently immobilized on Immobilon AV affmity membrane (Millipore).”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Common APOE variants affect Alzheimer's disease risk: APOE4 carries high risk, APOE3 is viewed as neutral, and APOE2 is relatively protective.
“Common variants of the apolipoprotein E gene (APOE) influence the risk of Alzheimer’s disease: APOE4 is linked to high risk, APOE3 is considered to confer a neutral risk, and APOE2 is associated with relative protection.2–5”
From <i>APOE3</i> Christchurch Heterozygosity and Autosomal Dominant Alzheimer’s Disease (2024) · cites this paper as [2]
The allele-association passage reports that APOE-e4 was significantly more frequent in patients from families with Alzheimer’s disease than in controls, supporting its link to elevated risk in that setting. Table 1 also lists lower E2 frequency in patients than controls, but the paper does not establish that E2 is protective or characterize E3 as neutral. Its findings concern primarily late-onset familial Alzheimer’s disease, not Alzheimer’s disease generally. (LLM, conf=0.88)
Experimental — accuracy not yet measuredAPOE4 is the strongest genetic risk factor for Alzheimer's disease.
“APOE4 is the strongest genetic risk factor for Alzheimer’s disease (AD)1–3.”
From APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes (2022) · cites this paper as [3]
The paper reports a significant association between APOE-e4 and late-onset familial Alzheimer’s disease: its allele frequency was 0.50 in affected patients versus 0.16 in controls. It does not compare APOE4 with other genetic risk factors to establish that it is the strongest, or establish the claim for Alzheimer’s disease generally. (LLM, conf=0.87)
Experimental — accuracy not yet measuredAPOE ε4 is the strongest genetic risk factor for the most common form of late-onset Alzheimer's disease.
“Apolipoprotein E ε4 (APOE ε4) is the strongest genetic risk factor for Alzheimer’s disease (AD).”
From Haploinsufficiency of Human APOE Reduces Amyloid Deposition in a Mouse Model of Amyloid-β Amyloidosis (2011) · cites this paper as Strittmatter et al., 1993
The allele-association passage (Materials and Methods; page not supplied) reports significantly higher APOE ε4 frequency in patients from late-onset familial Alzheimer’s disease families than in controls. The paper does not establish that ε4 is the strongest genetic risk factor relative to other factors, and it says a separate report will address sporadic Alzheimer’s disease. It therefore supports an association in the studied families, not the broader claim as stated. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe APOE4 allele is a major genetic risk factor for late-onset Alzheimer's disease.
“The APOE4 allele is the strongest genetic risk factor for late-onset Alzheimer's disease (AD).”
From APOE4 impairs the microglial response in Alzheimer’s disease by inducing TGFβ-mediated checkpoints (2023) · cites this paper as [8]
The allele-association passage (labeled Materials and Methods; page not provided) reports a significantly higher APOE-e4 frequency in familial Alzheimer disease patients than in controls, supporting its importance as a genetic risk factor. The paper does not compare APOE-e4 with other genetic risk factors to establish the citing sentence’s claim that it is the strongest, and its findings concern predominantly late-onset familial disease rather than all late-onset Alzheimer’s disease. (LLM, conf=0.86)
Experimental — accuracy not yet measuredAPOE4 was previously shown to accelerate AD progression in humans and in mouse models.
“The APOE4 allele is a major genetic risk factor for late-onset AD and was previously shown to accelerate AD progression in humans and in mouse models 6-11 .”
From APOE4 impairs the microglial response in Alzheimer’s disease by inducing TGFβ-mediated checkpoints (2023) · cites this paper as [8]
The allele-association passage reports a significantly higher APOE-e4 frequency in people with familial Alzheimer disease than in controls, supporting the genetic-risk portion of the citing sentence. It does not show that APOE4 accelerates disease progression in humans or mouse models; searches for progression and mouse models found no such result. (LLM, conf=0.86)
Experimental — accuracy not yet measured
APOE4 is the largest monogenetic risk factor for Alzheimer's disease, while APOE2 is protective.
“Importantly, the APOE4 variant is the largest monogenetic risk factor for Alzheimer’s disease, while APOE2 is protective1,2.”
From Common germline variants of the human APOE gene modulate melanoma progression and survival (2020) · cites this paper as [1]
The allele-association analysis (section labeled MATERIALS AND METHODS; page not provided) finds APOE-e4 significantly more frequent in patients with late-onset familial Alzheimer disease than in controls. Table 1 shows a lower E2 frequency in those patients, but the paper does not establish that E2 is protective or compare E4 with other genetic risk factors to support calling it the largest monogenetic risk factor for Alzheimer’s disease generally. (LLM, conf=0.87)
Experimental — accuracy not yet measuredAPOE ε4 allele is the highest genetic risk factor for LOAD.
“Among these genes, apolipoprotein E ( APOE ; especially the APOE ε 4 allele) is the highest genetic risk factor for LOAD [23,24].”
From Is there a role for B cells in Alzheimer's disease? (2026) · cites this paper as [24]
The allele-association passage (section labeled Materials and Methods; page unavailable) reports that APOE ε4 was significantly more frequent in patients with late-onset familial Alzheimer disease than in controls. It does not compare APOE ε4 with other genetic risk factors or establish that it is the highest risk factor for LOAD generally; the paper says sporadic disease will be addressed in another report. (LLM, conf=0.88)
Experimental — accuracy not yet measuredAPOE4 exacerbates AD-related pathologies, including amyloid-beta plaques, Tau tangles, neurodegeneration and neuroinflammation.
“It exacerbates AD-related pathologies, including amyloid-beta (Aβ) plaques, Tau tangles, neurodegeneration and neuroinflammation4–16.”
From The APOE-R136S mutation protects against APOE4-driven tau pathology, neurodegeneration, and neuroinflammation (2023) · cites this paper as [12]
The Abstract reports that ApoE binds amyloid-beta and is present in senile plaques and neurofibrillary tangles; it also reports an association between APOE-e4 and late-onset familial Alzheimer disease. The passage labeled MATERIALS AND METHODS suggests a possible role for ApoE-E4 but does not establish that this isoform exacerbates those lesions. The cited passages do not support exacerbation of neurodegeneration or neuroinflammation. Page numbers are unavailable in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredApoE ɛ2 and ɛ3 bind to Aβ; this binding is lost in the apoE ɛ4 variant.
