CoChat
Sign Up
Cited by 664Dementia and Cognitive Impairment ResearchAlzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration Mechanisms

Neuropathology of nondemented aging: presumptive evidence for preclinical Alzheimer disease

Open access
Price, Joseph L., McKeel, Daniel W., Buckles, Virginia D., Roe, Catherine M., Xiong, Chengjie, Grundman, Michael, Hansen, Lawrence A., Petersen, Ronald C. +13 more·2009·Neurobiology of Aging
DOI 10.1016/j.neurobiolaging.2009.04.002PMC PMC2737680
Open this paper in CoChat — free account

Abstract

Objective To determine the frequency and possible cognitive effect of histological Alzheimer’s disease (AD) in autopsied older nondemented individuals. Design Senile plaques (SPs) and neurofibrillary tangles (NFTs) were assessed quantitatively in 97 cases from 7 Alzheimer’s Disease Centers (ADCs). Neuropathological diagnoses of AD (npAD) were also made with four sets of criteria. Adjusted linear mixed models tested differences between participants with and without npAD on the quantitative neuropathology measures and psychometric test scores prior to death. Spearman rank-order correlations between AD lesions and psychometric scores at last assessment were calculated for cases with pathology in particular regions. Setting Washington University Alzheimer’s Disease Research Center. Participants Ninety-seven nondemented participants who were age 60 years or older at death (mean = 84 years). Results About 40% of nondemented individuals met at least some level of criteria for npAD; when strict criteria were used, about 20% of cases had npAD. Substantial overlap of Braak neurofibrillary stages occurred between npAD and no-npAD cases. Although there was no measurable cognitive impairment prior to death for either the no-npAD or npAD groups, cognitive function in nondemented aging appears to be degraded by the presence of NFTs and SPs. Conclusions Neuropathological processes related to AD in persons without dementia appear to be associated with subtle cognitive dysfunction and may represent a preclinical stage of the illness. By age 80–85 years, many nondemented older adults have substantial AD pathology.

AI snapshot

Written from the paper’s full text.

TL;DR

In 97 nondemented older adults autopsied across seven Alzheimer’s Disease Centers, a substantial minority had Alzheimer-type neuropathology, and higher plaque or tangle burden was linked to slightly poorer cognitive scores despite no clinical dementia. The results support the possibility of a presymptomatic Alzheimer stage, though the study cannot prove that these cases would have progressed.

Key findings

  • Depending on the criteria used, 39–47% of cases met some neuropathological AD threshold; stricter thresholds identified about 19–21%. Khachaturian criteria classified 47%, Washington University criteria 39%, CERAD any level 39% (19% possible, 19% probable, 2% definite), and NIA-Reagan any level 39% (20% low, 16% intermediate, 3% high).
  • Cases with and without neuropathological AD did not differ in age at death, interval from last assessment to death, education, or last psychometric performance.
  • Among cases with lesions in the relevant regions, greater AD pathology correlated with worse performance on episodic memory, category fluency, Trailmaking A and B, and the MMSE; neocortical diffuse senile plaque density best discriminated neuropathological AD from no neuropathological AD.
  • Braak stages ranged from 0 to V with a median of II. Older age correlated with higher Braak stage (r = .372, p < .001), limbic NFT density increased with age (r = .437, p < .001), plaque burden did not correlate with age (r = .089, p = .40), and neocortical plaque burden was weakly related to limbic NFT density (r = .196, p = .07).

Methods

  • The sample included 97 autopsied nondemented participants aged 60 or older at death (mean 84.3 ± 8.6 years; 55 women; mean education 15.4 ± 2.9 years; mean last MMSE 28.1 ± 2.1) from 7 Alzheimer’s Disease Centers, all with CDR 0 within 2 years of death; 11 CDR > 0 cases were assessed but not reported.
  • A central laboratory processed five brain regions uniformly, used silver and immunohistochemical stains, made consensus diagnoses with four criteria sets (Khachaturian, Washington University, CERAD, NIA-Reagan), assigned Braak stages, and quantified plaques and tangles using computerized stereology.
  • Analyses used linear mixed models adjusted for center and covariates, ROC/sensitivity analyses for diffuse plaques, and Spearman correlations between lesion densities and last psychometric scores.

