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Cited by 174Dementia and Cognitive Impairment ResearchAlzheimer's disease research and treatmentsNeurological Disease Mechanisms and Treatments

Ecology of the Aging Human Brain

Open access
Sonnen, Joshua A.·2011·Archives of Neurology
DOI 10.1001/archneurol.2011.157PMC PMC3218566
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Abstract

BACKGROUND: Alzheimer disease, cerebral vascular brain injury, and isocortical Lewy body disease (LBD) are the major contributors to dementia in community- and population-based studies. OBJECTIVE: To estimate the prevalence of clinically silent forms of these diseases in cognitively normal (CN) adults. DESIGN: Autopsy study. SETTING: Community- and population based. PARTICIPANTS: A total of 1672 brain autopsies from the Adult Changes in Thought study, Honolulu-Asia Aging Study, Nun Study, and Oregon Brain Aging Study, of which 424 met the criteria for CN. MAIN OUTCOME MEASURES: Of these, 336 cases had a comprehensive neuropathologic examination of neuritic plaque density, Braak stage for neurofibrillary tangles, LB distribution, and number of cerebral microinfarcts. RESULTS: Forty-seven percent of CN cases had moderate or frequent neuritic plaque density; of these, 6% also had Braak stage V or VI for neurofibrillary tangles. Fifteen percent of CN cases had medullary LBD; 8% also had nigral and 4% isocortical LBD. The presence of any cerebral microinfarcts was identified in 33% and of high-level cerebral microinfarcts in 10% of CN individuals. Overall, the burden of lesions in each individual and their comorbidity varied widely within each study but were similar across studies. CONCLUSIONS: These data show an individually varying complex convergence of subclinical diseases in the brain of older CN adults. Appreciating this ecology should help guide future biomarker and neuroimaging studies and clinical trials that focus on community- and population-based cohorts.

AI snapshot

Written from the paper’s full text.

TL;DR

In harmonized autopsies from four community- or population-based cohorts, clinically silent Alzheimer’s disease, microvascular brain injury, and Lewy body disease were common in cognitively normal older adults, with widely varying individual burden and co-morbidity. The findings suggest that the aging brain often contains multiple subclinical dementia-associated lesions, which should inform biomarker, neuroimaging, and prevention studies.

Key findings

  • Among 336 cognitively normal (CN) older adults with complete neuropathologic examination, 47% had moderate or frequent neuritic plaque (NP) density; only 6% of those also had Braak stage V or VI neurofibrillary tangles.
  • Lewy body disease (LBD) showed an apparent anatomic progression: 15% had medullary LBD, 8% also had nigral LBD, and 4% also had isocortical LBD.
  • Any cerebral microinfarcts (CMIs) were identified in 33% of CN individuals, and high-level CMIs (≥3) in 10%; there was no significant correlation between CERAD NP score and CMI categories.
  • Summary neuropathology score differed significantly across CN, lower cognitive function, and dementia groups (Kruskal-Wallis P < 0.0001; Dunn’s paired post tests P < 0.0001 for each comparison), and 10–15% of CN individuals harbored clinically silent AD, μVBI, and/or LBD at levels equal to or exceeding the average burden in dementia cases.

Methods

  • The study evaluated 1,672 brain autopsies from the Adult Changes in Thought (ACT) study, Honolulu-Asia Aging Study (HAAS), Nun Study (NS), and Oregon Brain Aging Study (OBAS); 424 met criteria for CN, and 336 had complete neuropathologic examination.
  • CN was defined as last clinical evaluation within 2 years of death, diagnosis of “not dementia,” and cognitive screening scores in the upper four quintiles (MMSE ≥24 for NS, MMSE ≥28 for OBAS, CASI ≥83 for HAAS, CASI >90 for ACT).
  • Harmonized histopathologic assessment included CERAD NP score, Braak staging for NFTs, α-synuclein immunohistochemistry for LBs, and screening H&E-stained sections for CMIs across the same 12 sections from six bilateral cerebral regions; analyses used descriptive prevalence, a summary neuropathology score, and non-parametric tests in GraphPad Prism.

Limitations

  • The paper states that interpretation of these cross-sectional autopsy data is limited, that the interval between last clinical evaluation and autopsy creates potential for misclassification especially given prodromal dementia, and that neuropathologic protocols likely have varying sensitivities.
  • The paper notes that LBD data were not collected identically across all studies (medulla in two studies, substantia nigra in three, isocortex in all four), that missing CMI data were the most frequent cause of incomplete evaluation, and that caution is needed in extrapolating findings to other ethnic or racial groups or societies.
  • Evident from the text: only 336 of 424 CN cases had complete neuropathologic evaluation, and the four cohorts differed in size, age, and sex composition, which the authors note may affect age-related correlation results.

