The DOI matches its Crossref record; 36 of the 36 references it cites were found in a registry or an index; 3 of the 8 sources its claims cite were checked for support.
Ecology of the Aging Human Brain
Open accessAbstract
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.
Overview
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.
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Claims the paper makes
27 Own result · 14 Own interpretation · 7 Own method · 4 No full text of the sources · 1 Supported · 1 Partly supported · accuracy not yet measured
Every source the paper cites for this claim was checked and supports it.
In the paper
“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.”
§ Ecology of aging human brain > DISCUSSION
What the sources say
- Supportedcites [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
The Comment section reports that 21% of cognitively unimpaired older participants were amyloid-positive on PiB PET. It explicitly says this estimate closely matches a postmortem finding of 18% meeting CERAD criteria for possible Alzheimer’s disease, supporting the claimed agreement in proportions. This paper does not itself measure CERAD neuritic-plaque scores. (LLM, conf=0.90)
- Supportedcites [35] Gomperts SN Rentz DM Moran E Imaging amyloid deposition in Lewy body diseases Neurology 2008 71 12 903 910 18794492 PMC2637553 source
The Discussion reports cortical PiB PET retention in more than 20% of apparently normal people and PiB positivity in 51% of the paper’s normal-control sample. This supports the cited paper’s role as a PET-imaging report in cognitively normal individuals; it does not need to supply the citing authors’ CERAD measurement. (LLM, conf=0.91)
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- 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
“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.”
§ Ecology of aging human brain > RESULTS
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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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
“it is uncommon for CN older individuals to have no neuropathologic evidence of disease(s) that can cause dementia”
§ Ecology of aging human brain > RESULTS
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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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
“4% isocortical LBD”
- Also stated in: § RESULTS · plain
“a further subset (4%) also had isocortical LBD”
§ Ecology of aging human brain > Abstract > RESULTS
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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- Also stated in: § RESULTS · 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
“15% of CN cases had medullary LBD”
- Also stated in: § RESULTS · plain
“15% showing medullary LBD”
§ Ecology of aging human brain > Abstract > RESULTS
plain- 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.
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- Also stated in: § RESULTS · 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
“8% also had nigral”
- Also stated in: § RESULTS · plain
“a subset of these (8%) also had LBD in substantia nigra”
§ Ecology of aging human brain > Abstract > RESULTS
plain- 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.
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- Also stated in: § RESULTS · 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
“Two of 116 CN cases from the ACT cohort had amygdala-only LBD; this was not evaluated in the other cohorts.”
§ Ecology of aging human brain > RESULTS
plainn = 116- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
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
“When all four cohorts were combined, there was a weak correlation between summary neuropathology score and age (Spearman ranked correlation P < 0.05)”
§ Ecology of aging human brain > RESULTS
plaincorrelational- 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.
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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
“of these 6% also had Braak stage V or VI for NFTs.”
- Also stated in: § RESULTS · plain
“However only 6% of these individuals also had Braak stage V or VI for NFTs.”
§ Ecology of aging human brain > Abstract > RESULTS
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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- Also stated in: § RESULTS · 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
“These data support the conclusion that individuals with LCF or dementia carry progressively greater average burden of lesions from AD, μVBI, and/or LBD.”
§ Ecology of aging human brain > RESULTS
boostedcorrelational- 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. 13
- The quote only partly states this claim. 1
- Probably not a substantial claim. 10
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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”
§ Ecology of aging human brain > DISCUSSION
What the sources say
- Partly supportedcites [33] Petersen RC Roberts RO Knopman DS Mild cognitive impairment: ten years later Arch Neurol 2009 66 12 1447 1455 20008648 PMC3081688 sourceExperimental — accuracy not yet measured
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)
hedgedconditional- 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.
- Partly 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
“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.”
§ Ecology of aging human brain > Abstract > RESULTS
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.
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It may state two separate claims as one.
- Also stated in: § RESULTS · 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
“high level CMIs in 10% of CN individuals”
- Also stated in: § RESULTS · plain
“of these 10% had ≥ 3 CMI”
§ Ecology of aging human brain > Abstract > RESULTS
plain- 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.
The quote only partly states this claim.
- Also stated in: § RESULTS · 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 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.”
§ Ecology of aging human brain > RESULTS
plaincorrelational- 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.
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
“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.”
§ Ecology of aging human brain > Abstract > RESULTS
boosted- 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.
- Also stated in: § RESULTS · 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
“Three instances of hippocampal sclerosis were observed (one each in ACT, HAAS and NS); each was co-morbid with AD and/or μVBI.”
§ Ecology of aging human brain > RESULTS
plaincorrelational- 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.
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
“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)”
§ Ecology of aging human brain > RESULTS
plaincorrelational- 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.
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
“Amygdala-only LBD appears to be uncommon in CN individuals as was hippocampal sclerosis.”
§ Ecology of aging human brain > DISCUSSION
hedged- 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.
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
“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.”
§ Ecology of aging human brain > DISCUSSION
plain- Asserted: passes — The authors put it forward as true.
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- 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
“Braak staging for NFTs was determined by the same method in all four studies.”
§ Ecology of aging human brain > METHODS > Histopathologic Scoring
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.
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
“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.”
§ Ecology of aging human brain > RESULTS
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: passes — The paper gives a reason why it holds.
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
“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.”
§ Ecology of aging human brain > DISCUSSION
boostedcorrelational- 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.
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
“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.”
§ Ecology of aging human brain > DISCUSSION
hedgedcorrelational- 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.
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
“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.”
§ Ecology of aging human brain > METHODS > Histopathologic Scoring
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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Probably not a substantial claim.
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
“Our results show an intricate complexity among clinically silent diseases.”
§ Ecology of aging human brain > DISCUSSION
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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Probably not a substantial claim.
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
“our neuropathologic protocols likely have varying sensitivities and this should be remembered when considering our estimates of disease burden.”
§ Ecology of aging human brain > DISCUSSION
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check 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. It may be too vague to check against evidence. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
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
“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.”
