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Cited by 1,530Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Soluble Amyloid β Peptide Concentration as a Predictor of Synaptic Change in Alzheimer's Disease

Open access
Lue, Lih-Fen, Kuo, Yu-Min, Roher, Alex E., Brachova, Libuse, Shen, Yong, Sue, Lucia, Beach, Thomas, Kurth, Janice H. +2 more·1999·The American Journal of Pathology
DOI 10.1016/s0002-9440(10)65184-xPMC PMC1866907
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Abstract

We have characterized amyloid beta peptide (Abeta) concentration, Abeta deposition, paired helical filament formation, cerebrovascular amyloid angiopathy, apolipoprotein E (ApoE) allotype, and synaptophysin concentration in entorhinal cortex and superior frontal gyrus of normal elderly control (ND) patients, Alzheimer's disease (AD) patients, and high pathology control (HPC) patients who meet pathological criteria for AD but show no synapse loss or overt antemortem symptoms of dementia. The measures of Abeta deposition, Abeta-immunoreactive plaques with and without cores, thioflavin histofluorescent plaques, and concentrations of insoluble Abeta, failed to distinguish HPC from AD patients and were poor correlates of synaptic change. By contrast, concentrations of soluble Abeta clearly distinguished HPC from AD patients and were a strong inverse correlate of synapse loss. Further investigation revealed that Abeta40, whether in soluble or insoluble form, was a particularly useful measure for classifying ND, HPC, and AD patients compared with Abeta42. Abeta40 is known to be elevated in cerebrovascular amyloid deposits, and Abeta40 (but not Abeta42) levels, cerebrovascular amyloid angiopathy, and ApoE4 allele frequency were all highly correlated with each other. Although paired helical filaments in the form of neurofibrillary tangles or a penumbra of neurites surrounding amyloid cores also distinguished HPC from AD patients, they were less robust predictors of synapse change compared with soluble Abeta, particularly soluble Abeta40. Previous experiments attempting to relate Abeta deposition to the neurodegeneration that underlies AD dementia may have failed because they assayed the classical, visible forms of the molecule, insoluble neuropil plaques, rather than the soluble, unseen forms of the molecule.

AI snapshot

Written from the paper’s full text.

TL;DR

In postmortem entorhinal cortex and superior frontal gyrus, soluble amyloid β peptide (Aβ) concentration—especially soluble Aβ40—distinguished high-pathology controls (HPC) from Alzheimer’s disease (AD) patients and inversely correlated with synapse loss, whereas insoluble Aβ and visible plaque measures did not. The authors argue that soluble, unseen Aβ rather than insoluble plaque deposits better explains Aβ-related synaptic change in AD.

Key findings

  • Soluble Aβ concentrations were sevenfold higher in HPC than ND patients and sevenfold lower in HPC than AD patients; soluble Aβ was a significant inverse within-subjects correlate of synapse loss across all groups (r = −0.58, P < 0.0001) and in HPC plus AD patients alone (r = −0.53, P < 0.002).
  • Soluble Aβ40 was the strongest predictor: in stepwise linear regression, soluble Aβ40 and Aβ42 accounted for 40% of variance in synaptic change, with no other significant predictors; in AD patients alone, R² = 0.38, P < 0.01, and soluble Aβ40 accounted for substantially more variance than soluble Aβ42.
  • Insoluble Aβ and plaque measures failed to distinguish HPC from AD patients: HPC had only 16% fewer thioflavin-positive plaques, 20% fewer plaques without cores, and 27% more plaques with cores than AD patients, all nonsignificant.
  • Aβ40 was more useful than Aβ42 for classifying groups: HPC vs AD differed significantly for soluble Aβ40 (F₁,₁₄ = 18.0, P < 0.0009) and insoluble Aβ40 (F₁,₁₄ = 5.3, P < 0.04), but not for soluble Aβ42 (F₁,₁₄ = 1.4, P > 0.50). ApoE4 allele frequency correlated with Aβ40 levels and cerebrovascular amyloid angiopathy, but not with Aβ42 levels.