Limitations

  • The authors state that the study used a convenience sample, could not assess genotype effects, had small samples for some cognitive associations, and faced variability in initial fixation and tissue processing across centers. They also note that plaques and tangles may be downstream of the pathogenic processes causing synaptic and neuronal degeneration, and that the study did not address early protein changes, later neuronal or synaptic loss, vascular lesions, or synucleinopathy.
  • The authors caution that findings from nondemented individuals may not extend to cases with manifest dementia, and that missing psychometric data and small numbers with both lesions and test results require interpretive caution.
  • Evident from the text: the cross-sectional autopsy design cannot establish whether pathology precedes or predicts dementia, and correlations weakened when all cases were included or when adjusting for age or education.

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

Integrity signals

Registry

Crossref · 10.1016/j.neurobiolaging.2009.04.002

Cites

64 of 64 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 62 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Correlations of neurofibrillary tangles with psychometric test scores were similar after adjustment for plaque burden within the same region.

    “Likewise, results were similar for the correlation of NFTs with the psychometric test scores after adjustment for plaque burden within the same region.”
    Quote in the paperNot a substantial claim
  • Findingown data

    Plaque burden was not significantly correlated with age, with a Spearman correlation of 0.089 and p equal to 0.40.

    “In contrast, plaque burden was not significantly correlated with age (Figure 4B; Spearman correlation=0.089, p=0.40).”
    Quote in the paperNot a substantial claim
  • Findingown data

    There was substantial overlap of Braak stages between neuropathological Alzheimer disease and no-neuropathological Alzheimer disease cases.

    “there was substantial overlap of the Braak stages between the npAD and no-npAD cases (Figure 3).”
    Quote in the paperSubstantial claim
  • Findingown data

    Spearman correlations between the quantitative neuropathological measures and all CERAD and NIA-Reagan outcomes yielded almost the identical rank order for association with diagnostic level.

    “Spearman correlations between the quantitative neuropathological measures and all outcomes of CERAD criteria (no AD or Possible, Probable, or Definite) and all outcomes of NIA-Reagan criteria (no AD or Low, Intermediate, or High) yielded almost the identical rank order for association with diagnostic level (Table 2).”
    Quote in the paperNot a substantial claim
  • Findingown data

    When strict criteria were used, about 20% of nondemented cases had neuropathological Alzheimer disease.

    “when strict criteria were used, about 20% of cases had npAD.”
    Quote in the paperSubstantial claim
  • Classified as probably not a substantial claim. 31
  • May combine two claims. 26

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

    Findingown data

    The mean interval from the last Alzheimer Disease Center assessment to death in the 97 cases was 0.7 plus or minus 0.5 years.

    “The mean interval from last ADC assessment to death in the 97 cases was 0.7 +/− 0.5 years.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    The study included 97 nondemented autopsied participants who were at least 60 years old at death, with a mean age of 84 years.

    “Ninety-seven nondemented participants who were age 60 years or older at death (mean = 84 years).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    There were no differences in mean age at death, interval between last clinical assessment and death, education, or psychometric performance at last assessment before death between cases with neuropathological Alzheimer disease and those without it using any of the four criteria.

    “There were no differences in mean age at death, interval between last clinical assessment and death, education, or psychometric performance at last assessment before death between cases with npAD versus those without npAD using any of the 4 criteria (even when restricted to Probable and Definite CERAD and Intermediate and High NIA-Reagan criteria) (Table 1).”
    Quote in the paperSubstantial claim

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

    Findingown data

    The four Braak stage 0 cases were relatively young, aged 66, 69, 72, and 72 years at death.

    “The 4 stage 0 cases were relatively young, aged 66, 69, 72, and 72 years at death.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The NIA-Reagan criteria identified neuropathological Alzheimer disease at any level in 39% of cases, comprising 20% Low, 16% Intermediate, and 3% High.

    “and any of the 3 levels of the NIA-Reagan criteria (20% Low, 16% Intermediate, and 3% High; 39% combined).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    After adjusting for age at death, all correlations in Table 3 remained significant except that between limbic diffuse senile plaques and Trailmaking B; limbic neurofibrillary tangles became significantly correlated with Trailmaking A and Digit Symbol.