§ Ecology of aging human brain > DISCUSSION
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
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Probably not a substantial claim. It may be too vague to check against evidence. 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
“Only those individuals whose last clinical evaluation was within 2 years of death were included in this study.”
§ Ecology of aging human brain > METHODS > Clinical Assessments
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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Probably not a substantial claim.
In the paper
“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).”
§ Ecology of aging human brain > DISCUSSION
What the sources say
- Not checked — no full text of the sourcecites [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
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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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
“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”
§ Ecology of aging human brain > METHODS > Clinical Assessments
plain- Asserted: passes — The authors put it forward as true.
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- 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.
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 regions evaluated for LBs overlapped among all studies only for frontal and temporal cortex.”
§ Ecology of aging human brain > METHODS > Histopathologic Scoring
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
“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.”
§ Ecology of aging human brain > RESULTS
hedgedcorrelationaln = 86 ·- Asserted: passes — The authors put it forward as true.
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- 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
“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”
§ Ecology of aging human brain > METHODS > Histopathologic Scoring
What the sources say
- Not checked — no full text of the sourcecites [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
plain- 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.
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
“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.”
§ Ecology of aging human brain > DISCUSSION
plainn = 336- 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.
- Also stated in: § DISCUSSION · plain
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.”
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?
In the citing paper
“Significantly, the severity and distribution of AD neuropathologic changes are much different (lower) in preclinical cases than in cases with clinically severe ADD (48, 108, 148-150).”
From Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature (2012) · cites this paper as [150]
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.
Rated major: it would touch a result — a value a result rests on, reported and recomputed p-values on opposite sides of the significance level, two passages that conflict with no sign which is right, or a cited work retracted before this paper was published.
In the paper
§ Ecology of aging human brain > RESULTS
“Overall, approximately one-third of CN older adults had CMI captured by our screening protocol; of these 10% had ≥ 3 CMI, a level of disease that is associated with increased risk of clinically evident dementia.19”
§ Ecology of aging human brain > DISCUSSION
“High burden of CMIs, meaning lesions at the magnitide significantly associated with dementia,19 was present in approximately one in ten CN older adults.”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Ecology of aging human brain > RESULTS
“we compared tissue burden of detergent-insoluble Aβ42 with CERAD NP score”
§ Ecology of aging human brain > RESULTS
“9.6 ± 4.6 ng/g detergent-soluble Aβ42”
Citations
Cites
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“None 23 (6)/5 (1) 6 (4) 0 (1) 29 (8) Sparse 15 (5)/3 (2) 7 (4) 1 (1) 23 (8) Moderate 13 (4)/1 (1) 8 (3) 3 (2) 24 (6) Frequent 12 (4)/0 (1) 9 (3) 3 (1) 24 (7) Total 63 (6)/9 (3) 30 (5) 7 (8) 100”
Dementia and Alzheimer Disease Incidence: A Prospective Cohort Study
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Heterogeneity of small vessel disease: a systematic review of MRI and histopathology correlations
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Sorted by citations
NIA‐AA Research Framework: Toward a biological definition of Alzheimer's disease
Jack, C. R., Bennett, D. A., Blennow, K., Carrillo, M. C., Dunn, B., Haeberlein, S. B., Holtzman, D. M., Jagust, W., Jessen, F., Karlawish, J., et al. (2018) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2018.02.018 · Cited by 10,537
Jack, C. R., Knopman, D. S., Jagust, W. J., Petersen, R. C., Weiner, M. W., Aisen, P. S., Shaw, L. M., Vemuri, P., Wiste, H. J., Weigand, S. D., et al. (2013) · The Lancet Neurology · doi:10.1016/s1474-4422(12)70291-0 · Cited by 4,396
Nelson, P. T., Alafuzoff, I., Bigio, E. H., Bouras, C., Braak, H., Cairns, N. J., Castellani, R. J., Crain, B. J., Davies, P., Tredici, K. D., et al. (2012) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e31825018f7 · Cited by 2,050
“Significantly, the severity and distribution of AD neuropathologic changes are much different (lower) in preclinical cases than in cases with clinically severe ADD (48, 108, 148 Y 150).”
BackgroundSelf-citationPrimary age-related tauopathy (PART): a common pathology associated with human aging
Crary, J. F., Trojanowski, J. Q., Schneider, J. A., Abisambra, J. F., Abner, E. L., Alafuzoff, I., Arnold, S. E., Attems, J., Beach, T. G., Bigio, E. H., et al. (2014) · Acta Neuropathologica · doi:10.1007/s00401-014-1349-0 · Cited by 1,467
“NFTs are practically universal in older persons’ brains [22, 30, 108, 132], and are also observed in a more limited distribution in many younger individuals [30, 32, 42].”
BackgroundBiomarker Modeling of Alzheimer’s Disease
Jack, C. R., & Holtzman, D. M. (2013) · Neuron · doi:10.1016/j.neuron.2013.12.003 · Cited by 1,002
Iadecola, C., Yaffe, K., Biller, J., Bratzke, L. C., Faraci, F. M., Gorelick, P. B., Gulati, M., Kamel, H., Knopman, D. S., Launer, L. J., et al. (2016) · Hypertension · doi:10.1161/hyp.0000000000000053 · Cited by 746
Zeppenfeld, D. M., Simon, M., Haswell, J. D., D’Abreo, D., Murchison, C., Quinn, J. F., Grafe, M. R., Woltjer, R. L., Kaye, J., & Iliff, J. J. (2017) · JAMA Neurology · doi:10.1001/jamaneurol.2016.4370 · Cited by 651
Vascular contributions to cognitive impairment and dementia including Alzheimer's disease
Snyder, H. M., Corriveau, R. A., Craft, S., Faber, J. E., Greenberg, S. M., Knopman, D., Lamb, B. T., Montine, T. J., Nedergaard, M., Schaffer, C. B., et al. (2015) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2014.10.008 · Cited by 603
The neuropathology and cerebrovascular mechanisms of dementia
Raz, L., Knoefel, J. E., & Bhaskar, K. (2015) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2015.164 · Cited by 512
“Several autopsy studies of nondemented, aged individuals confirm mixed cerebrovascular pathologies and neuropathologic findings, suggesting a complex and silent form of subclinical disease.(18,19) Additional support for this claim is derived from the seminal nun studies.”