Methods

  • Postmortem brain samples from 8 ND, 8 HPC, and 8 AD patients; HPC patients met pathological criteria for AD but showed no synapse loss or overt antemortem dementia symptoms. Entorhinal cortex and superior frontal gyrus were assayed.
  • Soluble and insoluble Aβ40/Aβ42 were measured by europium immunoassay; CSF Aβ42 was measured separately. Plaque type, cerebrovascular amyloid angiopathy, and paired helical filament formation were assessed by thioflavin histofluorescence and immunohistochemistry; synaptic density was estimated by synaptophysin Western blot; ApoE allele frequency was determined by PCR and restriction digestion.
  • Analyses used two-way repeated-measures ANOVA, Kruskal-Wallis and Mann-Whitney tests for nonparametric measures, Pearson correlations, and stepwise linear regression with synapse change as the outcome.

Limitations

  • Stated: the study lacked definitive premortem cognitive status data and therefore focused on postmortem synapse loss rather than dementia itself. The soluble/insoluble Aβ distinction is a working definition based on centrifugation, and the assay does not discriminate full-length Aβ from Aβ fragments.
  • Stated: ApoE4 representation was unbalanced—no ND patient carried an ApoE4 allele—which violates ANOVA assumptions; significant ApoE4 effects on plaque and tangle burden vanished when only HPC and AD groups or AD patients alone were considered.
  • Evident: sample sizes were small (8 per group), the design was correlational, and HPC classification was retrospective with possible misassignment of one ND and one HPC patient noted by the authors.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/s0002-9440(10)65184-x

Cites

35 of 35 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 16 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Soluble A␤ concentrations distinguished HPC from AD patients.

    “By contrast , concentrations of soluble A␤ clearly distinguished HPC from AD patients and were a strong inverse correlate of synapse loss.”
    • Also stated in: § Soluble and Insoluble A␤40 and A␤42 Concentrations (Figure 2) · plain
      “HPC patients had sevenfold higher soluble A␤ concentrations than ND patients (F 1,14 ϭ 10.0, P Ͻ 0.008) and sevenfold lower soluble A␤ concentrations than AD patients (F 1,14 ϭ 24.2, P Ͻ 0.003).”
    Quote in the paperSubstantial claim
  • Findingown data

    Soluble A␤ concentrations were a strong inverse correlate of synapse loss.

    “By contrast , concentrations of soluble A␤ clearly distinguished HPC from AD patients and were a strong inverse correlate of synapse loss.”
    • Also stated in: § Soluble and Insoluble A␤40 and A␤42 Concentrations (Figure 2) · plain
      “Soluble A␤ levels were a significant, inverse, within-subjects correlate of synapse loss regardless of whether all groups (r ϭ Ϫ0.58, P Ͻ 0.0001) or the HPC and AD groups (r ϭ Ϫ0.53, P Ͻ 0.002) were considered (Figure 3, A-C).”
    Quote in the paperSubstantial claim
  • Findingown data

    Measures of A␤ deposition were poor correlates of synaptic change.

    “The measures of A␤ deposition , A␤-immunoreactive plaques with and without cores , thioflavin histofluorescent plaques, and concentrations of insoluble A␤, failed to distinguish HPC from AD patients and were poor correlates of synaptic change.”
    • Also stated in: § A␤ Deposition · plain
      “Across the brain regions evaluated, none of these measures was a significant within-subjects correlate of synapse loss when all of the groups or the HPC and AD groups together were considered.”
    Quote in the paperSubstantial claim
  • Findingown data

    Of the many variables studied, soluble A␤ concentrations best distinguished HPC from AD patients.

    “Rather, of the many variables studied, soluble A␤ concentrations best distinguished HPC from AD patients.”
    Quote in the paperSubstantial claim
  • Findingown data

    Paired helical filaments in the form of neurofibrillary tangles or a penumbra of neurites surrounding amyloid cores distinguished HPC from AD patients.

    “Although paired helical filaments in the form of neurofibrillary tangles or a penumbra of neurites surrounding amyloid cores also distinguished HPC from AD patients, they were less robust predictors of synapse change compared with soluble A␤,”
    • Also stated in: § Paired Helical Filament Formation · plain
      “Paired helical filament formation in the form of thioflavin histofluorescent neurofibrillary tangles was significantly greater in HPC compared with ND patients (Ͼ1400%; F 1,14 ϭ 22.8, P Ͻ 0.0003), whereas it was significantly lower (Ͻ80%) in HPC compared with AD patients (F 1,14 ϭ 8.7, P Ͻ 0.02).”
    Quote in the paperNot a substantial claim
  • May combine two claims. 29
  • Classified as probably not a substantial claim. 15

  • May combine two claims.