“ApoE ɛ2 and ɛ3 bind to Aβ; however, this is lost in the apoE ɛ4 variant [11, 12].”
From Discovery of a Missense Mutation (Q222K) of the <i>APOE</i> Gene from the Australian Imaging, Biomarker and Lifestyle Study (2023) · cites this paper as [12]
The binding results (indexed under Materials and Methods; page unavailable) show that ApoE in cerebrospinal fluid binds Aβ peptide, but they do not establish binding separately for ε2 and ε3. A later passage says differences in binding among ApoE isoforms are a possibility; it does not show that binding is lost in ε4. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe APOE4 variant is the major genetic risk factor for Alzheimer's disease at the population level.
“The APOE4 variant of apolipoprotein E was identified 30 years ago as the major genetic risk factor for Alzheimer’s Disease (AD) at the population level (Bennett et al, 2009; Corder et al, 1993; Strittmatter et al, 1993)”
From APOE from astrocytes restores Alzheimer’s Aβ-pathology and DAM-like responses in APOE deficient microglia (2024) · cites this paper as Strittmatter et al, 1993
The Abstract (p. 1977) reports a significant association between APOE-e4 and late-onset familial Alzheimer disease. It does not establish that APOE4 is the major genetic risk factor for Alzheimer’s disease at the population level; the reported comparison is between affected members of families and age-matched controls. (LLM, conf=0.88)
Experimental — accuracy not yet measuredAPOE4 significantly alters signaling pathways associated with cholesterol homeostasis and transport.
“Consistent with APOE’s biological function2–6, APOE4 significantly altered signaling pathways associated with cholesterol homeostasis and transport.”
From APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes (2022) · cites this paper as [3]
APOE exists as three polymorphic alleles (APOE2, APOE3, APOE4) which encode three protein isoforms (apoE2, apoE3, and apoE4) distinguished by single amino acid substitutions at positions 112 and 158.
“APOE exists as three polymorphic alleles (APOE2, APOE3, APOE4) which encode three protein isoforms (apoE2, apoE3, and apoE4) distinguished by single amino acid substitutions at positions 112 and 158”
From Older adult APOE4 mice exhibit modest immunometabolic adaptation following microglial APOE2 replacement (2027) · cites this paper as Strittmatter et al., 1993
APOE is the strongest genetic risk factor for LOAD.
“APOE is the strongest genetic risk factor for LOAD”
From Alzheimer Disease: An Update on Pathobiology and Treatment Strategies (2019) · cites this paper as Strittmatter et al., 1993
Variants of the apolipoprotein E allele account for most cases of late-onset Alzheimer's disease.
“Variants of the apolipoprotein E allele appear to account for most cases of late-onset Alzheimer's disease”
From Preclinical Evidence of Alzheimer's Disease in Persons Homozygous for the ε4 Allele for Apolipoprotein E (1996) · cites this paper as [1]
The e4 allele is associated with an increased risk of Alzheimer's disease.
“the e4 allele has been associated with an increased risk of Alzheimer's disease, 1-7”
From Preclinical Evidence of Alzheimer's Disease in Persons Homozygous for the ε4 Allele for Apolipoprotein E (1996) · cites this paper as [1]
Inheritance of the e4 allele of APOE is the only well-established genetic risk factor for sporadic AD.
“Inheritance of the e4 allele of APOE is the only well-established genetic risk factor for sporadic AD (147).”
From Unraveling a Multifactorial Late-Onset Disease: From Genetic Susceptibility to Disease Mechanisms for Age-Related Macular Degeneration (2009) · cites this paper as [147]
Expression of the ApoE4 allele is a major risk factor for sporadic AD.
“expression of the ApoE4 allele, a major risk factor for sporadic AD (Corder et al., 1993; Schmechel et al., 1993; Strittmatter et al., 1993), may be involved.”
From The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease (2011) · cites this paper as Strittmatter et al., 1993
Statistics recomputed
Every reported test result, recomputed from its test statistic and degrees of freedom. A result shows as not adding up only once an independent check has confirmed it.
- Consistentz = 2.44reported p = .014 · recomputed p = .015
“(Z = 2.44, p = .014”
- Consistentz = 2.44reported p = .014 · recomputed p = .015
“Z = 2.44, p = .014”
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Self-check results appear here once an independent check has confirmed them.
Cites
Apolipoprotein E: Cholesterol Transport Protein with Expanding Role in Cell Biology
Mahley, R. W. (1988) · Science · doi:10.1126/science.3283935 · Cited by 4,028 · see citing works
Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI.
Hixson, J., & Vernier, D. (1990) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)43176-1 · Cited by 2,933 · see citing works
The molecular pathology of Alzheimer's disease
Selkoe, D. J. (1991) · Neuron · doi:10.1016/0896-6273(91)90052-2 · Cited by 2,708 · see citing works
Amyloid β-peptide is produced by cultured cells during normal metabolism
Haass, C., Schlossmacher, M. G., Hung, A. Y., Vigo-Pelfrey, C., Mellon, A., Ostaszewski, B. L., Lieberburg, I., Koo, E. H., Schenk, D., Teplow, D. B., et al. (1992) · Nature · doi:10.1038/359322a0 · Cited by 1,921 · see citing works
Namba, Y., Tomonaga, M., Kawasaki, H., Otomo, E., & Ikeda, K. (1991) · Brain Research · doi:10.1016/0006-8993(91)91092-f · Cited by 1,157 · see citing works
Apolipoprotein E genotyping by one-stage PCR
Wenham, P. R., Price, W. H., & Blundell, G. (1991) · The Lancet · doi:10.1016/0140-6736(91)92823-k · Cited by 1,070 · see citing works
Boyles, J. K., Pitas, R. E., Wilson, E., Mahley, R. W., & Taylor, J. M. (1985) · Journal of Clinical Investigation · doi:10.1172/jci112130 · Cited by 829 · see citing works
Apolipoprotein E: a pathological chaperone protein in patients with cerebral and systemic amyloid
Wisniewski, T., & Frangione, B. (1992) · Neuroscience Letters · doi:10.1016/0304-3940(92)90444-c · Cited by 802 · see citing works
Linkage studies in familial Alzheimer disease: evidence for chromosome 19 linkage.