ResultCerebral microinfarcts: the invisible lesions
Smith, E. E., Schneider, J. A., Wardlaw, J. M., & Greenberg, S. M. (2012) · The Lancet Neurology · doi:10.1016/s1474-4422(11)70307-6 · Cited by 456
Longitudinal tau PET in ageing and Alzheimer’s disease
Jack, C. R., Wiste, H. J., Schwarz, C. G., Lowe, V. J., Senjem, M. L., Vemuri, P., Weigand, S. D., Therneau, T. M., Knopman, D. S., Gunter, J. L., et al. (2018) · Brain · doi:10.1093/brain/awy059 · Cited by 452
“…are more likely to have comorbid non-Alzheimer’s disease brain pathological change (Markesbery et al., 2006; Schneider et al., 2009; Nelson et al., 2011; Sonnen et al., 2011) than younger individuals and therefore require less pathological tau to produce a similar level of cognitive impairment.”
BackgroundBeecham, G. W., Hamilton, K., Naj, A. C., Martin, E. R., Huentelman, M., Myers, A. J., Corneveaux, J. J., Hardy, J., Vonsattel, J.-P., Younkin, S. G., et al. (2014) · PLoS Genetics · doi:10.1371/journal.pgen.1004606 · Cited by 343
“Importantly, while each of these diseases exclusively can cause dementia, they commonly coexist in older patients with dementia [2].”
BackgroundLewczuk, P., Riederer, P. F., O’Bryant, S. E., Verbeek, M. M., Dubois, B., Visser, P. J., Jellinger, K. A., Engelborghs, S., Ramírez, A., Parnetti, L., et al. (2017) · The World Journal of Biological Psychiatry · doi:10.1080/15622975.2017.1375556 · Cited by 318
“…collection of the many non-AD pathologies that increase in prevalence with age (Jack et al. 2012), including CVaD, DLB, TDP 43, hippocampal sclerosis, argyrophylicgrain disease and PART (Schneider et al. 2007; Schneider et al. 2009; Nelson et al. 2011; Sonnen et al. 2011; Crary et al. 2014).”
BackgroundInfluentialSuspected non-Alzheimer disease pathophysiology — concept and controversy
Jack, C. R., Knopman, D. S., Chételat, G., Dickson, D. W., Fagan, A. M., Frisoni, G. B., Jagust, W. J., Mormino, E. C., Petersen, R. C., Sperling, R. A., et al. (2016) · Nature Reviews Neurology · doi:10.1038/nrneurol.2015.251 · Cited by 313
“First, non-AD processes are prevalent in the elderly population, as seen by autopsy studies 42–44, 51 , 80 , and these processes should The patterns of atrophy and hypo metabolism in non-AD conditions often overlap spatially with the patterns seen in AD.”
Healthy aging and the blood–brain barrier
Banks, W. A., Reed, M. J., Logsdon, A. F., Rhea, E. M., & Erickson, M. A. (2021) · Nature Aging · doi:10.1038/s43587-021-00043-5 · Cited by 319
Aging, the Central Nervous System, and Mobility
Rosso, A. L., Studenski, S. A., Chen, W., Aizenstein, H. J., Alexander, N. B., Bennett, D. A., Black, S. E., Camicioli, R. M., Carlson, M. C., Ferrucci, L., et al. (2013) · The Journals of Gerontology Series A · doi:10.1093/gerona/glt089 · Cited by 290
Consensus statement for diagnosis of subcortical small vessel disease
Rosenberg, G. A., Wallin, A., Wardlaw, J. M., Markus, H. S., Montaner, J., WOLFSON, L. I., Iadecola, C., Zloković, B. V., Joutel, A., Dichgans, M., et al. (2015) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2015.172 · Cited by 228
Dementia prevention: current epidemiological evidence and future perspective
Mangialasche, F., Kivipelto, M., Solomon, A., & Fratiglioni, L. (2012) · Alzheimer s Research & Therapy · doi:10.1186/alzrt104 · Cited by 204
Amyloid-first and neurodegeneration-first profiles characterize incident amyloid PET positivity
Jack, C. R., Wiste, H. J., Weigand, S. D., Knopman, D. S., Lowe, V. J., Vemuri, P., Mielke, M. M., Jones, D. T., Senjem, M. L., Gunter, J. L., et al. (2013) · Neurology · doi:10.1212/01.wnl.0000435556.21319.e4 · Cited by 203
“While entorhinal and hippocampal neurofibrillary tangles are commonly found at autopsy in the absence of amyloid plaques in middle-aged and older CN subjects, neurodegeneration in most elderly subjects is most commonly due to a mixture of pathologies rather than a single isolated pathophysiologic process.(36) Frequent…”
BackgroundWang, M., Ding, F., Deng, S., Guo, X., Wang, W., Iliff, J. J., & Nedergaard, M. (2017) · Journal of Neuroscience · doi:10.1523/jneurosci.2112-16.2017 · Cited by 199
“Aging exacerbates effect of microinfarcts on glymphatic function Because microinfarcts are a common feature of the aged (Vinters et al., 2000; Sonnen et al., 2011; Kövari et al., 2013), rather than the healthy young brain, we compared the effect of multiple microinfarcts on glymphatic function in 12-month-old animals…”
BackgroundRelation of neuropathology to cognition in persons without cognitive impairment
Bennett, D. A., Wilson, R. S., Boyle, P. A., Buchman, A. S., & Schneider, J. A. (2012) · Annals of Neurology · doi:10.1002/ana.23654 · Cited by 220
In Vivo Detection of Cerebral Cortical Microinfarcts with High-Resolution 7T MRI
van Veluw, S. J., Zwanenburg, J. J., Engelen-Lee, J., Spliet, W. G., Hendrikse, J., Luijten, P. R., & Biessels, G. J. (2013) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2012.196 · Cited by 193
Neuropathologic comorbidity and cognitive impairment in the Nun and Honolulu-Asia Aging Studies
White, L. R., Edland, S. D., Hemmy, L. S., Montine, K. S., Zarow, C., Sonnen, J. A., Uyehara‐Lock, J. H., Gelber, R. P., Ross, G. W., Petrovitch, H., et al. (2016) · Neurology · doi:10.1212/wnl.0000000000002480 · Cited by 174
Self-citationVascular Imaging Abnormalities and Cognition
Knopman, D. S., Griswold, M. E., Lirette, S. T., Gottesman, R. F., Kantarci, K., Sharrett, A. R., Jack, C. R., Graff‐Radford, J., Schneider, A. L. C., Windham, B. G., et al. (2015) · Stroke · doi:10.1161/strokeaha.114.007847 · Cited by 162
“With strong mediating influences, pathways (1) and (2) should be present, and the apparent pathway (3) should be attenuated when additionally adjusting for the potential mediator, as in pathway (4).”