    “Adjusting for age at death, all correlations reported in Table 3 remain significant except for that between limbic diffuse SPs and Trailmaking B (Spearman correlation=0.29, p=.16); conversely, the correlation become significant between limbic NFTs for Trailmaking A (Spearman correlation=−0.39, p=.003) and Digit Symbol (Spearman correlation=0.39, p=.04).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Inclusion of all cases regardless of whether they had Alzheimer disease lesions attenuated the correlations; neocortical plaque burden remained significantly correlated with Logical Memory-Delayed, limbic neurofibrillary tangles remained significantly correlated with the Mini Mental Status Examination, and neocortical neurofibrillary tangles were significantly correlated with the Mini MentalStatus

    “Inclusion of all cases in the analyses, regardless of whether they demonstrated AD lesions, attenuated the correlations, as expected. Nonetheless, neocortical plaque burden remained significantly correlated with Logical Memory-Delayed (Spearman correlation=−0.42, p=0.03). Limbic NFTs also remained significantly correlated with MMSE (Spearman correlation=−0.38, p<.001), and neocortical NFTs were”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    After adjusting for education, all correlations in Table 3 remained significant except those between limbic diffuse senile plaques and Trailmaking B and between neocortical diffuse senile plaques and Logical Memory Delayed.

    “Adjusting for education, all correlations reported in Table 3 still remain significant except for these between limbic diffuse SPs and Trailmaking B (Spearman correlation=0.36, p=.08) and between neocortical diffuse SPs and Logical Memory Delayed (Spearman correlation=−0.46, p=.06).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Braak neurofibrillary stages in the 97 cases ranged from 0 to V, with a median of Stage II.

    “Braak neurofibrillary stages in the 97 cases ranged from 0 (no NFTs observed) to V (widespread neocortical tangles), with a median value of Stage II (Stage 0, n=4; Stage I, n=31; Stage II, n=36; Stage III, n=15; Stage IV, n=8; Stage V, n=3).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The CERAD criteria identified neuropathological Alzheimer disease at any level in 39% of cases, comprising 19% Possible, 19% Probable, and 2% Definite.

    “identical to the number of cases meeting any of the 3 levels of npAD using CERAD criteria (19% Possible, 19% Probable, and 2% Definite AD; 39% with all levels combined,)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Among nondemented older adults, the frequency of npAD was approximately 20% when restricted to Probable/Definite CERAD and Intermediate/High NIA-Reagan criteria, and approximately 40% across all criteria levels.

    “First, consistent with previous reports, a substantial proportion of nondemented older adults were found to have npAD, with the frequency ranging from about 20% (when criteria are restricted to Probable/Definite CERAD and Intermediate/High NIA-Reagan) to about 40% (all levels of criteria).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The autopsy sample of nondemented older adults is representative enough that the estimated frequency of npAD applies to nondemented older adults generally.

  • May combine two claims.

    Findingown data

    Diffuse senile plaques, and consequently plaque burden, appear first in the neocortex and best discriminate npAD from no-npAD in nondemented aging.

    “Diffuse SPs and consequently plaque burden appear initially in the neocortex and best discriminate npAD and no-npAD in nondemented aging.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Neurofibrillary tangles were present in almost all cases in this series, although four of the youngest cases had few if any (Braak Stage 0).

    “NFTs were present in almost all of the cases in this series, although 4 of the youngest cases had few if any (Braak Stage 0).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Once present in the brain, both senile plaques and neurofibrillary tangles occur continuously, with no clear boundary between npAD and no-npAD.

    “Once present in the brain, both SPs and NFTs occur in a continuous manner, without a clear boundary between “npAD” and “no-npAD” (Figure 5).”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Neuropathological criteria for Alzheimer disease use senile plaque and neurofibrillary tangle densities to separate Alzheimer disease from aging because the distinction between the two has been considered quantitative rather than qualitative.

    “Neuropathological criteria for AD rely on densities of SPs and NFTs to discriminate AD from aging, as the distinction between the two conditions has been thought to be quantitative rather than qualitative.(Tomlinson et al., 1970; Arriagada et al., 1992)”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Tomlinson et al., 1970 source

      Not checked in the free run.

    • cites Arriagada et al., 1992 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Senile plaques and neurofibrillary tangles in nondemented older adults may represent Alzheimer disease before clinical expression, with lesions accumulating over many years before synaptic and neuronal damage produces symptoms.

    “Alternatively, the presence of SPs and NFTs in nondemented older adults may represent AD at a stage prior to its clinical expression,(Morris et al., 1996; Price & Morris, 1999; Troncoso et al., 1998; Hulette et al., 1998; Schmitt et al., 2000) in which the neuropathological lesions of AD accumulate over many years before sufficient synaptic and neuronal damage occurs to produce the symptoms of AD.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Morris et al., 1996 source

      Not checked in the free run.

    • cites Price & Morris, 1999

      Not checked in the free run.