(1991) · Europe PMC (PubMed Central) · Cited by 758 · see citing works
Self-citationPitas, R. E., Boyles, J. K., Lee, S. H., Hui, D., & Weisgraber, K. H. (1987) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)47945-8 · Cited by 714 · see citing works
Goldfarb, L. G., Petersen, R. B., Tabaton, M., Brown, P., LeBlanc, A. C., Montagna, P., Cortelli, P., Julien, J., Vital, C., Pendelbury, W. W., et al. (1992) · Science · doi:10.1126/science.1439789 · Cited by 713 · see citing works
Astrocytes synthesize apolipoprotein E and metabolize apolipoprotein E-containing lipoproteins
Pitas, R. E., Boyles, J. K., Lee, S. H., Foss, D., & Mahley, R. W. (1987) · Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism · doi:10.1016/0005-2760(87)90295-5 · Cited by 693 · see citing works
Fatal Familial Insomnia, a Prion Disease with a Mutation at Codon 178 of the Prion Protein Gene
Medori, R., Tritschler, H., LeBlanc, A., Villare, F., Manetto, V., Chen, H. Y., Xue, R., Leal, S. M., Montagna, P., Cortelli, P., et al. (1992) · New England Journal of Medicine · doi:10.1056/nejm199202133260704 · Cited by 605 · see citing works
Centre d'Etude du polymorphisme humain (CEPH): Collaborative genetic mapping of the human genome
Dausset, J. B., Cann, H. M., Cohen, D., Lathrop, M. G., Lalouel, J.-M., & White, R. L. (1990) · Genomics · doi:10.1016/0888-7543(90)90491-c · Cited by 575 · see citing works
Expression of apolipoprotein E during nerve degeneration and regeneration.
Ignatius, M. J., Gebicke‐Haerter, P. J., Skene, J. H. P., Schilling, J., Weisgraber, K. H., Mahley, R. W., & Shooter, E. M. (1986) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.83.4.1125 · Cited by 568 · see citing works
Boyles, J. K., Zoellner, C. D., Anderson, L. J., Kosik, L. M., Pitas, R. E., Weisgraber, K. H., Hui, D. Y., Mahley, R. W., Gebicke‐Haerter, P. J., & Ignatius, M. J. (1989) · Journal of Clinical Investigation · doi:10.1172/jci113943 · Cited by 533 · see citing works
Elshourbagy, N. A., Liao, W. S. ‐., Mahley, R. W., & Taylor, J. M. (1985) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.82.1.203 · Cited by 509 · see citing works
Apolipoprotein E polymorphism and coronary artery disease.
Menzel, H. J., Kladetzky, R. G., & Assmann, G. (1983) · Arteriosclerosis An Official Journal of the American Heart Association Inc · doi:10.1161/01.atv.3.4.310 · Cited by 344 · see citing works
Alzheimer's disease : basic mechanisms, diagnosis and therapeutic strategies
Iqbal, K. (1991) · Wiley eBooks · Cited by 322 · see citing works
Diedrich, J. F., Minnigan, H. J., Carp, R. I., Whitaker, J. N., Race, R., Frey, W. H., & Haase, A. T. (1991) · Journal of Virology · doi:10.1128/jvi.65.9.4759-4768.1991 · Cited by 295 · see citing works
Nerve injury stimulates the secretion of apolipoprotein E by nonneuronal cells.
Snipes, G. J., McGuire, C. B., Norden, J. J., & Freeman, J. A. (1986) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.83.4.1130 · Cited by 258 · see citing works
Beyreuther, K., & Masters, C. L. (1991) · Brain Pathology · doi:10.1111/j.1750-3639.1991.tb00667.x · Cited by 221 · see citing works
Handbook of Clinical Neurology
Greer, M. (1972) · Neurology · doi:10.1212/wnl.22.7.769 · Cited by 215 · see citing works
Association of an apolipoprotein CII allele with familial dementia of the Alzheimer type
Schellenberg, G. D., Deeb, S. S., Boehnke, M., Bryant, E. M., Martin, G. M., Lampe, T. H., & Bird, T. D. (1987) · Journal of Neurogenetics · doi:10.3109/01677068709102337 · Cited by 93 · see citing works
Allele‐specific sequencing confirms novel prion gene polymorphism in Creutzfeldt‐Jakob disease
Fink, J. K., Warren, J. T., Drury, I., et al. (1991) · Neurology · doi:10.1212/wnl.41.10.1647 · Cited by 25 · see citing works
Flagged first, then by citations
1 of the 26 references couldn’t be matched to a known paper.
Research works printed but not linked: 4
- [2]2. Ignatius, M. J., Gebicke-Harter, P. J., Skene, J. H. P., Schill- ing, J. W., Weisgraber, K. H., Mahley, R. W. & Shooter, E. M. (1986) Proc. Natl. Acad. Sci. USA 83, 1125-1129.
- [5]5. Elshourbagy, N. A., Liao, W. S., Mahley, R. W. & Taylor, J. M. (1985) Proc. Natl. Acad. Sci. USA 82, 203-207.
- [7]7. Snipes, G. J., McGuire, C. B., Norden, J. J. & Freeman, J. A. (1986) Proc. Nat!. Acad. Sci. USA 83, 1130-1134.
- [22]22. Roses, A. D., Pericak-Vance, M. A., Saunders, A. M., Schmechel, D., Goldgaber, D. & Strittmatter, W. (1993) Epi- lepsia, in press.