BackgroundMethodInfluentialGenetic variants and functional pathways associated with resilience to Alzheimer’s disease
Dumitrescu, L. C., Mahoney, E. R., Mukherjee, S., Lee, M. L., Bush, W. S., Engelman, C. D., Lu, Q., Fardo, D. W., Trittschuh, E. H., Mez, J., et al. (2020) · Brain · doi:10.1093/brain/awaa209 · Cited by 148
“In fact, among cognitively unimpaired volunteers agreeing to autopsy at the time of death, 70% have varying degrees of Alzheimer’s disease pathology (Sonnen et al., 2011), and 30% have sufficient neuropathology in their brain to meet neuropathological criteria for Alzheimer’s disease (i.”
BackgroundCognitive and social lifestyle: links with neuropathology and cognition in late life
Bennett, D. A., Arnold, S. E., Valenzuela, M., Brayne, C., & Schneider, J. A. (2013) · Acta Neuropathologica · doi:10.1007/s00401-013-1226-2 · Cited by 148
“Significant amounts of AD, CVD and LBD can be found in the brains of up to a third of persons without dementia and an even greater proportion of those with mild cognitive impairment (MCI) prior to death [13, 20–22, 35, 68, 94, 112, 124, 132].”
BackgroundDecreased Levels of Circulating Adiponectin in Mild Cognitive Impairment and Alzheimer’s Disease
Teixeira, A. L., Diniz, B. S., Campos, A. C., de Miranda, A. S., Rocha, N. P., Talib, L. L., Gattaz, W. F., & Forlenza, O. V. (2012) · NeuroMolecular Medicine · doi:10.1007/s12017-012-8201-2 · Cited by 138
Post-mortem assessment in vascular dementia: advances and aspirations
McAleese, K. E., Alafuzoff, I. I., Charidimou, A., Reuck, J. D., Grinberg, L. T., Hainsworth, A. H., Hortobágyi, T., Ince, P. G., Jellinger, K. A., Gao, J., et al. (2016) · BMC Medicine · doi:10.1186/s12916-016-0676-5 · Cited by 144
“In a study of 336 cognitively normal elderly adults, cerebral microinfarcts were seen in 33 % and high-level microinfarcts in 10 % [65].”
BackgroundProtective genes and pathways in Alzheimer’s disease: moving towards precision interventions
Seto, M., Weiner, R. L., Dumitrescu, L., & Hohman, T. J. (2021) · Molecular Neurodegeneration · doi:10.1186/s13024-021-00452-5 · Cited by 135
Neuropathological and transcriptomic characteristics of the aged brain
Miller, J. A., Guillozet-Bongaarts, A., Gibbons, L. E., Postupna, N., Renz, A., Beller, A. E., Sunkin, S. M., Ng, L., Rose, S. E., Smith, K. A., et al. (2017) · eLife · doi:10.7554/elife.31126 · Cited by 134
“observations in the ACT cohort (Sonnen et al., 2007; Sonnen et al., 2011) and other communityFigure 2.”
BackgroundResultInfluentialWhat causes neurodegenerative disease?
Armstrong, R. A. (2020) · Folia Neuropathologica · doi:10.5114/fn.2020.96707 · Cited by 143
“[183], 47% of cognitively normal individuals had moderate to frequent SP, 6% had NFT in layers V/VI of the cerebral cortex, and 15% had medullary LB.”
BackgroundRates of β-amyloid accumulation are independent of hippocampal neurodegeneration
Jack, C. R., Wiste, H. J., Knopman, D. S., Vemuri, P., Mielke, M. M., Weigand, S. D., Senjem, M. L., Gunter, J. L., Lowe, V. J., Gregg, B. E., et al. (2014) · Neurology · doi:10.1212/wnl.0000000000000386 · Cited by 129
“Tau PET ligands(26) will be essential to understanding the relationships between etiologically nonspecific imaging measures of neurodegeneration such as MRI and FDG-PET and the different underlying neurodegenerative processes that are common in the elderly.(24) We and others have previously reported that rates of Ab a…”
BackgroundCan we prevent Alzheimer's disease? Secondary “prevention” trials in Alzheimer's disease
Carrillo, M. C., Brashear, H. R., Logovinsky, V., Ryan, J. M., Feldman, H., Siemers, E., Abushakra, S. R., Hartley, D. M., Petersen, R. C., Khachaturian, A. S., et al. (2013) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2012.12.004 · Cited by 128
“[2] Sonnen JA, Santa Cruz K, Hemmy LS, Woltjer R, Leverenz JB, Montine KS, et al.”