    • cites Troncoso et al., 1998 source

      Not checked in the free run.

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

    Study design and conductreasoning

    Quantitative assessment used Bielschowsky-stained sections because they were more consistent given variable fixation, and immunohistochemical sections were routinely examined and compared with the silver-stained sections.

    “Analysis was based on Bielschowsky-stained sections because they were more consistent, given the variable state of fixation of the material from different sources, although immunohistochemical sections (singly stained for Aβ or PHF, or double stained for both Aβ and PHF) were routinely examined and compared with the silver stained sections.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Both observers were blind to the clinical and Clinical Dementia Rating status of the cases and to the neuropathological findings determined by the contributing Alzheimer Disease Centers.

    “Both observers were “blind” to the clinical and CDR status of the cases and to the neuropathological findings determined by the ADCs contributing the cases.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Neuropathological diagnoses were made by joint examination by two observers using a double-headed microscope to reach consensus.

    “The diagnoses were done by joint examination of each case by DWM and JLP, using a double-headed microscope to arrive at a consensus neuropathological diagnosis.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Some prior studies reported a negative effect of Alzheimer disease pathology on episodic memory only, without effects in other cognitive domains.

    “Some studies have reported a negative effect for episodic memory only,(Hulette et al., 1998; Schmitt et al., 2000; Bennett et al., 2006) without effects in other cognitive domains, while other studies found no relationship between AD pathology and any cognitive measure.(Knopman et al., 2003; Driscoll et al., 2006)”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Hulette et al., 1998 source

      Not checked in the free run.

    • cites Schmitt et al., 2000 source

      Not checked in the free run.

    • cites Bennett et al., 2006 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    Uniform tissue treatment and uniform staining in the central laboratory reduced variability in density measures despite possible tissue shrinkage.

    “Although density measures may be affected by tissue shrinkage, the uniform treatment of the tissue (formalin fixation and paraffin embedding) and uniform staining in the central laboratory reduced variability.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Clinicians at each Alzheimer Disease Center verified the nondemented status of each case.

    “Clinicians at each ADC verified the nondemented status for each case (the neuropathological diagnoses generated at the ADC performing the autopsy were not included in the eligibility criteria).”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    The central laboratory was blind to the cognitive status of each case.

    “all cases were coded so that the central laboratory was blind to the cognitive status of each case.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    The central laboratory provided a standard and uniform neuropathological assessment to avoid variability from different methods, criteria, and interpretations used at individual Alzheimer Disease Centers.

    “The Neuropathology Core (JLP, DWM) of Washington University’s Alzheimer’s Disease Research Center served as the “central laboratory” to provide a standard and uniform neuropathological assessment of each case and avoid the variability introduced by different methods, criteria, and interpretations used at individual ADCs.(Mirra et al., 1994; Alafuzoff et al., 2006)”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Mirra et al., 1994 source

      Not checked in the free run.

    • cites Alafuzoff et al., 2006 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Other prior studies found no relationship between Alzheimer disease pathology and any cognitive measure.

    “while other studies found no relationship between AD pathology and any cognitive measure.(Knopman et al., 2003; Driscoll et al., 2006)”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Knopman et al., 2003 source

      Not checked in the free run.

    • cites Driscoll et al., 2006 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Previous studies of neuropathological Alzheimer disease in nondemented aging used cases collected at a single site, and comparison of results has been difficult because neuropathological methods and criteria differed.

    “Previous studies of neuropathological AD in nondemented aging have been based on cases collected at a single site(Price & Morris, 1999; Galvin et al., 2005; Bennett et al., 2006), and comparison of results has been difficult because neuropathological methods and criteria differed in these studies.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Price & Morris, 1999

      Not checked in the free run.

    • cites Galvin et al., 2005 source

      Not checked in the free run.

    • cites Bennett et al., 2006 source

      Not checked in the free run.

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

    Study design and conductnone given

    Plaque burden, defined as the percent area occupied by plaques relative to total sampled area, is unaffected by tissue shrinkage.

    “Plaque burden was defined as the percent area occupied by plaques in relation to the total area sampled and is unaffected by tissue shrinkage.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Earlier neuropathological studies reported similar frequencies of npAD in nondemented cases; one study found that 37.3% of 134 cognitively normal older adults autopsied at a mean age of 82-85 years met Intermediate/High NIA-Reagan criteria for npAD.