    Findingown data

    A␤40 (but not A␤42) levels, cerebrovascular amyloid angiopathy, and ApoE4 allele frequency were all highly correlated with each other.

    “A␤40 is known to be elevated in cerebrovascular amyloid deposits, and A␤40 (but not A␤42) levels , cerebrovascular amyloid angiopathy , and ApoE4 allele frequency were all highly correlated with each other.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: A␤40 is elevated in cerebrovascular amyloid deposits.

  • May combine two claims.

    Findingown data

    Cerebrovascular amyloid angiopathy successfully discriminated HPC from ND patients and HPC from AD patients.

    “This variable successfully discriminated HPC from ND patients (U ϭ 88, P Ͻ 0.02) and HPC from AD patients (U ϭ 62, P Ͻ 0.007).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    PHF1 immunoreactivity of neurites surrounding amyloid cores was significantly lower in HPC compared with AD patients but statistically similar in HPC and ND patients.

    “PHF1 immunoreactivity of neurites surrounding amyloid cores was also significantly lower (Ͼ80%) in HPC compared with AD patients (F 1,14 ϭ 11.9, P Ͻ 0.004), but was statistically similar (0% difference) in HPC and ND patients (F 1,14 ϭ 0.0, P Ͼ 0.50).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The HPC group exhibited significantly greater numbers of thioflavin histofluorescent plaques (>1200%), plaques without cores (>4800%), or plaques with cores (>2700%) compared with the ND group.

    “The HPC group exhibited significantly greater numbers of thioflavin histofluorescent plaques (Ͼ1200%; F 1,14 ϭ 35.2, P Ͻ 0.0001), plaques without cores (Ͼ4800%; F 1,14 ϭ 38.3, P Ͻ 0.0001), or plaques with cores (Ͼ2700%; F 1,14 ϭ 26.6, P Ͻ 0.0002) compared with the ND group”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    HPC patients had sevenfold higher soluble A␤ concentrations than ND patients and sevenfold lower soluble A␤ concentrations than AD patients.

    “In contrast to the results for insoluble A␤, HPC patients had sevenfold higher soluble A␤ concentrations than ND patients (F 1,14 ϭ 10.0, P Ͻ 0.008) and sevenfold lower soluble A␤ concentrations than AD patients (F 1,14 ϭ 24.2, P Ͻ 0.003).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Both PHF measures (tangles and PHF1 immunoreactivity) were significant, inverse, within-subjects correlates of synaptic loss.

    “Both measures were significant, inverse, within-subjects correlates of synaptic loss (for tangles, R all groups ϭ Ϫ0.45, P Ͻ 0.002, and R HPCϩAD ϭ Ϫ0.38, P Ͻ 0.04; for PHF1 immunoreactivity, R all groups ϭ Ϫ0.48, P Ͻ 0.006, and R HPCϩAD ϭ Ϫ0.44, P Ͻ 0.02; Figure 4).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The association of soluble A␤40 with synapse changes was especially striking and could be observed in AD patients alone even in a single brain region.

    “The association of soluble A␤40 with synapse changes was especially striking and could be observed in AD patients alone even in a single brain region (Figure 3D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Insoluble A␤ levels within groups were often highly variable; mean insoluble A␤40 in AD entorhinal cortex was 53.7 ± 25.9 g/g, 38-fold higher than HPC entorhinal cortex, but one-half of AD patients had concentrations less than 4 g/g, overlapping HPC values, leading to a nonsignificant comparison.

    “Although in some instances there was a substantial difference among group means, insoluble A␤ levels within groups were often highly variable.Mean insoluble A␤40 in AD entorhi-nal cortex, for example, was 53.7 Ϯ 25.9 g/g, some 38-fold higher than the mean for HPC entorhinal cortex.However, one-half of the AD patients actually had concentrations less than 4 g/g, substantially overlapping the values”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The comparison of HPC with AD patients barely reached significance for insoluble A␤42 and did not reach significance for soluble A␤42.