BackgroundCortical cerebral microinfarcts on 3T MRI
Hilal, S., Sikking, E., Shaik, M. A., Chan, Q. L., van Veluw, S. J., Vrooman, H. A., Cheng, C., Sabanayagam, C., Cheung, C. Y.-L., Wong, T. Y., et al. (2016) · Neurology · doi:10.1212/wnl.0000000000003110 · Cited by 122
“Recent autopsy studies have shown that cerebral microinfarcts (CMIs) are highly prevalent not only in patients with dementia (43% in Alzheimer disease and 62% in vascular dementia) but also in elderly persons without dementia (up to 33%).(3,4) These CMIs can be present in all brain regions, possibly more in the cerebr…”
BackgroundAlzheimer's disease: The next frontier—Special Report 2017
Karlawish, J. H., Jack, C. R., Rocca, W. A., Snyder, H. M., & Carrillo, M. C. (2017) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2017.02.006 · Cited by 124
“[33] Sonnen JA, Santa Cruz K, Hemmy LS, Woltjer R, Leverenz JB,”
BackgroundMRI and MRS predictors of mild cognitive impairment in a population-based sample
Kantarci, K., Weigand, S. D., Przybelski, S. A., Preboske, G. M., Pankratz, V. S., Vemuri, P., Senjem, M. L., Murphy, M. C., Gunter, J. L., Machulda, M. M., et al. (2013) · Neurology · doi:10.1212/wnl.0b013e31829a3329 · Cited by 112
Pignolo, R. J. (2018) · Mayo Clinic Proceedings · doi:10.1016/j.mayocp.2018.10.005 · Cited by 113
Rodent Models of Vascular Cognitive Impairment
Yang, Y. R., Kimura‐Ohba, S., Thompson, J., & Rosenberg, G. A. (2016) · Translational Stroke Research · doi:10.1007/s12975-016-0486-2 · Cited by 109
“Elderly patients with dementia often show multiple pathological changes, including amyloid plaques, phosphorylated Tau, α-synuclein, and microinfarcts [24].”
Brain pathologies in extreme old age
Neltner, J. H., Abner, E. L., Jicha, G. A., Schmitt, F. A., Patel, E., Poon, L. W., Marla, G., Green, R. C., Davey, A., Johnson, M. A., et al. (2015) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2015.10.009 · Cited by 106
“…et al., 2015, Corrada, et al., 2012, Dickson, 2009, Erten-Lyons, et al., 2013, Jellinger and Attems, 2010a, Jellinger and Attems, 2010b, Jicha, et al., 2012, Kawas, et al., 2015, Kovacs, et al., 2013, Magaki, et al., 2014, Serrano-Pozo, et al., 2013, Sonnen, et al., 2011, Toledo, et al., 2013).”
Ritchie, C. W., Terrera, G. M., & Quinn, T. J. (2015) · Alzheimer s Research & Therapy · doi:10.1186/s13195-015-0113-6 · Cited by 106
Lopatko Lindman, K., Hemmingsson, E., Weidung, B., Brännström, J., Josefsson, M., Olsson, J., Elgh, F., Nordström, P., & Lövheim, H. (2021) · Alzheimer's & Dementia: Translational Research & Clinical Interventions · doi:10.1002/trc2.12119 · Cited by 99
Latimer, C. S., Burke, B. T., Liachko, N. F., Currey, H. N., Kilgore, M. D., Gibbons, L. E., Henriksen, J. C., Darvas, M., Domoto‐Reilly, K., Jayadev, S., et al. (2019) · Acta Neuropathologica Communications · doi:10.1186/s40478-019-0743-1 · Cited by 102
“Individuals with multiple co-morbid pathologies are more likely to experience cognitive symptoms [56, 91]; conversely, those who reach advanced age without cognitive impairment harbor fewer co-existing pathologies on average compared to those with dementia [48, 92].”
InfluentialRosenberg, G. A., Bjerke, M., & Wallin, A. (2014) · Stroke · doi:10.1161/strokeaha.113.004534 · Cited by 99
Selective alterations of neurons and circuits related to early memory loss in Alzheimer’s disease
Llorens-Martı́n, M., Blázquez‐Llorca, L., Benavides‐Piccione, R., Rábano, A., Hernández, F., Ávila, J., & DeFelipe, J. (2014) · Frontiers in Neuroanatomy · doi:10.3389/fnana.2014.00038 · Cited by 94
“…it is true that the pathology of AD is associated with advanced age, there is still a low proportion of aged non-AD subjects that develop no neurofibrillary pathology whatsoever (Sonnen et al., 2011; Jicha et al., 2012) suggesting that such pathology is not simply an inevitable consequence of age.”
BackgroundNeuropathological approaches to cerebral aging and neuroplasticity
Jellinger, K. A., & Attems, J. (2013) · Dialogues in Clinical Neuroscience · doi:10.31887/dcns.2013.15.1/kjellinger · Cited by 94
“The burden of brain lesions and comorbidities varied widely within each study but was similar across studies.(86) Among 418 nondemented participants of the Religious Order study (mean age 88.”
BackgroundBrenowitz, W. D., Keene, C. D., Hawes, S. E., Hubbard, R. A., Longstreth, W. T., Woltjer, R. L., Crane, P. K., Larson, E. B., & Kukull, W. A. (2017) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2017.01.017 · Cited by 88
“However, other studies have found no relationship between VBI and amyloid burden (Sonnen et al., 2011; Vemuri et al., 2015).”
BackgroundResultIncreased Number of Microinfarcts in Alzheimer Disease at 7-T MR Imaging
van Rooden, S., Goos, J. D. C., van Opstal, A. M., Versluis, M. J., Webb, A. G., Blauw, G. J., van der Flier, W. M., Scheltens, P., Barkhof, F., van Buchem, M. A., et al. (2014) · Radiology · doi:10.1148/radiol.13130743 · Cited by 86
The pathobiology of neurovascular aging
Santisteban, M. M., & Iadecola, C. (2025) · Neuron · doi:10.1016/j.neuron.2024.12.014 · Cited by 102
Alzheimer’s Disease Neuropathological Comorbidities are Common in the Younger-Old
Beach, T. G., & Malek‐Ahmadi, M. H. (2020) · Journal of Alzheimer s Disease · doi:10.3233/jad-201213 · Cited by 88
“These “AD-LB” cases are most often clinically silent [22] and diagnosed as probable ADD.”