    “Earlier neuropathological studies also reported similar frequency of npAD in nondemented cases, including one reporting that 37.3% of 134 cognitively normal older adults, autopsied at a mean age between 82–85 years, met “Intermediate/High” NIA-Reagan criteria for npAD.(Bennett et al., 2006)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Bennett et al., 2006 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    The NIA-Reagan criteria were not intended to characterize nondemented individuals or those with incipient dementia.

    “The NIA-Reagan criteria were not intended to characterize nondemented individuals or those with incipient dementia.(National Institute on Aging & Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer’s Disease, 1997)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites National Institute on Aging & Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer’s Disease, 1997

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Neuropathological processes related to Alzheimer disease in persons without dementia appear associated with subtle cognitive dysfunction and may represent a preclinical stage of the illness.

    “Neuropathological processes related to AD in persons without dementia appear to be associated with subtle cognitive dysfunction and may represent a preclinical stage of the illness.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    The CERAD and NIA-Reagan criteria are much more commonly used in practice and research.

    “In practice and research, however, the CERAD and NIA-Reagan criteria are much more commonly used.(Schmitt et al., 2000; Knopman et al., 2003; Bennett et al., 2006)”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Schmitt et al., 2000 source

      Not checked in the free run.

    • cites Knopman et al., 2003 source

      Not checked in the free run.

    • cites Bennett et al., 2006 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Senile plaques and neurofibrillary tangles characterize the neuropathological substrate of AD.

    “However, SPs and NFTs characterize the neuropathological substrate of AD and synaptic and neuronal loss developing from these or other lesions appear to be critical for the expression of cognitive symptoms.(Masliah et al., 2001; Price et al., 2001)”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Masliah et al., 2001 source

      Not checked in the free run.

    • cites Price et al., 2001 source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductown data

    There were almost no statistical differences in age at death, years of education, or gender between participants missing data for the last psychometric tests before death and those completing the tests, except for Trailmaking A, where mean education was 16.0 years for participants with data versus 14.4 years for those with missing data.

    “Another limitation was missing data in some cases, although there were almost no statistical differences for age at death, years of education, and gender between participants missing data for the last psychometric tests before death and those completing the tests. The only exception was Trailmaking A, where the mean years of education was 16.0 for participants with data vs. 14.4 for participants”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    The Washington University criteria were considered primary because they were based on discriminative analyses of neuropathological data.

    “In this report, the Washington University criteria were considered “primary” because they were based on discriminative analyses of neuropathological data.(McKeel et al., 2004)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites McKeel et al., 2004 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mismatches between neurofibrillary tangle and senile plaque densities are well recognized and can make categorization with NIA-Reagan criteria difficult, because those criteria assume a strong correlation between NP density and NFT distribution.

    “Mismatches between NFT and SP densities are well-recognized(Dickson, 1995) and can present difficulties in categorization with NIA-Reagan criteria, which assume a strong correlation between NP density (reflected in the CERAD score) and NFT distribution (reflected in the Braak stage).(Geddes et al., 1997)”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Dickson, 1995 source

      Not checked in the free run.

    • cites Geddes et al., 1997 source

      Not checked in the free run.

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

    Premisecitation

    Age-related neurofibrillary change may accelerate in the presence of Aβ lesions.

    “Age-related neurofibrillary change may accelerate in the presence of Aβ lesions.(Price & Morris, 1999)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Price & Morris, 1999

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Neuronal loss in the entorhinal cortex or hippocampal field CA1 is absent in preclinical npAD, whereas cases with equivalent neuropathological lesion burden but symptomatic very mild DAT (CDR = 0.5) show substantial cell loss.

    “Neuronal loss in the entorhinal cortex or hippocampal field CA1 has been shown to be absent in preclinical npAD compared with substantial cell loss in cases with equivalent neuropathological lesion burden but with symptomatic very mild DAT (CDR = 0.5).(Gomez-Isla et al., 1996; Price et al., 2001; West et al., 2004)”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Gomez-Isla et al., 1996 source

      Not checked in the free run.

    • cites Price et al., 2001 source

      Not checked in the free run.

    • cites West et al., 2004 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    The NIA-Reagan working group stated that the appearance of even one senile plaque or neurofibrillary tangle in the brain represents a pathological event.

    “The working group that formulated the NIA-Reagan criteria stated that the appearance of even one SP or NFT in the brain represents a pathological event, (National Institute on Aging & Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer’s Disease, 1997)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites National Institute on Aging & Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer’s Disease, 1997

      Not checked in the free run.