Cited by
Sorted by citations
Corder, E. H., Saunders, A. M., Strittmatter, W. J., Schmechel, D. E., Gaskell, P. C., Small, G. W., Roses, A. D., Haines, J. L., & Pericak-Vance, M. A. (1993) · Science · doi:10.1126/science.8346443 · Cited by 9,429 · see citing works
Self-citationAlzheimer's Disease: Genes, Proteins, and Therapy
Selkoe, D. J. (2001) · Physiological Reviews · doi:10.1152/physrev.2001.81.2.741 · Cited by 6,063 · see citing works
Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease
Sherrington, R., Rogaev, E. I., Liang, Y., Rogaeva, E. A., Levesque, G., Ikeda, M., Chi, H., Lin, C., Li, G., Holman, K., et al. (1995) · Nature · doi:10.1038/375754a0 · Cited by 4,051 · see citing works
Self-citationGauthier, S. G., Reisberg, ., Zaudig, M., Petersen, R. C., Ritchie, K. A., Broich, K., Belleville, S., Brodaty, H., Bennett, D. A., Chertkow, H. M., et al. (2006) · The Lancet · doi:10.1016/s0140-6736(06)68542-5 · Cited by 3,920 · see citing works
Lambert, M. P., Barlow, A. K., Chromy, B. A., Edwards, C., Freed, R., Liosatos, M., Morgan, T. E., Rozovsky, I., Trommer, B., Viola, K. L., et al. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.11.6448 · Cited by 3,506 · see citing works
Alzheimer Disease: An Update on Pathobiology and Treatment Strategies
Long, J. M., & Holtzman, D. M. (2019) · Cell · doi:10.1016/j.cell.2019.09.001 · Cited by 3,204 · see citing works
“APOE is the strongest genetic risk factor for LOAD (Corder et al., 1993; Strittmatter et al., 1993).”
Influential<i>TREM2</i> Variants in Alzheimer's Disease
Guerreiro, R., Wojtas, A., Bras, J., Carrasquillo, M., Rogaeva, E., Majounie, E., Cruchaga, C., Sassi, C., Kauwe, J. S. K., Younkin, S., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1211851 · Cited by 3,020 · see citing works
The molecular pathology of Alzheimer's disease
Selkoe, D. J. (1991) · Neuron · doi:10.1016/0896-6273(91)90052-2 · Cited by 2,708 · see citing works
Variant of <i>TREM2</i> Associated with the Risk of Alzheimer's Disease
Jonsson, T., Stefansson, H., Steinberg, S., Jonsdottir, I., Jonsson, P. V., Snaedal, J., Bjornsson, S., Huttenlocher, J., Levey, A. I., Lah, J. J., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1211103 · Cited by 2,558 · see citing works
Karran, E., Mercken, M., & Strooper, B. D. (2011) · Nature Reviews Drug Discovery · doi:10.1038/nrd3505 · Cited by 2,188 · see citing works
“The apolipoprotein E ( APOE ) gene represents the major genetic risk factor for A”
BackgroundA Century of Alzheimer's Disease
Goedert, M., & Spillantini, M. G. (2006) · Science · doi:10.1126/science.1132814 · Cited by 2,106 · see citing works
The glymphatic system: a beginner's guide
Jessen, N. A., Munk, A. S. F., Lundgaard, I., & Nedergaard, M. (2015) · Neurochemical Research · doi:10.1007/s11064-015-1581-6 · Cited by 2,075 · see citing works
“maintaining homeostasis necessary for a healthy environment of the brain [60, 61].”
Microglia in Alzheimer’s disease
Hansen, D. V., Hanson, J. E., & Sheng, M. (2018) · Journal of Cell Biology · doi:10.1083/jcb.201709069 · Cited by 1,935 · see citing works
Amyloid Beta: Structure, Biology and Structure-Based Therapeutic Development
Chen, G.-F., Xu, T.-H., Yan, Y., Zhou, Y.-R., Jiang, Y., Melcher, K., & Xu, H. E. (2017) · Acta Pharmacologica Sinica · doi:10.1038/aps.2017.28 · Cited by 1,965 · see citing works
RAGE and amyloid-β peptide neurotoxicity in Alzheimer's disease
Yan, S. D., Chen, X., Fu, J., Chen, M., Zhu, H., Roher, A., Slattery, T., Zhao, L., Nagashima, M., Morser, J., et al. (1996) · Nature · doi:10.1038/382685a0 · Cited by 2,012 · see citing works
Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease
Corder, E. H., Saunders, A. M., Risch, N. J., Strittmatter, W. J., Schmechel, D. E., Gaskell, P. C., Rimmler, J. B., Locke, P. A., Conneally, P. M., Schmader, K. E., et al. (1994) · Nature Genetics · doi:10.1038/ng0694-180 · Cited by 1,920 · see citing works
Self-citationTwenty years of the Alzheimer's disease amyloid hypothesis: a genetic perspective
Tanzi, R. E., & Bertram, L. (2005) · Cell · doi:10.1016/j.cell.2005.02.008 · Cited by 1,849 · see citing works
Masters, C. L., Bateman, R., Blennow, K., Rowe, C. C., Sperling, R. A., & Cummings, J. L. (2015) · Nature Reviews Disease Primers · doi:10.1038/nrdp.2015.56 · Cited by 1,853 · see citing works
Enriched environments, experience-dependent plasticity and disorders of the nervous system
Nithianantharajah, J., & Hannan, A. J. (2006) · Nature Reviews Neuroscience · doi:10.1038/nrn1970 · Cited by 1,771 · see citing works
The role of apolipoprotein E in Alzheimer's disease
Kim, J., Basak, J. M., & Holtzman, D. M. (2009) · Neuron · doi:10.1016/j.neuron.2009.06.026 · Cited by 1,661 · see citing works
Translating cell biology into therapeutic advances in Alzheimer's disease
Selkoe, D. J. (1999) · Nature · doi:10.1038/399a023 · Cited by 1,588 · see citing works
Schmechel, D. E., Saunders, A. M., Strittmatter, W. J., Crain, B. J., Hulette, C. M., Joo, S. H., Pericak-Vance, M. A., Goldgaber, D., & Roses, A. D. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.20.9649 · Cited by 1,525 · see citing works
Self-citationEffects of antioxidant enzymes in the molecular control of reactive oxygen species toxicology
Matés, J. M. (2000) · Toxicology · doi:10.1016/s0300-483x(00)00306-1 · Cited by 1,510 · see citing works
Neuronal loss correlates with but exceeds neurofibrillary tangles in Alzheimer's disease
Gómez‐Isla, T., Hollister, R., West, H., Mui, S., Growdon, J. H., Petersen, R. C., Parisi, J. E., & Hyman, B. T. (1997) · Annals of Neurology · doi:10.1002/ana.410410106 · Cited by 1,489 · see citing works
Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer disease.