Spinocerebellar ataxia 27B: A novel, frequent and potentially treatable ataxia
Pellerin, D., Danzi, M. C., Renaud, M., Houlden, H., Synofzik, M., Zuchner, S. L., & Brais, B. (2024) · Clinical and Translational Medicine · doi:10.1002/ctm2.1504 · Cited by 83
The effects of exercise on hypothalamic neurodegeneration of Alzheimer’s disease mouse model
Do, K., Laing, B. T., Landry, T., Bunner, W., Mersaud, N., Matsubara, T., Li, P.-X., Yuan, Y., Lu, Q., & Hu, H. (2018) · PLoS ONE · doi:10.1371/journal.pone.0190205 · Cited by 82
The Role of Genetics in Advancing Precision Medicine for Alzheimer’s Disease—A Narrative Review
Freudenberg‐Hua, Y., Li, W., & Davies, P. (2018) · Frontiers in Medicine · doi:10.3389/fmed.2018.00108 · Cited by 80
“It is important to note that AD pathologies were also found in nearly all brain autopsies of cognitively normal individuals above age 80, even among those considered as high-cognitive performers (28, 29).”
BackgroundLatimer, C. S., Keene, C. D., Flanagan, M. E., Hemmy, L. S., Lim, K. O., White, L. R., Montine, K. S., & Montine, T. J. (2017) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/nlx030 · Cited by 73
Dallaire‐Théroux, C., Callahan, B. L., Potvin, O., Saïkali, S., & Duchesne, S. (2017) · Journal of Alzheimer s Disease · doi:10.3233/jad-161028 · Cited by 71
GLP-1 Receptor Agonists in Neurodegeneration: Neurovascular Unit in the Spotlight
Monti, G., Moreira, D. G., Richner, M., Mutsaers, H. A. M., Ferreira, N., & Jan, A. (2022) · Cells · doi:10.3390/cells11132023 · Cited by 72
Microinfarcts are common and strongly related to dementia in the oldest‐old: The 90+ study
Corrada, M. M., Sonnen, J. A., Kim, R. C., & Kawas, C. H. (2016) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2016.04.006 · Cited by 71
“These measures pioneered in the Honolulu Asia Aging Study (HAAS) [2] have been validated in other population-based and community-based autopsy studies [9].”
MethodSelf-citationCognitive Resilience to Alzheimer’s Disease Pathology in the Human Brain
Bowles, E. J. A., Crane, P. K., Walker, R. L., Chubak, J., LaCroix, A. Z., Anderson, M. L., Rosenberg, D. E., Keene, C. D., & Larson, E. B. (2019) · Journal of Alzheimer s Disease · doi:10.3233/jad-180942 · Cited by 70
“We added Lewy Body Disease to the regression model because it has been associated with resilience in other publications.[10, 19, 34] We adjusted for age at baseline and age at death because age is an important potential confounder of the association between other factors and resilience.”
Association between Various Brain Pathologies and Gait Disturbance
Wennberg, A. M. V., Savica, R., & Mielke, M. M. (2017) · Dementia and Geriatric Cognitive Disorders · doi:10.1159/000456541 · Cited by 66
Ferroptosis of Microglia in Aging Human White Matter Injury
Adeniyi, P. A., Gong, X., MacGregor, E., Degener-O’Brien, K., McClendon, E., Garcia, M., Romero, O., Russell, J., Srivastava, T., Miller, J. A., et al. (2023) · Annals of Neurology · doi:10.1002/ana.26770 · Cited by 62
BLOOD-BRAIN BARRIER PERMEABILITY IN AGING AND ALZHEIMER’S DISEASE
Rosenberg, G. A. (2014) · The Journal of Prevention of Alzheimer s Disease · doi:10.14283/jpad.2014.25 · Cited by 63
“Vascular disease progresses relentlessly with aging, intersecting with AD after age 70 with an increasing number of normal people showing amyloid and tau deposits and microinfarcts at autopsy; this is consistent with the large number of patients with mixed dementia (7).”
ResultBennett, D. A. (2017) · PLoS Medicine · doi:10.1371/journal.pmed.1002256 · Cited by 64
Sarro, L., Tosakulwong, N., Schwarz, C. G., Graff‐Radford, J., Przybelski, S. A., Lesnick, T. G., Zuk, S. M., Reid, R. I., Raman, M. R., Boeve, B. F., et al. (2016) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2016.07.003 · Cited by 62
“Cerebrovascular disease (CVD) may coexist with both AD and Lewy body disease [1–6], particularly in the oldest old [7,8].”
BackgroundBeach, T., Malek-Ahmadi, M., ZAMRINI, E. Y., Adler, C. H., Sabbagh, M. N., Shill, H. A., Jacobson, S. A., Belden, C. M., Caselli, R. J., Woodruff, B. K., et al. (2019) · PLoS ONE · doi:10.1371/journal.pone.0217566 · Cited by 56
“These “AD-LB” cases are most often clinically silent [1] and diagnosed as probable ADD.”
BackgroundRegional Tau Effects on Prospective Cognitive Change in Cognitively Normal Older Adults
Chen, X., Cassady, K. E., Adams, J. N., Harrison, T. M., Baker, S. L., & Jagust, W. J. (2020) · Journal of Neuroscience · doi:10.1523/jneurosci.2111-20.2020 · Cited by 61
“This early EC tau increases with age and has been reported in individuals without Ab pathology (Sonnen et al., 2011; Jack et al., 2019; Schöll et al., 2019).”