    “For example, the comparison of HPC with AD patients barely reached signifi- cance for insoluble A␤42 (F 1,14 ϭ 7.2, P Ͻ 0.02) and did not reach significance for soluble A␤42 (F 1,14 ϭ 1.4, P Ͼ 0.50).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Paired helical filament formation in the form of thioflavin histofluorescent neurofibrillary tangles was significantly greater in HPC compared with ND patients and significantly lower in HPC compared with AD patients.

    “Paired helical filament formation in the form of thioflavin histofluorescent neurofibrillary tangles was significantly greater in HPC compared with ND patients (Ͼ1400%; F 1,14 ϭ 22.8, P Ͻ 0.0003), whereas it was significantly lower (Ͻ80%) in HPC compared with AD patients (F 1,14 ϭ 8.7, P Ͻ 0.02).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Soluble A␤40 was a very robust predictor of synapse loss, giving significant inverse correlations over all patients and within the AD group alone.

    “Soluble A␤40, in particular, was a very robust predictor of synapse loss, giving significant inverse correlations over all patients and within the AD group alone.”
    • Also stated in: § Soluble and Insoluble A␤40 and A␤42 Concentrations (Figure 2) · hedged
      “The association of soluble A␤40 with synapse changes was especially striking and could be observed in AD patients alone even in a single brain region (Figure 3D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    ApoE4 allele distributions were: none of ND patients heterozygous or homozygous; three HPC heterozygous and none homozygous; three AD heterozygous and three homozygous.

    “Of the ND patients sampled, none were heterozygous or homozygous for the ApoE4 allele.Of the HPC patients sampled, three were heterozygous and none were homozygous for the E4 allele.Of the AD patients sampled, three were heterozygous and three were homozygous for the E4 allele.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    HPC patients had only 16% fewer thioflavin-positive plaques, 20% fewer plaques without cores, and 27% more plaques with cores compared with AD patients, and these differences were not significant.

    “Indeed, HPC patients had only 16% fewer thioflavin-positive plaques (F 1,14 ϭ 0.6, P Ͼ 0.50), 20% fewer plaques without cores (F 1,14 ϭ 1.4, P Ͼ 0.50), and 27% more plaques with cores (F 1,14 ϭ 0.6, P Ͼ 0.50).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    HPC patients had significantly higher (>36%) synaptophysin immunoreactivity on Western blot analysis compared with AD patients, whereas they did not differ from ND patients (7% difference).

    “As in our previous study, 5 HPC patients had significantly higher (Ͼ36%) synaptophysin immunoreactivity on Western blot analysis compared with AD patients (F 1,14 ϭ 25.8, P Ͻ 0.0003), whereas they did not differ from ND patients on this measure (F 1,14 ϭ 1.9, P Ͼ 0.50, 7% difference; Table 1).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [5] Lue, 1996, Inflammation, Aβ deposition, and neurofibrillary tangle formation as correlates of Alzheimer's disease neurodegeneration, J Neuropathol Exp Neurol source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Soluble A␤42, measured in ventricular CSF, distinguished HPC from AD but not ND patients.

    “Soluble A␤42, measured in ventricular CSF, also distinguished HPC from AD (F 1,14 ϭ 9.3, P Ͻ 0.01) but not ND (F 1,14 ϭ 0.1, P Ͼ 0.5) patients.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In contrast to previous qualitative observations, the type and number of A␤ deposits were similar in HPC and AD groups.

    “In contrast to previous qualitative observations wherein an absence of cored A␤ deposits was suggested to discriminate HPC from AD patients, 3,8 we found the type and number of A␤ deposits to be similar in these groups.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [3] Dickson, 1991, Identification of normal and pathological aging in prospectively studied nondemented elderly humans, Neurobiol Aging source

      Not checked in the free run.

    • cites [8] Dickson, 1995, Apolipoprotein E immunoreactivity is increased in amyloid deposits of Alzheimer's disease, but not pathological aging or diffuse Lewy body disease

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Insoluble A␤ (insoluble A␤40 plus A␤42) distinguished HPC from ND patients but failed to discriminate HPC from AD patients.