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

Integrity signals

Registry

Crossref · 10.1001/archneurol.2011.157

Cites

36 of 36 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

3 of 8 cited sources checked · 2 supported · 0 flagged · accuracy not yet measured

  • Interpretationcitation

    The proportion of cognitively normal older adults with moderate or frequent CERAD NP score matches well with reports using fibrillar Aβ PET imaging in cognitively normal individuals.

    “The proportion of CN older adults with moderate or frequent CERAD NP score, a metric significantly correlated with Aβ peptide-immunoreactive plaque area and detergent-insoluble Aβ42 accumulation, matches well with reports using fibrillar Aβ PET imaging in cognitively normal individuals.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [34] Aizenstein HJ Nebes RD Saxton JA Frequent amyloid deposition without significant cognitive impairment among the elderly Arch Neurol 2008 65 11 1509 1517 19001171 PMC2636844 source
    • cites [35] Gomperts SN Rentz DM Moran E Imaging amyloid deposition in Lewy body diseases Neurology 2008 71 12 903 910 18794492 PMC2637553 source
  • Findingown data

    There were no instances of other less common diseases that can cause dementia (e.g., fronto-temporal lobar degeneration or prion disease) in this cohort of cognitively normal individuals.

    “There were no instances of other less common diseases that can cause dementia in this cohort of CN individuals, e.g., fronto-temporal lobar degeneration or prion disease.”
    Quote in the paperNot a substantial claim
  • Findingown data

    It is uncommon for cognitively normal older individuals to have no neuropathologic evidence of disease(s) that can cause dementia.

    “it is uncommon for CN older individuals to have no neuropathologic evidence of disease(s) that can cause dementia”
    Quote in the paperSubstantial claim
  • Findingown data

    4% of cognitively normal older adults also had isocortical LBD.

    “4% isocortical LBD”
    • Also stated in: § RESULTS · plain
      “a further subset (4%) also had isocortical LBD”
    Quote in the paperNot a substantial claim
  • Findingown data

    15% of cognitively normal older adults had medullary Lewy body disease (LBD).

    “15% of CN cases had medullary LBD”
    • Also stated in: § RESULTS · plain
      “15% showing medullary LBD”
    Quote in the paperNot a substantial claim
  • May combine two claims. 13
  • The quote only partly states this claim. 1
  • Classified as probably not a substantial claim. 10

  • May combine two claims.

    Premisecitation

    Any interval between last clinical evaluation and autopsy creates a potential for misclassification, especially since progression to dementia typically seems to be preceded by a prodrome.

    “Any interval between last clinical evaluation and autopsy creates a potential for misclassification, especially since progression to dementia typically seems to be preceded by a prodrome.33”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [33] Petersen RC Roberts RO Knopman DS Mild cognitive impairment: ten years later Arch Neurol 2009 66 12 1447 1455 20008648 PMC3081688 source

      The History section describes mild cognitive impairment as a prodromal condition distinct from dementia, supporting the point that dementia can be preceded by a prodrome. The Neuropathological Analysis section discusses clinical classifications and findings after death, but does not say that any interval between the last clinical evaluation and autopsy creates a risk of misclassification. No page numbers are available in our copy. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    The overall burden of lesions in each individual and their co-morbidity varied widely within each study.

    “Overall burden of lesions in each individual and their co-morbidity varied widely within each study”
    • Also stated in: § RESULTS · plain
      “the burden of diseases ranged widely within each study and showed substantial individually varying co-morbidity.”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    10% of cognitively normal older adults had high level CMIs (≥3 CMIs).

    “high level CMIs in 10% of CN individuals”
    • Also stated in: § RESULTS · plain
      “of these 10% had ≥ 3 CMI”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The Kruskal-Wallis test for the three groups (CN, LCF, dementia) was significant (P < 0.0001), as were Dunn's corrected paired post tests for each of the three paired comparisons (P < 0.0001).

    “the overall result of Kruskal-Wallis test was significant (P < 0.0001) for the three groups, as was Dunn’s corrected paired post tests (P < 0.0001) for each of the three paired comparisons.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The overall burden of lesions and co-morbidity were similar among the four studies.

    “but were similar among studies.”
    • Also stated in: § RESULTS · plain
      “Results from ACT (Figure 1A), HAAS (Figure 1B), NS (Figure 1C), and OBAS (Figure 1D) are similar”
    • Also stated in: § DISCUSSION · boosted
      “the extent of co-morbidity was remarkably similar in CN older adults among the four studies.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Three instances of hippocampal sclerosis were observed (one each in ACT, HAAS and NS), each co-morbid with AD and/or μVBI.

