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Soluble Amyloid β Peptide Concentration as a Predictor of Synaptic Change in Alzheimer's Disease
Open accessAbstract
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.
Overview
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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.
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Claims the paper makes
39 Own result · 13 Not checked yet · 8 Own method · 5 Own interpretation · 4 No basis given · 1 Supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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 A40 and A42 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).”
§ Soluble Amyloid  Peptide Concentration as a Predictor of Synaptic Change in Alzheimer's Disease > Abstract
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- Also stated in: § Soluble and Insoluble A40 and A42 Concentrations (Figure 2) · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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 A40 and A42 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).”
§ Soluble Amyloid  Peptide Concentration as a Predictor of Synaptic Change in Alzheimer's Disease > Abstract
boostedstates an association- Asserted: passes — The authors put it forward as true.
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- Also stated in: § Soluble and Insoluble A40 and A42 Concentrations (Figure 2) · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Soluble Amyloid  Peptide Concentration as a Predictor of Synaptic Change in Alzheimer's Disease > Abstract
plain- Asserted: passes — The authors put it forward as true.
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- Also stated in: § A Deposition · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Rather, of the many variables studied, soluble A concentrations best distinguished HPC from AD patients.”
§ Soluble Amyloid  Peptide Concentration as a Predictor of Synaptic Change in Alzheimer's Disease > Abstract
plainstates an association- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Soluble Amyloid  Peptide Concentration as a Predictor of Synaptic Change in Alzheimer's Disease > Abstract
plainstates an association- Asserted: passes — The authors put it forward as true.
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- Also stated in: § Paired Helical Filament Formation · plain
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In the paper
“These distributions resulted in a significant difference in ApoE4 allele frequency among the groups (KW ϭ 9.99, P Ͻ 0.01).”
§ Soluble Amyloid  Peptide Concentration as a Predictor of Synaptic Change in Alzheimer's Disease > Apolipoprotein E Allele Frequency
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In the paper
“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.”
§ Soluble Amyloid  Peptide Concentration as a Predictor of Synaptic Change in Alzheimer's Disease > A Deposition
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In the paper
“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).”
§ Soluble Amyloid  Peptide Concentration as a Predictor of Synaptic Change in Alzheimer's Disease > Soluble and Insoluble A40 and A42 Concentrations (Figure 2)
plainstates an association- Asserted: passes — The authors put it forward as true.
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In the paper
“By contrast, HPC and AD patients differed significantly, sometimes by as much as 50-fold, with respect to A40 (for the soluble form, F 1,14 ϭ 18.0, P Ͻ 0.0009; for the insoluble form, F 1,14 ϭ 5.3, P Ͻ 0.04).”
§ Soluble Amyloid  Peptide Concentration as a Predictor of Synaptic Change in Alzheimer's Disease > Soluble and Insoluble A40 and A42 Concentrations (Figure 2)
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In the paper
“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
“these measures failed to distinguish HPC from AD patients.”
§ Soluble Amyloid  Peptide Concentration as a Predictor of Synaptic Change in Alzheimer's Disease > Abstract
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- Also stated in: § A Deposition · plain
- Probably not a substantial claim. 15
- It may state two separate claims as one. 29
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In the paper
“Nearly identical results were obtained in our previous research with six other HPC patients.5”
§ Soluble Amyloid  Peptide Concentration as a Predictor of Synaptic Change in Alzheimer's Disease > Discussion
What the sources say
- Supportedcites [5] Lue, 1996, Inflammation, Aβ deposition, and neurofibrillary tangle formation as correlates of Alzheimer's disease neurodegeneration, J Neuropathol Exp Neurol source
Materials and Methods (p. 1) identifies six HPC patients in this study. The Neurodegeneration results (p. 2) and Discussion (p. 5) report findings for those patients, so the cited paper is the previous six-patient HPC research the sentence identifies. Our copy cannot independently compare its results with those of the citing authors' later study. (LLM, conf=0.87)
plainn = 6- Asserted: passes — The authors put it forward as true.