    “Like the A␤ plaques that can be seen under the microscope, concentrations of insoluble A␤ (insoluble A␤40 plus A␤42) distinguished HPC from ND patients (F 1,14 ϭ 89.2, P Ͻ 0.0001), but failed to discriminate HPC from AD patients (F 1,14 ϭ 2.8, P Ͼ 0.30).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Neither insoluble Aβ42 nor the other measures associated with it accounted for AD synapse loss or the absence of overt dementia in HPC patients.

    “neither it nor the other measures associated with it (eg, neuropil plaques) accounted for AD synapse loss or the absence of overt dementia in HPC patients.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Synaptophysin optical density is a valid measure of synaptic density.

  • May combine two claims.

    Findingown data

    Only one of eight HPC patients exhibited any tangles in superior frontal gyrus, and these were sparse.

    “Only one of eight HPC patients exhibited any tangles in superior frontal gyrus, and these were sparse”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingnone given

    Several of the variables assayed here meet this criterion, and several others do not.

    “Several of the variables assayed here meet this criterion, and several others do not.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    The demonstration that a significant correlation across several experimental groups continues to hold when only one group or another is examined strengthens any within-subjects inferences drawn from the data.

    “Similarly, the demonstration that a significant correlation across several experimental groups continues to hold when only one group or another is examined also strengthens any within-subjects inferences that might be drawn from the data.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Patients were selected for study without any prior knowledge of their ApoE types.

    “We note that patients were selected for study without any prior knowledge of their ApoE types.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    Patients in the AD, HPC, and ND groups were well matched, with statistically similar values for age, gender, postmortem interval, and length of sample storage.

    “Patients in the AD, HPC, and ND groups were well matched, with statistically similar values for age, gender, postmortem interval, and length of sample storage.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The soluble fraction appears to contain A␤ oligomers in size ranges >100 kd, 30 to 100 kd, 10 to 30 kd, and <10 kd, corresponding to assemblies of >22 molecules, 7 to 22 molecules, 3 to 7 molecules, and monomers/dimers.

    “By ultrafiltration and molecular sieving the soluble fraction appears to contain A␤ oligomers that fall within the following size ranges: Ͼ100 kd, 30 to 100 kd, 10 to 30 kd, and Ͻ10 kd, corresponding to assemblies of Ͼ22 molecules, 7 to 22 molecules, 3 to 7 molecules, and monomers/dimers.15”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [15] Kuo, 1996, Water-soluble Aβ(N-40, N-42) oligomers in normal and Alzheimer disease brains, J Biol Chem source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductreasoning

    In the absence of more definitive premortem cognitive status data, the present research focuses on synapse loss, a postmortem correlate of dementia, and not on dementia itself.

    “Nonetheless, in the absence of more definitive premortem cognitive status data, the present research focuses on a correlate of dementia that is quantifiable postmortem, synapse loss, 11,12 and not on dementia itself.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [11] Scheff, 1990, Quantitative assessment of cortical synaptic density in Alzheimer's disease, Neurobiol Aging source

      Not checked in the free run.

    • cites [12] Terry, 1991, Physical basis of cognitive alteration in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment, Ann Neurol source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    No material differences were observed in staining by antibodies 6E10 and 4G8, and the mean is presented.

    “No material differences were observed in staining by these antibodies, and the mean is presented here.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductown data

    The CSF A␤42 data point for one patient was excluded because it was more than seven standard deviations from the other patients and more than twice the next highest, and this exclusion altered the significance test by ANOVA from P < 0.10 to P < 0.01.

    “The CSF A␤42 data point for one patient was excluded from analysis because it exhibited a mean value more than seven standard deviations from the other patients and more than twice that of the next highest patient.This exclusion altered the significance test by ANOVA from P Ͻ 0.10 to P Ͻ 0.01.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    The EuIA assay correctly distinguishes A␤40 from A␤42 carboxy terminus but does not discriminate full-length A␤ from A␤ fragments.

    “We note that, while correctly distinguishing the A␤40 from the A␤42 carboxy terminus of the peptides, our EuIA assay does not discriminate fulllength A␤ from A␤ fragments.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductreasoning

    To ensure that significant correlations did not result simply from an anchoring of the data at one extreme by ND patients, Pearson's tests were re-run using HPC and AD patients only.