    “Three instances of hippocampal sclerosis were observed (one each in ACT, HAAS and NS); each was co-morbid with AD and/or μVBI.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The weak combined correlation between summary neuropathology score and age was driven by the relatively younger ACT cohort (P < 0.01), with no significant correlation in the other three cohorts (P > 0.05).

    “however, this was driven by the relatively younger ACT cohort of men and women (Spearman ranked correlation P < 0.01) but none of the other three cohorts (Spearman ranked correlation P > 0.05)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Amygdala-only LBD appears to be uncommon in CN individuals as was hippocampal sclerosis.

    “Amygdala-only LBD appears to be uncommon in CN individuals as was hippocampal sclerosis.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    A similarly sized subset of individuals with dementia have a burden of lesions in cerebrum that is less than the average burden in cognitively normal individuals.

    “a similarly sized subset of individuals with dementia have a burden of lesions in cerebrum that is less than the average burden in CN individuals.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    Braak staging for NFTs was determined by the same method in all four studies.

    “Braak staging for NFTs was determined by the same method in all four studies.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    While accumulation of cerebral cortical Aβ is common, the full spectrum of pathologic changes of AD is relatively uncommon in cognitively normal older adults.

    “Interpretation of these necessarily cross-sectional data is limited but does suggest that, while accumulation of cerebral cortical Aβ is common, the full spectrum of pathologic changes of AD is relatively uncommon in CN older adults.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Clinically silent AD, μVBI, and LBD are prevalent and commonly co-morbid but with extensive individual variation.

    “Our results from four independent community- or population-based studies of brain aging and dementia demonstrate that clinically silent AD, μVBI, and LBD are prevalent and commonly co-morbid but with extensive individual variation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Future imaging modalities for LBD should expect to detect medullary LBD in approximately one in six CN individuals; about one-half of these also will have nigral LBD, and about one-half of those with midbrain LBD will have isocortical LBD.

    “Our data suggest that future imaging modalities for LBD should expect to detect medullary LBD in approximately one in six CN individuals; about one-half of these also will have nigral LBD, and about one-half of those with midbrain LBD will have isocortical LBD.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    CMIs were determined in all four studies by the same method of screening H&E-stained sections of cerebrum for infarcts not observed grossly.

    “CMIs were determined in all four studies by the same method of screening hematoxylin & eosin (H&E)-stained sections of cerebrum for infarcts that were not observed grossly.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationown data

    Our results show an intricate complexity among clinically silent diseases.

    “Our results show an intricate complexity among clinically silent diseases.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based).

    Study design and conductnone given

    Our neuropathologic protocols likely have varying sensitivities, which should be remembered when considering estimates of disease burden.

    “our neuropathologic protocols likely have varying sensitivities and this should be remembered when considering our estimates of disease burden.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Interpretationnone given

    We should be cautious in extrapolating these validated findings in non-demented or cognitively normal individuals to other ethnic or racial groups or other societies.

    “Nevertheless, we should be cautious in extrapolating these validated findings in non-demented or CN individuals to other ethnic or racial groups or other societies.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Only individuals whose last clinical evaluation was within 2 years of death were included.

    “Only those individuals whose last clinical evaluation was within 2 years of death were included in this study.”
    Quote in the paperSubstantial claim

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

    Interpretationcitation

    These results are consistent with neuroimaging estimates of white matter hyperintensities.

    “These results are consistent with neuroimaging estimates of white matter hyperintensities, imaging abnormalities that appear to derive at least in part from pathogenic mechanisms overlapping with those that produce CMIs (reviewed in 36).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [36] Gouw AA Seewann A van der Flier WM Heterogeneity of small vessel disease: a systematic review of MRI and histopathology correlations J Neurol Neurosurg Psychiatry 2010 20935330 source

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    To minimize misclassification, the analysis was restricted to subjects whose scores on their respective cognitive screening test at last evaluation were in the upper four quintiles for the entire cohort.

    “To minimize misclassification we further restricted analysis to subjects whose scores on their respective cognitive screening test at last evaluation was in the upper four quintiles for the entire cohort”
    Quote in the paperSubstantial claim

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

    Study design and conductreasoning

    The regions evaluated for LBs overlapped among all studies only for frontal and temporal cortex.

    “The regions evaluated for LBs overlapped among all studies only for frontal and temporal cortex.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    CERAD NP score is highly significantly correlated with cerebral cortical burden of plaque-associated Aβ peptides as determined by immunohistochemistry with antibody 6E10 and with cerebral cortical detergent-insoluble Aβ42.