BackgroundCholerton, B., Larson, E. B., Quinn, J. F., Zabetian, C. P., Mata, I. F., Keene, C. D., Flanagan, M. E., Crane, P. K., Grabowski, T. J., Montine, K. S., et al. (2015) · American Journal Of Pathology · doi:10.1016/j.ajpath.2015.12.001 · Cited by 61
“In a collaborative study that pooled data from 1672 brain autopsies from multiple population- and community-based studies, the most common neuropathologic finding was some combination of these diseases, leaving open the extent to which each disease may have contributed to cognitive decline.(5) More important, 424 cogn…”
BackgroundResultAntemortem MRI findings associated with microinfarcts at autopsy
Raman, M. R., Preboske, G. M., Przybelski, S. A., Gunter, J. L., Senjem, M. L., Vemuri, P., Murphy, M. C., Murray, M. E., Boeve, B. F., Knopman, D. S., et al. (2014) · Neurology · doi:10.1212/wnl.0000000000000471 · Cited by 46
“They were participants in one of 3 prospective studies during the years of 1999 through 2011: (1) dementia clinic–based Mayo Clinic Alzheimer’s Disease Research Center; (2) community clinic–based Alzheimer’s Disease Patient Registry; or (3) populationbased Mayo Clinic Study of Aging.”
BackgroundMixed neuropathologies and associations with domain-specific cognitive decline
Brenowitz, W. D., Hubbard, R. A., Keene, C. D., Hawes, S. E., Longstreth, W. T., Woltjer, R. L., & Kukull, W. A. (2017) · Neurology · doi:10.1212/wnl.0000000000004567 · Cited by 49
“In prior studies, ADNC as measured by Braak stage of neurofibrillary tangles, LBD as manifest by cortical Lewy bodies, and VBI as represented by gross and microscopic infarcts have been associated with lower cognitive function or cognitive decline in multiple domains.(5,7) Two studies that reported testing interaction…”
BackgroundBeach, T. G., Adler, C. H., Zhang, N., Serrano, G. E., Sue, L. I., Driver‐Dunckley, E. D., Mehta, S. H., Zamrini, E., Sabbagh, M. N., Shill, H. A., et al. (2020) · PLoS ONE · doi:10.1371/journal.pone.0231720 · Cited by 43
“ADD and DLB often co-exist unknown to clinicians, and as this comorbidity may affect the presentation, rate of cognitive decline, and response to therapeutic agents [1-22], clinical trials for both conditions may be impaired.”
BackgroundMultiple pathologies are common in Alzheimer patients in clinical trials
Wang, B. W., Lu, E., Mackenzie, I. R. A., Assaly, M., Jacova, C., Lee, P. E., Beattie, B. L., & Hsiung, G. Y. R. (2012) · Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques · doi:10.1017/s0317167100015316 · Cited by 41
Dodge, H. H., Zhu, J. Y., Woltjer, R. L., Nelson, P. T., Bennett, D. A., Cairns, N. J., Fardo, D. W., Kaye, J. A., Erten‐Lyons, D., Mattek, N., et al. (2016) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2016.11.003 · Cited by 40
“Studies have also shown the significance of vascular disease in the pathogenesis of AD [5–10] and that comorbid cerebrovascular pathology plays a key role for clinical expression of dementia, especially among the oldest old [11,12] where mixed pathology is common [13,14].”
BackgroundResultMorales, L. G. F., Correa‐Basurto, J., & Rosales‐Hernández, M. C. (2021) · Antioxidants · doi:10.3390/antiox10020218 · Cited by 39
“AD is characterized neuropathologically by the presence of neurofibrillary tangles (NFTs), formed by the intraneuronal accumulation of Tau protein filaments and by senile plaques formed mostly by deposits of Aβ peptide [35,36].”
BackgroundInflammatory Biomarkers Aid in Diagnosis of Dementia
Erhardt, E. B., Adair, J. C., Knoefel, J. E., Caprihan, A., Prestopnik, J., Thompson, J., Hobson, S., Siegel, D., & Rosenberg, G. A. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.717344 · Cited by 42
Gene-based GWAS and biological pathway analysis of the resilience of executive functioning
Initiative, A. D. N., Mukherjee, S., Kim, S., Ramanan, V. K., Gibbons, L. E., Nho, K. T., Glymour, M. M., Ertekin‐Taner, N., Montine, T. J., Saykin, A. J., et al. (2013) · Brain Imaging and Behavior · doi:10.1007/s11682-013-9259-7 · Cited by 38
Vascular cognitive impairment: Advances and trends
Barbay, M., Taillia, H., Nédélec-Ciceri, C., Arnoux, A., Puy, L., Wiener, E., Canaple, S., Lamy, C., Godefroy, O., & Roussel, M. (2017) · Revue Neurologique · doi:10.1016/j.neurol.2017.06.009 · Cited by 39
“[21] Sonnen JA, Santa Cruz K, Hemmy LS, Woltjer R, Leverenz JB, Montine KS, et al.”
BackgroundRosenberg, G. A., Prestopnik, J., Adair, J. C., Huisa, B. N., Knoefel, J. E., Caprihan, A., Gasparovic, C., Thompson, J. F., Erhardt, E. B., & Schrader, R. (2015) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp-2014-309421 · Cited by 39
The correlation between neuropathology levels and cognitive performance in centenarians
Zhang, M., Ganz, A. B., Rohde, S. K., Lorenz, L. M. C., Rozemüller, A. J. M., van Vliet, K., Graat, M., Sikkes, S. A. M., Reinders, M. J. T., Scheltens, P., et al. (2023) · Alzheimer s & Dementia · doi:10.1002/alz.13087 · Cited by 34
Zhao, Y., Tudorascu, D., López, O. L., Cohen, A. D., Mathis, C. A., Aizenstein, H. J., Price, J. C., Kuller, L. H., Kamboh, M. I., DeKosky, S. T., et al. (2017) · JAMA Neurology · doi:10.1001/jamaneurol.2017.3029 · Cited by 35
Shoob, S., Buchbinder, N., Shinikamin, O., Gold, O., Baeloha, H., Langberg, T., Zarhin, D., Shapira, I., Braun, G., Habib, N., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-42721-5 · Cited by 33
Pathogenesis and Treatment of Vascular Cognitive Impairment
Jellinger, K. A. (2014) · Neurodegenerative Disease Management · doi:10.2217/nmt.14.37 · Cited by 30
Perceptions of stigma among people affected by early- and late-onset Alzheimer’s disease
Ashworth, R. (2017) · Journal of Health Psychology · doi:10.1177/1359105317720818 · Cited by 33
Absence of C9ORF72 expanded or intermediate repeats in autopsy‐confirmed Parkinson's disease
Nuytemans, K., Inchausti, V., Beecham, G. W., Wang, L., Dickson, D. W., Trojanowski, J. Q., Lee, V. M. ‐., Mash, D. C., Frosch, M. P., Foroud, T., et al. (2014) · Movement Disorders · doi:10.1002/mds.25838 · Cited by 28
“Recently, clinical controls have been shown to present with some measure of “disease”-associated change upon autopsy (38), allowing for the possibility that the asymptomatic intermediate repeat copy carriers will still present with pathological indications of disease.”