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

    Study design and conductnone given

    The study could not assess a genotype effect.

    “Limitations of the study include the use of a convenience sample, inability to assess a genotype effect, small sample sizes for some of the cognitive associations, and variability in initial fixation and tissue processing at individual ADCs that may have influenced immunohistochemical staining and quantitative measurement of neuritic SPs.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Subtle cognitive deficits can be detected many years before AD diagnosis.

    “Subtle cognitive deficits can be detected many years before AD diagnosis(Elias et al., 2000; Kawas et al., 2003; Saxton et al., 2004; Tierney et al., 2005) but have not previously been correlated with AD lesions in nondemented individuals.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Elias et al., 2000 source

      Not checked in the free run.

    • cites Kawas et al., 2003 source

      Not checked in the free run.

    • cites Saxton et al., 2004 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The subtle cognitive deficits, although not detectable in individual subjects and insufficient to produce dementia, suggest that neurofibrillary and Aβ lesions, including diffuse senile plaques, exert harmful effects.

    “Although not detectable in individual subjects, and insufficient to produce dementia, these deficits nonetheless suggest that the neurofibrillary and Aβ lesions, including diffuse SPs, exert deleterious effects.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The cognitive deficits associated with AD lesions in nondemented individuals are attributable to those lesions rather than to other pathologies or measurement error.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    The sample of 97 individuals was sufficiently large to permit preliminary analyses of the cognitive correlates of AD lesions in the absence of dementia.

    “Finally, the sample of 97 individuals was sufficiently large to permit preliminary analyses of the cognitive correlates of AD lesions in the absence of dementia.”
    Quote in the paperSubstantial claim

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

    Interpretationcitation

    Senile plaques and neurofibrillary tangles may be downstream consequences of the pathophysiological processes responsible for the synaptic and neuronal degeneration that produces cognitive deficits in AD.

    “Another limitation is that SPs and NFTs may be downstream consequences of the pathophysiological processes responsible for the synaptic and neuronal degeneration that produces cognitive deficits in AD.(Shankar et al., 2008)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Shankar et al., 2008 source

      Not checked in the free run.

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

    Study design and conductnone given

    The study used a convenience sample.

    “Limitations of the study include the use of a convenience sample, inability to assess a genotype effect, small sample sizes for some of the cognitive associations, and variability in initial fixation and tissue processing at individual ADCs that may have influenced immunohistochemical staining and quantitative measurement of neuritic SPs.”
    Quote in the paperNot a substantial claim

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

    Study design and conductcitation

    Because inter-laboratory variation exists in assessing AD lesions and neuropathological diagnosis, the contributed sections were processed uniformly and interpreted at one center.

    “Third, because there remains inter-laboratory variation in assessing AD lesions and consequently in neuropathological diagnosis,(Alafuzoff et al., 2006) the contributed sections were processed uniformly and interpreted at one center.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Alafuzoff et al., 2006 source

      Not checked in the free run.

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

    Study design and conductnone given

    Sample sizes for some of the cognitive associations were small.

    “Limitations of the study include the use of a convenience sample, inability to assess a genotype effect, small sample sizes for some of the cognitive associations, and variability in initial fixation and tissue processing at individual ADCs that may have influenced immunohistochemical staining and quantitative measurement of neuritic SPs.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The findings are consistent with, but do not prove, the concept of preclinical AD.

    “The findings of this study are consistent with (but do not prove) the concept of preclinical AD.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The autopsy sample of nondemented older adults is representative enough that the estimated frequency of npAD applies to nondemented older adults generally.
    • Rests on an assumption: The cognitive deficits associated with AD lesions in nondemented individuals are attributable to those lesions rather than to other pathologies or measurement error.

  • May combine two claims.

    Premisecitation

    The pathobiological relevance of even diffuse senile plaques for AD is consistent with evidence that soluble Aβ dimers and oligomers, before the stage of senile plaques, have neurotoxic effects and are associated with decreases in long-term potentiation, dendritic spine density, and memory performance in experimental models.

    “The pathobiological relevance of even diffuse SPs for AD is consistent with evidence that soluble Aβ dimers and oligomers, prior to the stage of SPs, have neurotoxic effects(Hung et al., 2008) and are associated with decreases in long term potentiation, dendritic spine density, and memory performance in experimental models.(Shankar et al., 2008)”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Hung et al., 2008 source

      Not checked in the free run.

    • cites Shankar et al., 2008 source

      Not checked in the free run.