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In the paper
“A40 is known to be elevated in cerebrovascular amyloid deposits, and A40 (but not A42) levels , cerebrovascular amyloid angiopathy , and ApoE4 allele frequency were all highly correlated with each other.”
§ Soluble Amyloid  Peptide Concentration as a Predictor of Synaptic Change in Alzheimer's Disease > Abstract
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- Rests on an assumption: A40 is elevated in cerebrovascular amyloid deposits.
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In the paper
“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).”
§ Soluble Amyloid  Peptide Concentration as a Predictor of Synaptic Change in Alzheimer's Disease > Cerebrovascular Amyloid Angiopathy
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In the paper
“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).”
§ Soluble Amyloid  Peptide Concentration as a Predictor of Synaptic Change in Alzheimer's Disease > Paired Helical Filament Formation
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In the paper
“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”
§ Soluble Amyloid  Peptide Concentration as a Predictor of Synaptic Change in Alzheimer's Disease > A Deposition
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In the paper
“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).”
§ Soluble Amyloid  Peptide Concentration as a Predictor of Synaptic Change in Alzheimer's Disease > Soluble and Insoluble A40 and A42 Concentrations (Figure 2)
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In the paper
“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).”
§ Soluble Amyloid  Peptide Concentration as a Predictor of Synaptic Change in Alzheimer's Disease > Paired Helical Filament Formation
plainstates an association- Asserted: passes — The authors put it forward as true.
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In the paper
“The association of soluble A40 with synapse changes was especially striking and could be observed in AD patients alone even in a single brain region (Figure 3D).”
§ Soluble Amyloid  Peptide Concentration as a Predictor of Synaptic Change in Alzheimer's Disease > Soluble and Insoluble A40 and A42 Concentrations (Figure 2)
hedgedstates an association- Asserted: passes — The authors put it forward as true.
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In the paper
“Although in some instances there was a substantial difference among group means, insoluble A levels within groups were often highly variable.Mean insoluble A40 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”
§ Soluble Amyloid  Peptide Concentration as a Predictor of Synaptic Change in Alzheimer's Disease > Soluble and Insoluble A40 and A42 Concentrations (Figure 2)
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“For example, the comparison of HPC with AD patients barely reached signifi- cance for insoluble A42 (F 1,14 ϭ 7.2, P Ͻ 0.02) and did not reach significance for soluble A42 (F 1,14 ϭ 1.4, P Ͼ 0.50).”
§ Soluble Amyloid  Peptide Concentration as a Predictor of Synaptic Change in Alzheimer's Disease > Soluble and Insoluble A40 and A42 Concentrations (Figure 2)
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Soluble Amyloid  Peptide Concentration as a Predictor of Synaptic Change in Alzheimer's Disease > Paired Helical Filament Formation
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It may state two separate claims as one.
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In the paper
“Soluble A40, 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 A40 and A42 Concentrations (Figure 2) · hedged
“The association of soluble A40 with synapse changes was especially striking and could be observed in AD patients alone even in a single brain region (Figure 3D).”
§ Soluble Amyloid  Peptide Concentration as a Predictor of Synaptic Change in Alzheimer's Disease > Abstract
boostedstates an association- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Also stated in: § Soluble and Insoluble A40 and A42 Concentrations (Figure 2) · hedged
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In the paper
“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.”
§ Soluble Amyloid  Peptide Concentration as a Predictor of Synaptic Change in Alzheimer's Disease > Apolipoprotein E Allele Frequency
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In the paper
“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).”
§ Soluble Amyloid  Peptide Concentration as a Predictor of Synaptic Change in Alzheimer's Disease > A Deposition
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In the paper
“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).”
§ Soluble Amyloid  Peptide Concentration as a Predictor of Synaptic Change in Alzheimer's Disease > Synaptic Density
What the sources say
- Not checked yetcites [5] Lue, 1996, Inflammation, Aβ deposition, and neurofibrillary tangle formation as correlates of Alzheimer's disease neurodegeneration, J Neuropathol Exp Neurol source
plainn = 5- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Soluble A42, 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.”