Uéda, K., Fukushima, H., Masliah, E., Xia, Y., Iwai, A., Yoshimoto, M., Otero, D. A., Kondo, J. D. M., Ihara, Y., & Saitoh, T. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.23.11282 · Cited by 1,469 · see citing works
Larson, E. B., Wang, L., Bowen, J. D., McCormick, W. C., Teri, L., Crane, P., & Kukull, W. (2006) · Annals of Internal Medicine · doi:10.7326/0003-4819-144-2-200601170-00004 · Cited by 1,463 · see citing works
Disease-Associated Microglia: A Universal Immune Sensor of Neurodegeneration
Deczkowska, A., Keren-Shaul, H., Weiner, A., Colonna, M., Schwartz, M., & Amit, I. (2018) · Cell · doi:10.1016/j.cell.2018.05.003 · Cited by 1,474 · see citing works
Alzheimer’s Disease: The Challenge of the Second Century
Holtzman, D. M., Morris, J. C., & Goate, A. M. (2011) · Science Translational Medicine · doi:10.1126/scitranslmed.3002369 · Cited by 1,424 · see citing works
“The e4 allele is a genetic risk factor for LOAD, whereas the e2 allele is protective (114, 115).”
BackgroundAlbert Hofman, D., Ott, A., Breteler, M. M. B., Bots, M. L., Slooter, A. J. C., van Harskamp, F., van Duijn, C. M., Broeckhoven, C. V., & Grobbee, D. E. (1997) · The Lancet · doi:10.1016/s0140-6736(96)09328-2 · Cited by 1,365 · see citing works
Reiman, E. M., Caselli, R. J., Yun, L. S., Chen, K., Bandy, D., Minoshima, S., Thibodeau, S. N., & Osborne, D. (1996) · New England Journal of Medicine · doi:10.1056/nejm199603213341202 · Cited by 1,366 · see citing works
Strittmatter, W. J., Weisgraber, K. H., Huang, D. Y., Dong, L. M., Salvesen, G. S., Pericak-Vance, M., Schmechel, D., Saunders, A. M., Goldgaber, D., & Roses, A. D. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.17.8098 · Cited by 1,363 · see citing works
Self-citationThe cognitive neuroscience of ageing
Grady, C. (2012) · Nature Reviews Neuroscience · doi:10.1038/nrn3256 · Cited by 1,286 · see citing works
Iwai, A., Masliah, E., Yoshimoto, M., Ge, N., Flanagan, L., Rohan de Silva, H. A., Kittel, A., & Saitoh, T. (1995) · Neuron · doi:10.1016/0896-6273(95)90302-x · Cited by 1,316 · see citing works
MCGEER, P., & MCGEER, E. (1995) · Brain Research Reviews · doi:10.1016/0165-0173(95)00011-9 · Cited by 1,287 · see citing works
Simons, K., & Ikonen, E. (2000) · Science · doi:10.1126/science.290.5497.1721 · Cited by 1,277 · see citing works
ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy
Initiative, A. D. N., Shi, Y., Yamada, K., Liddelow, S. A., Smith, S. T., Zhao, L., Luo, W., Tsai, R. M., Spina, S., Grinberg, L. T., et al. (2017) · Nature · doi:10.1038/nature24016 · Cited by 1,220 · see citing works
Lin, Y.-T., Seo, J., Gao, F., Feldman, H. M., Wen, H.-L., Penney, J., Cam, H. P., Gjoneska, E., Raja, W. K., Cheng, J., et al. (2018) · Neuron · doi:10.1016/j.neuron.2018.05.008 · Cited by 1,125 · see citing works
“The earliest identified and most significantly associated genetic risk factor for sAD is the E4 allele of the APOE which markedly increases AD risk relative to the APOE3 allele, while the APOE2 allele is considered protective (Corder et al., 1993; Lambert et al., 2013; Strittmatter et al., 1993).”
Genetic architectures of psychiatric disorders: the emerging picture and its implications
Sullivan, P. F., Daly, M. J., & O'Donovan, M. (2012) · Nature Reviews Genetics · doi:10.1038/nrg3240 · Cited by 1,177 · see citing works
Apolipoprotein E and its receptors in Alzheimer's disease: pathways, pathogenesis and therapy
Bu, G. (2009) · Nature Reviews Neuroscience · doi:10.1038/nrn2620 · Cited by 1,168 · see citing works
“This risk allele, which was discovered in 1993 by Strittmatter, Roses and colleague”
BackgroundStructural Brain Changes in Aging: Courses, Causes and Cognitive Consequences
Fjell, A. M., & Walhovd, K. B. (2010) · Reviews in the Neurosciences · doi:10.1515/revneuro.2010.21.3.187 · Cited by 1,085 · see citing works
Apolipoprotein E in sporadic Alzheimer's disease: Allelic variation and receptor interactions
William Rebeck, G., Reiter, J. S., Strickland, D. K., & Hyman, B. T. (1993) · Neuron · doi:10.1016/0896-6273(93)90070-8 · Cited by 1,107 · see citing works
Apolipoprotein E polymorphism and Alzheimer's disease
Poirier, J., Bertrand, P., Poirier, J., Kogan, S., Gauthier, S., Poirier, J., Gauthier, S., Davignon, J., Bouthillier, D., & Davignon, J. (1993) · The Lancet · doi:10.1016/0140-6736(93)91705-q · Cited by 1,108 · see citing works
Amyloidogenic processing of the Alzheimer β-amyloid precursor protein depends on lipid rafts
Ehehalt, R., Keller, P., Haass, C., Thiele, C., & Simons, K. (2003) · The Journal of Cell Biology · doi:10.1083/jcb.200207113 · Cited by 1,107 · see citing works
Genetic associations with human longevity at the APOE and ACE loci
Schächter, F., Faure-Delanef, L., Guénot, F., Rouger, H., Froguel, P., Lesueur-Ginot, L., & Cohen, D. (1994) · Nature Genetics · doi:10.1038/ng0194-29 · Cited by 1,095 · see citing works
The Alzheimer's Disease-Associated Amyloid β-Protein Is an Antimicrobial Peptide
Soscia, S. J., Kirby, J. E., Washicosky, K. J., Tucker, S. M., Ingelsson, M., Hyman, B., Burton, M. A., Goldstein, L. E., Duong, S., Tanzi, R. E., et al. (2010) · PLoS ONE · doi:10.1371/journal.pone.0009505 · Cited by 1,060 · see citing works
“At the other end of the spectrum, consistent with the increase risk of AD associated with the e4 variant of the apolipoprotein E gene [68], carriers of the e4 allele are reported to have higher rates of CNS infection for several of these pathogens [69].”