    “To ensure that significant correlations did not result simply from an anchoring of the data at one extreme by ND patients, Pearson's tests were re-run using HPC and AD patients only.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Previous studies have found significant differences in CSF A␤42 when AD patients were compared with ND patients.

    “We note that previous studies have found significant differences in CSF A␤42 when AD patients were compared with ND patients (cf Ref. 16).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Ref. 16

      Not checked in the free run.

  • May combine two claims.

    Study design and conductown data

    The study and others did not include balanced representation of ApoE4 allele frequency in all patient groups because patients were randomly selected from the available autopsy pool; no ND patient was heterozygous or homozygous for ApoE4.

    “Although all of the measures of visible AD pathology (ie, thioflavin histofluorescent plaques, diffuse plaques, cored plaques, PHF1-immunoreactive plaques, and thioflavin histofluorescent tangles) exhibited significant effects of ApoE4 allele frequency, it is important to recognize that our study and others (cf Ref. 22) did not include balanced representation of ApoE4 allele frequency in all of”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Ref. 22

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Counts of the various elements were recorded by an observer blind to disease state.

    “As in our previous research, 5 counts of the various elements at ϫ100 final magnification were recorded by an observer blind to disease state.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] Lue, 1996, Inflammation, Aβ deposition, and neurofibrillary tangle formation as correlates of Alzheimer's disease neurodegeneration, J Neuropathol Exp Neurol source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    ApoE4 appears mainly to increase cerebrovascular amyloid burden, as previously reported, as well as soluble amyloid burden.

    “Rather, ApoE4 appears mainly to increase cerebrovascular amyloid burden, as previously reported, 33 as well as soluble amyloid burden.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [33] Olichney, 1996, The apolipoprotein E ε4 allele is associated with increased neuritic plaques and cerebral amyloid angiopathy in Alzheimer's disease and Lewy body variant, Neurology source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Insoluble Aβ42 is the primary constituent of the neuritic plaque.

    “the primary constituent of the neuritic plaque.29”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [29] Roher, 1993, β-Amyloid-(42) is a major component of cerebrovascular amyloid deposits: implications for the pathology of Alzheimer's disease, Proc Natl Acad Sci USA source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Although the two brain regions have different predilections for AD changes, such changes occur in parallel in both structures.

    “suggesting that although the two brain regions have different predilections for AD changes, such changes occur in parallel in both structures.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    One would expect a pathophysiologically relevant process to be present in AD patients but significantly reduced or absent in HPC or preclinical AD patients.

    “That is, one would expect a pathophysiologically relevant process to be present in AD patients but significantly reduced or absent in HPC or preclinical AD patients.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: HPC patients represent a preclinical or early AD state relevant to understanding AD pathophysiology.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Nearly identical results were obtained in the authors' previous research with six other HPC patients.

    “Nearly identical results were obtained in our previous research with six other HPC patients.5”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] Lue, 1996, Inflammation, Aβ deposition, and neurofibrillary tangle formation as correlates of Alzheimer's disease neurodegeneration, J Neuropathol Exp Neurol source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Similar results on brain regional changes in AD pathology were obtained in the authors' previous study of ND, HPC, and AD patients.

    “Similar results on brain regional changes in AD pathology were obtained in our previous study of ND, HPC, and AD patients.5”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] Lue, 1996, Inflammation, Aβ deposition, and neurofibrillary tangle formation as correlates of Alzheimer's disease neurodegeneration, J Neuropathol Exp Neurol source

      Not checked in the free run.

38 of 38

  • The paper relies on this without support.

    A␤40 is elevated in cerebrovascular amyloid deposits.

    “A␤40 is known to be elevated in cerebrovascular amyloid deposits”

  • The paper relies on this without support.

    HPC patients represent a preclinical or early AD state relevant to understanding AD pathophysiology.

    “Comparisons of HPC with AD patients can help indicate pathophysiological processes that may be critical to the development of overt dementia.”

  • The paper relies on this without support.

    Synaptophysin optical density is a valid measure of synaptic density.

    “Synaptic density estimates from synaptophysin Western blot analysis (synaptic density OD)”
3 of 3

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?

  • Aβ accumulation is associated with perturbations in synaptic function, neuronal loss, and memory and cognitive impairments.