§ Soluble Amyloid  Peptide Concentration as a Predictor of Synaptic Change in Alzheimer's Disease > Soluble and Insoluble A40 and A42 Concentrations (Figure 2)
plainstates an association- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ Soluble Amyloid  Peptide Concentration as a Predictor of Synaptic Change in Alzheimer's Disease > Abstract
What the sources say
- Not checked yetcites [3] Dickson, 1991, Identification of normal and pathological aging in prospectively studied nondemented elderly humans, Neurobiol Aging source
- Not checked yetcites [8] Dickson, 1995, Apolipoprotein E immunoreactivity is increased in amyloid deposits of Alzheimer's disease, but not pathological aging or diffuse Lewy body disease
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Like the A plaques that can be seen under the microscope, concentrations of insoluble A (insoluble A40 plus A42) 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).”
§ Soluble Amyloid  Peptide Concentration as a Predictor of Synaptic Change in Alzheimer's Disease > Soluble and Insoluble A40 and A42 Concentrations (Figure 2)
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Soluble Amyloid  Peptide Concentration as a Predictor of Synaptic Change in Alzheimer's Disease > Discussion
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Synaptophysin optical density is a valid measure of synaptic density.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Only one of eight HPC patients exhibited any tangles in superior frontal gyrus, and these were sparse”
§ Soluble Amyloid  Peptide Concentration as a Predictor of Synaptic Change in Alzheimer's Disease > Discussion
plainn = 8- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Several of the variables assayed here meet this criterion, and several others do not.”
§ Soluble Amyloid  Peptide Concentration as a Predictor of Synaptic Change in Alzheimer's Disease > Discussion
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Soluble Amyloid  Peptide Concentration as a Predictor of Synaptic Change in Alzheimer's Disease > Abstract
hedgedstates an association- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“We note that patients were selected for study without any prior knowledge of their ApoE types.”
§ Soluble Amyloid  Peptide Concentration as a Predictor of Synaptic Change in Alzheimer's Disease > Apolipoprotein E Allele Frequency
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Soluble Amyloid  Peptide Concentration as a Predictor of Synaptic Change in Alzheimer's Disease > Patient Entry Characteristics
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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”
§ Soluble Amyloid  Peptide Concentration as a Predictor of Synaptic Change in Alzheimer's Disease > Soluble and Insoluble A40 and A42 Europium Immunoassay (EuIA)
What the sources say
- Not checked yetcites [15] Kuo, 1996, Water-soluble Aβ(N-40, N-42) oligomers in normal and Alzheimer disease brains, J Biol Chem source
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ Soluble Amyloid  Peptide Concentration as a Predictor of Synaptic Change in Alzheimer's Disease > Patient Samples
What the sources say
- Not checked yetcites [11] Scheff, 1990, Quantitative assessment of cortical synaptic density in Alzheimer's disease, Neurobiol Aging source
- Not checked yetcites [12] Terry, 1991, Physical basis of cognitive alteration in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment, Ann Neurol source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“No material differences were observed in staining by these antibodies, and the mean is presented here.”
§ Soluble Amyloid  Peptide Concentration as a Predictor of Synaptic Change in Alzheimer's Disease > Immunohistochemistry and Quantification of Plaque Type, Cerebrovascular Amyloid Angiopathy, and Paired Helical Filament Formation
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The CSF A42 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.”
§ Soluble Amyloid  Peptide Concentration as a Predictor of Synaptic Change in Alzheimer's Disease > Statistics
plainSingle case ·- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“We note that, while correctly distinguishing the A40 from the A42 carboxy terminus of the peptides, our EuIA assay does not discriminate fulllength A from A fragments.”