    “These results indicate that CERAD NP score, a measure that was applied across all four studies, is highly significantly correlated with cerebral cortical burden of plaque-associated Aβ peptides as determined by immunohistochemistry with antibody 6E10 and with cerebral cortical detergent-insoluble Aβ42.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductcitation

    HAAS screened more regions of cerebrum for microinfarcts than the other studies; however, all data presented here are limited to the same twelve sections from the same six bilateral cerebral regions.

    “HAAS screened more regions of cerebrum for microinfarcts than the other studies; however, all data presented here are limited to the same twelve sections from the same six bilateral cerebral regions as previously described.19”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [19] Sonnen JA Larson EB Crane PK Pathological correlates of dementia in a longitudinal, population-based sample of aging Ann Neurol 2007 62 4 406 413 17879383 source

  • May combine two claims.

    Interpretationown data

    AD, μVBI, and LBD were prevalent among cognitively normal older adults.

    “Our major conclusions are (i) AD, μVBI, and LBD were prevalent among CN older adults”
    • Also stated in: § DISCUSSION · plain
      “clinically silent AD, μVBI, and LBD are prevalent and commonly co-morbid but with extensive individual variation.”
    Quote in the paperSubstantial claim
24 of 24

  • The paper relies on this without support.

    There are as yet no validated neuroimaging or biomarker protocols for μVBI or LBD, so current information on clinically silent forms of these diseases is available only from autopsy-based studies.

    “Since there are as yet no validated neuroimaging or biomarker protocols for μVBI or LBD, current information on clinically silent forms of these diseases is available only from autopsy-based studies.”

  • The paper relies on this without support.

    The screening protocol for CMIs has been shown independently in HAAS and ACT to be correlated with other forms of VBI, such as lacunes and territorial infarcts.

    “This screening protocol for CMIs has been shown independently in HAAS and ACT to be correlated with others forms of VBI, such as lacunes and territorial infarcts.”
2 of 2

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?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • High CMI burden has conflicting denominators

    Major

    The Results say 10% of CN adults with any CMI had at least three CMIs. The Discussion instead says approximately one in ten of all CN adults had a high CMI burden. Since only about one-third had any CMI, those two prevalence statements cannot both be correct.

  • Aβ42 measurement is described as both soluble and insoluble

    Minor

    The same comparison is introduced as measuring detergent-insoluble Aβ42, but its reported concentrations are labeled detergent-soluble Aβ42.

2 of 2

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. [17]Montine TJ Sonnen JA Mini-Forum on Clinical-Pathologic Correlations in Population- and Community-Based Studies of Brain Aging Journal of Alzheimer’s disease 2009 18 643 725

Cited by

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Related

Authors
Sonnen, J. A.
Affiliations
University of Washington (US)
Corresponding author
Sonnen, Joshua A.
ORCID
Sonnen, Joshua A.
Venue
Archives of Neurology
Publisher
American Medical Association (AMA)
Published
2011-08-01
Volume
68
Issue
8
Pages
1049
ISSN
0003-9942 (ISSN-L)
DOI
10.1001/archneurol.2011.157
PMC
PMC3218566
OpenAlex
W2131428961
Semantic Scholar
83fa5578cb861ec34b69f3898d76445f8adbbafc
Cited by
174
References
36
Citations by year
2026: 4 · 2025: 5 · 2024: 6 · 2023: 8 · 2022: 13 · 2021: 16 · 2020: 10 · 2019: 10 · 2018: 8 · 2017: 15 · 2016: 18 · 2015: 15 · 2014: 14 · 2013: 17 · 2012: 13
FWCI
9.05
Type
journal article
Language
en
Open access
Locations
  • Archives of Neurology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion)
Funders
  • National Institutes of Health (5p30ag008017-30, 5r01ag011378-25)
  • National Institute on Aging (AG 05136, P50 AG 005136, AG008017, R01 AG023801, R01-AG011378, U01 AG006781, R37AG011378, P30-AG008017, AG-11378, R01AG017155, AG-06781)
  • National Institute of Neurological Disorders and Stroke (P50NS062684, NS62684)
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 › Neurological Disease Mechanisms and Treatments
Keywords
Alzheimer's disease, cognitively normal older adults, neuritic plaques, neurofibrillary tangles, cerebral microinfarcts, Lewy bodies, neuropathology, comorbidities, brain aging
MeSH terms
Aged, Aged, 80 and over, Aging, Alzheimer Disease, Brain, Female, Hawaii, Humans, Male, Oregon, Dementia, Vascular, Cohort Studies, Prevalence, Lewy Body Disease

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