Yeh, F. L., Wang, Y., Tom, I., Gonzalez, L. C., & Sheng, M. (2016) · Neuron · doi:10.1016/j.neuron.2016.06.015 · Cited by 943 · see citing works
A Gene Map of the Human Genome
Schuler, G. D., Boguski, M. S., Stewart, E. A., Stein, L. D., Gyapay, G., Rice, K. M., White, R. E., Rodriguez‐Tomé, P., Aggarwal, A., Bajorek, E. S., et al. (1996) · Science · doi:10.1126/science.274.5287.540 · Cited by 1,046 · see citing works
Clinical epidemiology of Alzheimer&rsquo;s disease: assessing sex and gender differences
Mielke, M., Vemuri, P., & Rocca, W. (2014) · Clinical Epidemiology · doi:10.2147/clep.s37929 · Cited by 1,021 · see citing works
“The ε4 allele of the apolipoprotein ε (APOE) gene is the strongest known genetic risk factor for late-onset AD.(86,87) Compared to non-carriers, heterozygous carriers of one ε4 allele are 3–4 times more likely to develop AD, whereas the risk for homozygous carriers is even higher.”
Role of Glutamate and NMDA Receptors in Alzheimer’s Disease
Wang, R., & Reddy, P. H. (2017) · Journal of Alzheimer’s Disease · doi:10.3233/jad-160763 · Cited by 1,009 · see citing works
Hypercholesterolemia Accelerates the Alzheimer's Amyloid Pathology in a Transgenic Mouse Model
Refolo, L. M., Pappolla, M. A., Malester, B., LaFrancois, J. J., Bryant‐Thomas, T., Wang, R., Tint, G. S., Sambamurti, K., & Duff, K. (2000) · Neurobiology of Disease · doi:10.1006/nbdi.2000.0304 · Cited by 1,003 · see citing works
Functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer's dementia
Reiman, E. M., Chen, K., Alexander, G. E., Caselli, R. J., Bandy, D., Osborne, D., Saunders, A. M., & Hardy, J. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2635903100 · Cited by 977 · see citing works
Self-citationMechanisms of Neuronal Degeneration in Alzheimer's Disease
Yankner, B. A. (1996) · Neuron · doi:10.1016/s0896-6273(00)80115-4 · Cited by 947 · see citing works
Holtzman, D. M., Bales, K. R., Tenkova, T., Fagan, A. M., Parsadanian, M., Sartorius, L. J., Mackey, B., Olney, J., McKeel, D., Wozniak, D., et al. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.050004797 · Cited by 937 · see citing works
Cerebral amyloid angiopathy and Alzheimer disease — one peptide, two pathways
Greenberg, S. M., Bacskai, B. J., Hernandez-Guillamon, M., Pruzin, J., Sperling, R., & van Veluw, S. J. (2020) · Nature Reviews Neurology · doi:10.1038/s41582-019-0281-2 · Cited by 947 · see citing works
Mahley, R. W., Weisgraber, K. H., & Huang, Y. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0600549103 · Cited by 912 · see citing works
Variations in DNA elucidate molecular networks that cause disease
Chen, Y., Zhu, J., Lum, P. Y., Yang, X., Pinto, S., MacNeil, D. J., Zhang, C., Lamb, J., Edwards, S., Sieberts, S. K., et al. (2008) · Nature · doi:10.1038/nature06757 · Cited by 887 · see citing works
Brain glucose metabolism in the early and specific diagnosis of Alzheimer?s disease
Mosconi, L. (2005) · European Journal of Nuclear Medicine and Molecular Imaging · doi:10.1007/s00259-005-1762-7 · Cited by 900 · see citing works
Apolipoprotein E in Alzheimer’s disease and other neurological disorders
Verghese, P. B., Castellano, J. M., & Holtzman, D. M. (2011) · The Lancet Neurology · doi:10.1016/s1474-4422(10)70325-2 · Cited by 857 · see citing works
Ma, J., Yee, A., Brewer, H. B., Das, S., & Potter, H. (1994) · Nature · doi:10.1038/372092a0 · Cited by 871 · see citing works
Cell biology of protein misfolding: the examples of Alzheimer's and Parkinson's diseases
Selkoe, D. J. (2004) · Nature Cell Biology · doi:10.1038/ncb1104-1054 · Cited by 863 · see citing works
Apolipoprotein E: Structure and function in lipid metabolism, neurobiology, and Alzheimer’s diseases
Huang, Y., & Mahley, R. W. (2014) · Neurobiology of Disease · doi:10.1016/j.nbd.2014.08.025 · Cited by 829 · see citing works
The Genetics of Alzheimer Disease: Back to the Future
Bertram, L., Lill, C. M., & Tanzi, R. E. (2010) · Neuron · doi:10.1016/j.neuron.2010.10.013 · Cited by 834 · see citing works
<i>APOE</i> predicts amyloid‐beta but not tau Alzheimer pathology in cognitively normal aging
Morris, J. C., Roe, C. M., Xiong, C., Fagan, A. M., Goate, A. M., Holtzman, D. M., & Mintun, M. A. (2010) · Annals of Neurology · doi:10.1002/ana.21843 · Cited by 830 · see citing works
Apolipoprotein E: Structure-Function Relationships
Weisgraber, K. H. (1994) · Advances in Protein Chemistry · doi:10.1016/s0065-3233(08)60642-7 · Cited by 830 · see citing works
Alzheimer's Disease: Molecular Understanding Predicts Amyloid-Based Therapeutics
Selkoe, D. J., & Schenk, D. (2003) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.43.100901.140248 · Cited by 816 · see citing works
Apolipoprotein E and Apolipoprotein E Receptors: Normal Biology and Roles in Alzheimer Disease
Holtzman, D. M., Herz, J., & Bu, G. (2012) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a006312 · Cited by 782 · see citing works
“…Cite this article as Cold Spring Harb Perspect Med 2012;2:a006312 1 w w w .p er sp ec ti ve si n m ed ic in e. o rg E (APOE) genotype, with the 14 allele being an AD risk factor and the 12 allele being protective relative to the prevalent 13 allele (Corder et al. 1993; Strittmatter et al. 1993a).”