§ Soluble Amyloid  Peptide Concentration as a Predictor of Synaptic Change in Alzheimer's Disease > Soluble and Insoluble A40 and A42 Europium Immunoassay (EuIA)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Soluble Amyloid  Peptide Concentration as a Predictor of Synaptic Change in Alzheimer's Disease > Statistics
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“We note that previous studies have found significant differences in CSF A42 when AD patients were compared with ND patients (cf Ref. 16).”
§ Soluble Amyloid  Peptide Concentration as a Predictor of Synaptic Change in Alzheimer's Disease > Statistics
What the sources say
- Not checked yetcites Ref. 16
plainstates an association- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“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”
§ Soluble Amyloid  Peptide Concentration as a Predictor of Synaptic Change in Alzheimer's Disease > Apolipoprotein E Allele Frequency
What the sources say
- Not checked yetcites Ref. 22
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“As in our previous research, 5 counts of the various elements at ϫ100 final magnification were recorded by an observer blind to disease state.”
§ Soluble Amyloid  Peptide Concentration as a Predictor of Synaptic Change in Alzheimer's Disease > Immunohistochemistry and Quantification of Plaque Type, Cerebrovascular Amyloid Angiopathy, and Paired Helical Filament Formation
What the sources say
- Not checked yetcites [5] Lue, 1996, Inflammation, Aβ deposition, and neurofibrillary tangle formation as correlates of Alzheimer's disease neurodegeneration, J Neuropathol Exp Neurol source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Rather, ApoE4 appears mainly to increase cerebrovascular amyloid burden, as previously reported, 33 as well as soluble amyloid burden.”
§ Soluble Amyloid  Peptide Concentration as a Predictor of Synaptic Change in Alzheimer's Disease > Discussion
What the sources say
- Not checked yetcites [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
hedgedstates a cause- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“the primary constituent of the neuritic plaque.29”
§ Soluble Amyloid  Peptide Concentration as a Predictor of Synaptic Change in Alzheimer's Disease > Discussion
What the sources say
- Not checked yetcites [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
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“suggesting that although the two brain regions have different predilections for AD changes, such changes occur in parallel in both structures.”
§ Soluble Amyloid  Peptide Concentration as a Predictor of Synaptic Change in Alzheimer's Disease > Brain Regional Differences
hedgedstates an association- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ Soluble Amyloid  Peptide Concentration as a Predictor of Synaptic Change in Alzheimer's Disease > Discussion
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds.
- Rests on an assumption: HPC patients represent a preclinical or early AD state relevant to understanding AD pathophysiology.
In the paper
“Similar results on brain regional changes in AD pathology were obtained in our previous study of ND, HPC, and AD patients.5”
§ Soluble Amyloid  Peptide Concentration as a Predictor of Synaptic Change in Alzheimer's Disease > Brain Regional Differences
What the sources say
- Not checked yetcites [5] Lue, 1996, Inflammation, Aβ deposition, and neurofibrillary tangle formation as correlates of Alzheimer's disease neurodegeneration, J Neuropathol Exp Neurol source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper relies on this without support.
A40 is elevated in cerebrovascular amyloid deposits.
“A40 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)”
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?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“This interaction assessed biophysically, in the postmortem brain from individuals with Alzheimer’s disease, corroborates in vitro and in vivo evidence of displacement of amyloid-β oligomers [64], representing a potential mechanism of action underlying the protection against amyloid-β oligomer-induced synaptic degradation [153,154,155,156,157] observed with S2R modulators [64].”
From Sigma-2 Receptors—From Basic Biology to Therapeutic Target: A Focus on Age-Related Degenerative Diseases (2023) · cites this paper as [154]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“We and others have observed that oligomeric amyloid beta (Aβ) peptide causes synaptic dysfunction, accumulates within in synapses, and is associated with synapse loss around plaques [34, 41, 52, 60, 64].”
From Transmembrane protein 97 is a potential synaptic amyloid beta receptor in human Alzheimer’s disease (2024) · cites this paper as [41]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“We and others have observed that oligomeric amyloid beta (Aβ) peptide causes synaptic dysfunction, accumulates within in synapses, and is associated with synapse loss around plaques [34, 41, 52, 60, 64].”