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

    Study design and conductnone given

    Variability in initial fixation and tissue processing at individual ADCs may have influenced immunohistochemical staining and quantitative measurement of neuritic senile plaques.

    “Limitations of the study include the use of a convenience sample, inability to assess a genotype effect, small sample sizes for some of the cognitive associations, and variability in initial fixation and tissue processing at individual ADCs that may have influenced immunohistochemical staining and quantitative measurement of neuritic SPs.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Neurofibrillary lesions may have greater relevance for cognitive impairment once the clinical symptoms of AD are expressed.

    “For example, neurofibrillary lesions may have greater relevance for cognitive impairment once the clinical symptoms of AD are expressed.(Bennett et al., 2004)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Bennett et al., 2004 source

      Not checked in the free run.

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

    Premisecitation

    Senile plaques and neurofibrillary tangles may elicit a host response that contributes to the neurotoxicity of AD.

    “for example, SPs and NFTs may elicit a host response that contributes to the neurotoxicity of AD.(Castellani et al., 2008)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Castellani et al., 2008 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 conductcitation

    This study did not address the early protein changes leading to senile plaques and neurofibrillary tangles, or the later synaptic or neuronal loss and other potential factors that could contribute to cognitive dysfunction.

    “This study did not address the early protein changes that lead to SPs and NFTs or the later synaptic or neuronal loss and other potential factors (e.g., vascular lesions; synucleinopathy) that could contribute to cognitive dysfunction; for example, SPs and NFTs may elicit a host response that contributes to the neurotoxicity of AD.(Castellani et al., 2008)”
    Quote in the paperNot a substantial claim
52 of 52

  • The paper relies on this without support.

    The autopsied sample from seven Alzheimer Disease Centers is representative of nondemented older adults in the general population.

    “By age 80–85 years, many nondemented older adults have substantial AD pathology.”

  • The paper relies on this without support.

    The observed associations between Alzheimer disease lesions and cognitive test scores are not due to other brain pathologies or unmeasured confounders.

    “In all cases, greater pathology was associated with poorer cognitive performance at last assessment on measures of episodic memory (Logical Memory Delayed), semantic knowledge (Category Fluency), visuospatial ability (Trailmaking A), and executive function (Trailmaking B) as well as on a general measure, the MMSE.”

  • The paper relies on this without support.

    The four published neuropathological criteria validly classify neuropathological Alzheimer disease in nondemented older adults even though they were developed for dementia.

    “Each case was assessed in accordance with 4 published criteria for the neuropathological diagnosis of AD.”

  • The paper relies on this without support.

    The autopsy sample of nondemented older adults is representative enough that the estimated frequency of npAD applies to nondemented older adults generally.

    “The finding that up to 40% of nondemented individuals with a mean age of death of 84 years have npAD corresponds with some estimates of the prevalence of clinically apparent DAT in this age group.(Hebert et al., 2003)”

  • The paper relies on this without support.

    The cognitive deficits associated with AD lesions in nondemented individuals are attributable to those lesions rather than to other pathologies or measurement error.

    “This study did not address the early protein changes that lead to SPs and NFTs or the later synaptic or neuronal loss and other potential factors (e.g., vascular lesions; synucleinopathy) that could contribute to cognitive dysfunction; for example, SPs and NFTs may elicit a host response that contributes to the neurotoxicity of AD.(Castellani et al., 2008)”
5 of 5

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?

  • There is only a weak correlation between the degree of cognitive impairment and the presence of plaques or neurofibrillary tangles.

    “However, there is only a weak correlation between the degree of cognitive impairment and the presence of plaques or neurofibrillary tangles (Price et al., 2009)”

    From The influence of phospho-tau on dendritic spines of cortical pyramidal neurons in patients with Alzheimer’s disease (2013) · cites this paper as Price et al., 2009

    The Results (Quantitative Neuropathological Assessment; page unavailable) report correlations between plaque or tangle measures and cognitive test scores, some modest in size. But the participants had no individually measurable cognitive impairment, so the study does not establish a weak correlation between lesion presence and the degree of clinical impairment. Its explicitly described “weak” correlation is between plaque burden and tangle density, not between lesions and cognition. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Aβ deposition is not exclusive to individuals with AD as it can be found also in nondemented elderly individuals.

    “It is important to note that Aβ deposition is not exclusive to individuals with AD as it can be found also in nondemented elderly individuals (64).”