BackgroundInfluentialA Familial Alzheimer's Disease Locus on Chromosome 1
Levy‐Lahad, E., Wijsman, E. M., Nemens, E. J., Anderson, L., Goddard, K. A. B., Weber, J. L., Bird, T. D., & Schellenberg, G. D. (1995) · Science · doi:10.1126/science.7638621 · Cited by 811 · see citing works
The amyloid hypothesis for Alzheimer’s disease: A critical reappraisal
Hardy, J. (2009) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2009.06181.x · Cited by 814 · see citing works
Differential Effects of Apolipoproteins E3 and E4 on Neuronal Growth in Vitro
Nathan, B. P., Bellosta, S., Sanan, D. A., Weisgraber, K. H., Mahley, R. W., & Pitas, R. E. (1994) · Science · doi:10.1126/science.8171342 · Cited by 795 · see citing works
López, J. A., González, H. M., & Léger, G. C. (2019) · Handbook of clinical neurology · doi:10.1016/b978-0-12-804766-8.00013-3 · Cited by 834 · see citing works
Amyloid β-Protein and the Genetics of Alzheimer's Disease
Selkoe, D. J. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.31.18295 · Cited by 798 · see citing works
The Alzheimer’s disease mitochondrial cascade hypothesis: progress and perspectives
Swerdlow, R. H., Burns, J. M., & Khan, S. M. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2013.09.010 · Cited by 786 · see citing works
Reiman, E. M., Chen, K., Liu, X., Bandy, D., Yu, M., Lee, W., Ayutyanont, N., Keppler, J., Reeder, S. A., Langbaum, J. B. S., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0900345106 · Cited by 785 · see citing works
“The APOE 4 allele is associated with increased cerebral and vascular A deposition in AD (25), and the ApoE E4 isoform is associated with increased A binding, fibrillization, and cerebral and vascular A deposition (13, 26), as well as with decreased ApoE-mediated A clearance and degradation (27–29).”
BackgroundThe case for rejecting the amyloid cascade hypothesis
Herrup, K. (2015) · Nature Neuroscience · doi:10.1038/nn.4017 · Cited by 768 · see citing works
The Genetics of Alzheimer's Disease
Bertram, L., & Tanzi, R. E. (2012) · Progress in molecular biology and translational science · doi:10.1016/b978-0-12-385883-2.00008-4 · Cited by 784 · see citing works
apoE isoform–specific disruption of amyloid β peptide clearance from mouse brain
Deane, R., Sagare, A., Hamm, K., Parisi, M., Lane, S., Finn, M. B., Holtzman, D. M., & Zlokovic, B. V. (2008) · Journal of Clinical Investigation · doi:10.1172/jci36663 · Cited by 771 · see citing works
ApoE in Alzheimer’s disease: pathophysiology and therapeutic strategies
Raulin, A.-C., Doss, S. V., Trottier, Z. A., Ikezu, T. C., Bu, G., & Liu, C.-C. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00574-4 · Cited by 756 · see citing works
“APOE4 is a major genetic risk factor for AD in a gene dose-dependent manner increasing risk by up to 15 fold in homozygotes [13], whereas APOE2 reduces AD risk by almost half and contributes to longevity [14].”
BackgroundPetersen, R. C. (1995) · JAMA · doi:10.1001/jama.1995.03520400044042 · Cited by 783 · see citing works
Walking and Dementia in Physically Capable Elderly Men
Abbott, R. D. (2004) · JAMA · doi:10.1001/jama.292.12.1447 · Cited by 743 · see citing works
Thirty years of Alzheimer's disease genetics: the implications of systematic meta-analyses
Bertram, L., & Tanzi, R. E. (2008) · Nature Reviews Neuroscience · doi:10.1038/nrn2494 · Cited by 747 · see citing works
Šimić, G., Leko, M. B., Wray, S., Harrington, C. R., Delalle, I., Milošević, N. J., Bažadona, D., Buée, L., de Silva, R., Giovanni, G. D., et al. (2016) · Biomolecules · doi:10.3390/biom6010006 · Cited by 698 · see citing works
“The next nine genes with the highest association with LOAD are: BIN1 (BF = 23.4) that encodes several isoforms of a nucleoplasmic adaptor protein, one of which was identified as MYC-interacting protein, CLU (BF = 20.1) that encodes apolipoprotein J, ABCA7 (BF = 18.8) for ATP-binding cassette, subfamily A [ABC1], membe…”
BackgroundInfluentialTREM2 — a key player in microglial biology and Alzheimer disease
Ulland, T. K., & Colonna, M. (2018) · Nature Reviews Neurology · doi:10.1038/s41582-018-0072-1 · Cited by 735 · see citing works
History and progress of hypotheses and clinical trials for Alzheimer’s disease
Liu, P.-P., Xie, Y., Meng, X.-Y., & Kang, J.-S. (2019) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-019-0063-8 · Cited by 723 · see citing works
APOLIPOPROTEIN E ALLELES AS RISK FACTORS IN ALZHEIMER'S DISEASE
Roses, M. D. (1996) · Annual Review of Medicine · doi:10.1146/annurev.med.47.1.387 · Cited by 707 · see citing works
Self-citationApolipoprotein E and Alzheimer disease.