From Transmembrane protein 97 is a potential synaptic amyloid beta receptor in human Alzheimer’s disease (2024) · cites this paper as [41]
Experimental — accuracy not yet measuredThe check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“We and others have observed that oligomeric amyloid beta (Aβ) peptide causes synaptic dysfunction, accumulates within in synapses, and is associated with synapse loss around plaques [34, 41, 52, 60, 64].”
From Transmembrane protein 97 is a potential synaptic amyloid beta receptor in human Alzheimer’s disease (2024) · cites this paper as [41]
Experimental — accuracy not yet measured
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
Citations
Cites
Neuropathological stageing of Alzheimer-related changes.
Braak, H., & Braak, E. (1991) · Acta Neuropathologica · doi:10.1007/bf00308809 · Cited by 16,123
Mirra, S. S., Heyman, A., McKeel, D., Sumi, S. M., Crain, B. J., Brownlee, L. M., Vogel, F. S., Hughes, J. P., Belle, G. V., Berg, L., et al. (1991) · Neurology · doi:10.1212/wnl.41.4.479 · Cited by 4,961
Terry, R. D., Masliah, E., Salmon, D. P., Butters, N., DeTeresa, R., Hill, R., Hansen, L. A., & Katzman, R. (1991) · Annals of Neurology · doi:10.1002/ana.410300410 · Cited by 4,397
Blessed, G., Tomlinson, B. E., & Roth, M. (1968) · British Journal of Psychiatry · doi:10.1192/bjp.114.512.797 · Cited by 4,117
Diffusible, nonfibrillar ligands derived from Aβ 1–42 are potent central nervous system neurotoxins
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
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
Katzman, R., Terry, R., DeTeresa, R., Brown, T., Davies, P., Fuld, P., Renbing, X., & Peck, A. (1988) · Annals of Neurology · doi:10.1002/ana.410230206 · Cited by 1,225
Roher, A. E., Lowenson, J. D., Clarke, S., Woods, A. S., Cotter, R. J., Gowing, E., & Ball, M. J. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.22.10836 · Cited by 740
Self-citationIdentification of normal and pathological aging in prospectively studied nondemented elderly humans
Dickson, D. W., Crystal, H. A., Mattiace, L. A., Masur, D. M., Blau, A. D., Davies, P., Yen, S.-H., & Aronson, M. K. (1992) · Neurobiology of Aging · doi:10.1016/0197-4580(92)90027-u · Cited by 643
Arriagada, P. V., Marzloff, K., & Hyman, B. T. (1992) · Neurology · doi:10.1212/wnl.42.9.1681 · Cited by 638
Cited by
Sorted by citations
The Amyloid Hypothesis of Alzheimer’s Disease: Progress and Problems on the Road to Therapeutics
Hardy, J., & Selkoe, D. J. (2002) · Science · doi:10.1126/science.1072994 · Cited by 13,864
Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid β-peptide
Haass, C., & Selkoe, D. J. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2101 · Cited by 4,744
Querfurth, H. W., & LaFerla, F. M. (2010) · New England Journal of Medicine · doi:10.1056/nejmra0909142 · Cited by 4,569
Inflammation and Alzheimer’s disease
Akiyama, H. (2000) · Neurobiology of Aging · doi:10.1016/s0197-4580(00)00124-x · Cited by 4,514
Alzheimer's Disease Is a Synaptic Failure
Selkoe, D. J. (2002) · Science · doi:10.1126/science.1074069 · Cited by 4,420
Metadata
- 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
- Venue
- The American Journal of Pathology
- Publisher
- Elsevier BV
- Published
- 1999-09
- Volume
- 155
- Issue
- 3
- Pages
- 853-862
- ISSN
- 0002-9440 (ISSN-L)
- 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
- bronze
- doi.org
- Locations
- American Journal Of Pathology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Alzheimer's Association
- National Institute on Aging (AGO7367, AG11925)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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.
A language model drew the claims from the paper on 2026-10-10, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-10 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
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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