    From Modeling late-onset Alzheimer’s disease neuropathology via direct neuronal reprogramming (2024) · cites this paper as [64]

  • Aged individuals can harbor a high burden of AD brain lesions at autopsy while remaining cognitively intact, indicating resilience to AD pathology.

    “several studies have revealed the existence of aged individuals harboring a high burden of brain lesions at autopsy while remaining cognitively intact, indicating resilience to AD pathology [3, 7, 21, 22, 56, 57, 68, 76, 78, 96].”

    From Enhanced microglial dynamics and a paucity of tau seeding in the amyloid plaque microenvironment contribute to cognitive resilience in Alzheimer’s disease (2024) · cites this paper as [76]

  • A significant proportion of subjects with no overt evidence of cognitive impairment in the final assessment prior to death have neuropathological diagnoses of AD.

    “Among individuals who showed no overt evidence of cognitive impairment in the final assessment prior to death, post-mortem studies showed a significant proportion of subjects with neuropathological diagnoses of AD”

    From Repair of Oxidative DNA Damage, Cell-Cycle Regulation and Neuronal Death May Influence the Clinical Manifestation of Alzheimer’s Disease (2014) · cites this paper as [10]

  • In preclinical Alzheimer's disease cases, there is no measurable cognitive impairment per se, but cognitive function is degraded in the presence of plaques and tangles.

    “Supporting this notion, Price et al. reported no measureable cognitive impairment per se in such preclinical AD cases, but degraded cognitive function in the presence of plaques and tangles (Price, et al., 2009).”

    From Cellular, synaptic, and biochemical features of resilient cognition in Alzheimer’s disease (2013) · cites this paper as Price, et al., 2009

Cites

Flagged first, then by citations

1 of the 65 references couldn’t be matched to a known paper.

Cited by

Sorted by citations

Related

Authors
Price, J. L., McKeel, D. W., Buckles, V. D., Roe, C. M., Xiong, C., Grundman, M., Hansen, L. A., Petersen, R. C., Parisi, J. E., Dickson, D. W., Smith, C. D., Davis, D. G., Schmitt, F. A., Markesbery, W. R., Kaye, J., Kurlan, R., Hulette, C., Kurland, B. F., Higdon, R., Kukull, W., & Morris, J. C.
Affiliations
  • Washington University in St. Louis (US)
  • Elan Pharmaceuticals, Inc. (Ireland) (IE)
  • University of California San Diego (US)
  • Mayo Clinic (US)
  • University of Kentucky (US)
  • Central Baptist Hospital (US)
  • Oregon Health & Science University (US)
  • University of Rochester Medicine (US)
  • Duke University (US)
  • Fred Hutch Cancer Center (US)
  • University of Washington (US)
Corresponding author
Morris, John C.
ORCID
Venue
Neurobiology of Aging
Publisher
Elsevier BV
Published
2009-07
Volume
30
Issue
7
Pages
1026-1036
ISSN
0197-4580 (ISSN-L)
DOI
10.1016/j.neurobiolaging.2009.04.002
PMC
PMC2737680
OpenAlex
W2114222094
Semantic Scholar
56b77cd6ec3334e93ca55ab8412c4c9a608abbd6
Cited by
661
References
65
Citations by year
2026: 17 · 2025: 17 · 2024: 21 · 2023: 29 · 2022: 31 · 2021: 38 · 2020: 30 · 2019: 37 · 2018: 48 · 2017: 34 · 2016: 54 · 2015: 49 · 2014: 47 · 2013: 38 · 2012: 60
FWCI
34.43
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Neurobiology of Aging (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (UL1TR000448)
  • National Institute on Aging (P30AG028383, P30AG028377, U01AG016976, P50AG005131, P30AG008017, U01-AG 16976, P 50 AG05681, P50AG005681, P01 AG0 3991, P01AG003991, P30AG008665, P01AG026276, P50AG016574)
  • National Center for Research Resources (UL1RR024992)
  • National Center for Advancing Translational Sciences
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
preclinical Alzheimer's disease, Alzheimer's disease pathology, amyloid plaques, neurofibrillary tangles, cognitive impairment, older adults
MeSH terms
Aged, Aged, 80 and over, Aging, Alzheimer Disease, Brain, Cognition Disorders, Female, Humans, Male, Middle Aged, Neuropsychological Tests, Psychometrics, Severity of Illness Index, Statistics as Topic, Linear Models, Neurofibrillary Tangles, Age Distribution, Disease Progression, Early Diagnosis, 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 2026-10-05.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-05.

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