Strittmatter, W. J., & Roses, A. D. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.11.4725 · Cited by 699 · see citing works
Self-citationMotter, R., Vigo‐Pelfrey, C., Kholodenko, D., Barbour, R., Johnson‐Wood, K., Galasko, D., Chang, L., Miller, B., Clark, C., Green, R., et al. (1995) · Annals of Neurology · doi:10.1002/ana.410380413 · Cited by 701 · see citing works
Mahley, R. W., & Ji, Z.-S. (1999) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)33334-4 · Cited by 693 · see citing works
The genetic epidemiology of neurodegenerative disease
Bertram, L. (2005) · Journal of Clinical Investigation · doi:10.1172/jci24761 · Cited by 680 · see citing works
Schaefer, E. J., Bongard, V., Beiser, A. S., Lamon-Fava, S., Robins, S. J., Au, R., Tucker, K. L., Kyle, D. J., Wilson, P. W. F., & Wolf, P. A. (2006) · Archives of Neurology · doi:10.1001/archneur.63.11.1545 · Cited by 686 · see citing works
Risner, M. E., Saunders, A. M., Altman, J. F. B., Ormandy, G. C., Craft, S., Foley, I. M., Zvartau-Hind, M. E., Hosford, D. A., Roses, A. D., & for the Rosiglitazone in Alzheimer's Disease Study Group (2006) · The Pharmacogenomics Journal · doi:10.1038/sj.tpj.6500369 · Cited by 686 · see citing works
Self-citationChronic disability trends in elderly United States populations: 1982–1994
Mantón, K. G., Corder, L. S., & Stallard, E. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.6.2593 · Cited by 679 · see citing works
Yankner, B. A., Lu, T., & Loerch, P. (2008) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev.pathmechdis.2.010506.092044 · Cited by 677 · see citing works
Serum Total Cholesterol, Apolipoprotein E {FC12}e4 Allele, and Alzheimer’s Disease
Notkola, I.-L., Sulkava, R. O., Pekkanen, J., Erkinjuntti, T., Ehnholm, C., Kivinen, P., Tuomilehto, J., & Nissinen, A. (1998) · Neuroepidemiology · doi:10.1159/000026149 · Cited by 666 · see citing works
Vascular risk factors for Alzheimer’s disease:
Breteler, M. M. B. (2000) · Neurobiology of Aging · doi:10.1016/s0197-4580(99)00110-4 · Cited by 664 · see citing works
Apolipoprotein E (APOE) allele distribution in the world. Is APOE*4 a ‘thrifty’ allele?
Corbo, R. M., & Scacchi, R. (1999) · Annals of Human Genetics · doi:10.1046/j.1469-1809.1999.6340301.x · Cited by 653 · see citing works
Johnson‐Wood, K., Lee, M., Motter, R. N., Hu, K., Gordon, G., Barbour, R., Khan, K., Gordon, M. N., Tan, H. T., Games, D., et al. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.4.1550 · Cited by 634 · see citing works
Andreasen, N., Hesse, C., Davidsson, P., Minthon, L., Wallin, A., Winblad, B., Vanderstichele, H., Vanmechelen, E., & Blennow, K. (1999) · Archives of Neurology · doi:10.1001/archneur.56.6.673 · Cited by 660 · see citing works
Berg, L., McKeel, D. W., Miller, J. P., Storandt, M., Rubin, E. H., Morris, J. C., Baty, J., Coats, M., Norton, J., Goate, A. M., et al. (1998) · Archives of Neurology · doi:10.1001/archneur.55.3.326 · Cited by 657 · see citing works
Self-citationMesholam, R. I., Moberg, P. J., Mahr, R. N., & Doty, R. L. (1998) · Archives of Neurology · doi:10.1001/archneur.55.1.84 · Cited by 643 · see citing works
Apolipoprotein E Is a Ligand for Triggering Receptor Expressed on Myeloid Cells 2 (TREM2)
Atagi, Y., Liu, C.-C., Painter, M. M., Chen, X.-F., Verbeeck, C., Zheng, H., Li, X., Rademakers, R., Kang, S. S., Xu, H., et al. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.679043 · Cited by 587 · see citing works
- Authors
- Strittmatter, W. J., Saunders, A. M., Schmechel, D., Pericak-Vance, M., Enghild, J., Salvesen, G. S., & Roses, A. D.
- Affiliations
- Duke University (US)
- Department of Medicine (Neurology), Joseph and Kathleen Bryan Alzheimer's Disease Research Center, Duke University Medical Center, Durham, NC 27710.
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 1993-03
- Volume
- 90
- Issue
- 5
- Pages
- 1977-1981
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC46003
- OpenAlex
- W2021181758
- Cited by
- 4,268
- References
- 26
- Citations by year
- 2026: 67 · 2025: 107 · 2024: 97 · 2023: 108 · 2022: 99 · 2021: 106 · 2020: 116 · 2019: 111 · 2018: 117 · 2017: 104 · 2016: 121 · 2015: 140 · 2014: 123 · 2013: 112 · 2012: 134
- FWCI
- 125.11
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r35ag007922-07)
- National Institute on Aging (5P50 AG-O5128, P50AG005128, 5R35 AG-O7922)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- apolipoprotein E, APOE ε4, amyloid-beta, amyloid plaques, amyloid binding, allele frequency, genetic association, Alzheimer disease pathogenesis
- MeSH terms
- Alleles, Alzheimer Disease, Amino Acid Sequence, Animals, Apolipoproteins E, Brain, Gene Frequency, Humans, Lemur, Molecular Sequence Data, Peptides, Protein Binding, Solubility, Amyloid beta-Peptides
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-01.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-01.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