    “Aβ accumulation is associated with perturbations in synaptic function, neuronal loss, and memory and cognitive impairments (Lue et al., 1999; Akiyama et al., 2000b; Palop and Mucke, 2010).”

    From Mechanisms Underlying the Rapid Peroxisome Proliferator-Activated Receptor-γ-Mediated Amyloid Clearance and Reversal of Cognitive Deficits in a Murine Model of Alzheimer's Disease (2012) · cites this paper as Lue et al., 1999

    The Abstract reports that soluble Aβ concentrations were strongly associated with synapse loss, supporting the synaptic part of the claim. But it says insoluble Aβ deposits were poor correlates of synaptic change, so the finding does not apply to Aβ accumulation indiscriminately. The Patient Samples section says the study focused on synapse loss rather than dementia itself; it does not establish an association with neuronal loss or measured memory and cognitive impairment. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Extracellular amyloid-β deposits like senile plaques might represent a relatively innocuous endpoint of the amyloid-β aggregation process, while soluble and smaller amyloid-β aggregates show higher toxicity and a greater correlation with cognitive decline and neurodegeneration.

    “Extracellular Aβ deposits like senile plaques might represent a relatively innocuous endpoint of the Aβ aggregation process, while soluble and smaller Aβ aggregates show higher toxicity and a greater correlation with cognitive decline and neurodegeneration [58, 76].”

    From Senescence-related impairment of autophagy induces toxic intraneuronal amyloid-β accumulation in a mouse model of amyloid pathology (2023) · cites this paper as [76]

  • Biochemical studies on human AD brain indicated that the soluble pool of Aβ42 correlated best with degree of cognitive loss.

    “biochemical studies on human AD brain indicated that the soluble pool of Aβ42 correlated best with degree of cognitive loss [108, 118, 130].”

    From Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease (2010) · cites this paper as [108]

  • Studies have increasingly differentiated between soluble and insoluble pools of Aβ within the brain, where it is the increase in the soluble pool of Aβ42 that tracks best with cognitive decline in AD.

    “Studies have increasingly differentiated between soluble and insoluble pools of Aβ within the brain, where it is the increase in the soluble pool of Aβ42 that tracks best with cognitive decline in AD [108, 118, 130].”

    From Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease (2010) · cites this paper as [108]

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Authors
Lue, L.-F., Kuo, Y.-M., Roher, A. E., Brachova, L., Shen, Y., Sue, L., Beach, T., Kurth, J. H., Rydel, R. E., & Rogers, J.
Affiliations
Banner Sun Health Research Institute (US)
Corresponding author
Rogers, Joseph
ORCID
Venue
The American Journal of Pathology
Publisher
Elsevier BV
Published
1999-09
Volume
155
Issue
3
Pages
853-862
ISSN
0002-9440 (ISSN-L)
DOI
10.1016/s0002-9440(10)65184-x
PMC
PMC1866907
OpenAlex
W2063236931
Semantic Scholar
22fb633031eb687184bfd9795f0a27b7a1d29ebd
Cited by
1,530
References
35
Citations by year
2026: 15 · 2025: 24 · 2024: 26 · 2023: 35 · 2022: 31 · 2021: 36 · 2020: 54 · 2019: 36 · 2018: 56 · 2017: 52 · 2016: 77 · 2015: 65 · 2014: 84 · 2013: 91 · 2012: 98
FWCI
18.88
Type
journal article
Language
en
Open access
Licence
Locations
  • American Journal Of Pathology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Alzheimer&apos;s Association
  • National Institute on Aging (AGO7367, AG11925)
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
Alzheimer's disease, soluble amyloid-beta, Aβ40, amyloid-beta 42, synaptic loss, synaptic changes, entorhinal cortex, superior frontal gyrus, paired helical filaments, neurofibrillary tangles, APOE ε4, synaptophysin, neurodegeneration
MeSH terms
Aged, Aged, 80 and over, Alzheimer Disease, Apolipoproteins E, Brain, Diagnosis, Differential, Female, Gene Frequency, Humans, Immunohistochemistry, Male, Peptide Fragments, Predictive Value of Tests, Synapses, Amyloid beta-Peptides, Cerebral Amyloid Angiopathy, Neurofibrillary Tangles, Plaque, Amyloid

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 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

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.

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