Atherosclerotic Risk Factors, Vascular Cognitive Impairment, and Alzheimer Disease
Kovacic, J. C., & Fuster, V. (2012) · Mount Sinai Journal of Medicine A Journal of Translational and Personalized Medicine · doi:10.1002/msj.21347 · Cited by 27
Retinal Biomarkers of Alzheimer Disease
Lee, C. S., & Apte, R. S. (2020) · American Journal of Ophthalmology · doi:10.1016/j.ajo.2020.04.040 · Cited by 27
Association of cerebral microvascular dysfunction and white matter injury in Alzheimer’s disease
Bagi, Z. A., Kroenke, C. D., Fopiano, K. A., Tian, Y., Filosa, J. A., Sherman, L. S., Larson, E. B., Keene, C. D., Degener-O’Brien, K., Adeniyi, P. A., et al. (2022) · GeroScience · doi:10.1007/s11357-022-00585-5 · Cited by 27
Rosenberg, G. A. (2016) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-015-0277-4 · Cited by 27
“A large autopsy series of relatively normal persons showed that by the time of death, it was common to have pathological protein accumulations of b-amyloid, a-synuclein, along with microinflarcts (Sonnen et al. 2011).”
Whole genome deconvolution unveils Alzheimer’s resilient epigenetic signature
Berson, E., Sreenivas, A., Phongpreecha, T., Perna, A., Grandi, F. C., Xue, L., Ravindra, N. G., Payrovnaziri, S. N., Mataraso, S. J., Kim, Y., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-40611-4 · Cited by 25
“Weperformedunivariateanalysisoncelltype-speci fi cexpressionfrom RAD, NC, ADD, independently for each cell type.”
BackgroundInfluentialComparative Incidence of Conformational, Neurodegenerative Disorders
de Pedro‐Cuesta, J., Rábano, A., Martínez‐Martín, P., Ruiz-Tovar, M., Alcalde-Cabero, E., Almazán‐Isla, J., Avellanal, F., & Calero, M. (2015) · PLoS ONE · doi:10.1371/journal.pone.0137342 · Cited by 25
“, 76% [4], in the 1990s, when many PD screening surveys were conducted, and the presence of neuritic Aβ plaques or tau deposits in considerable proportions of non-demented persons [5,6] seriously undermine the validity of numerators and denominators of clinical PD and AD incidence counts respectively.”
BackgroundResultInfluentialMolecular Imaging of Alzheimer Disease Pathology
Kantarci, K. (2014) · American Journal of Neuroradiology · doi:10.3174/ajnr.a3847 · Cited by 24
Blood-brain barrier biomarkers
Zapata-Acevedo, J. F., Mantilla-Galindo, A., Vargas-Sánchez, K., & González-Reyes, R. E. (2024) · Advances in clinical chemistry · doi:10.1016/bs.acc.2024.04.004 · Cited by 23
Ueda, Y., Satoh, M., Tabei, K., Kida, H., Ii, Y., Asahi, M., Maeda, M., Sakuma, H., & Tomimoto, H. (2016) · Journal of Alzheimer s Disease · doi:10.3233/jad-151008 · Cited by 23
“They are encountered in 16 to 46% of elderly people in any cause of death [4] or 33% in cognitively normal elderly people [9].”
Alterations of functional circuitry in aging brain and the impact of mutated APP expression
Bearer, E. L., Manifold-Wheeler, B. C., Medina, C. S., Gonzales, A., Chaves, F. L., & Jacobs, R. E. (2018) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2018.06.018 · Cited by 25
“Alzheimer’s disease (AD) accounts for half of all dementias, with associated cognitive decline characterized by deficits in episodic memory, short-term memory, impaired judgment and synapse loss (Keller, 2006; Reitz et al., 2011; Sonnen et al., 2011).”
BackgroundClinician-judged hearing impairment and associations with neuropathologic burden
Brenowitz, W. D., Besser, L. M., Kukull, W. A., Keene, C. D., Glymour, M. M., & Yaffe, K. S. (2020) · Neurology · doi:10.1212/wnl.0000000000010575 · Cited by 22
Khalifa, K. N., Bergland, A. K., Soennesyn, H., Oppedal, K., Oesterhus, R., Dalen, I., Larsen, A. I., Fladby, T., Brooker, H. J., Wesnes, K. A., et al. (2020) · Frontiers in Neurology · doi:10.3389/fneur.2020.00916 · Cited by 22
Exploring common genetic contributors to neuroprotection from amyloid pathology
Seto, M., Mahoney, E. R., Dumitrescu, L. C., Ramanan, V. K., Engelman, C. D., Deming, Y. K., Albert, M., Johnson, S. C., Zetterberg, H., Blennow, K., et al. (2022) · Brain Communications · doi:10.1093/braincomms/fcac066 · Cited by 17
Metalloproteinases and neurodegenerative diseases: pathophysiological and therapeutic perspectives
Rosenberg, G. A. (2015) · Metalloproteinases In Medicine · doi:10.2147/mnm.s68849 · Cited by 21
“This situation has been remedied by the use of animal models, which are very helpful in unraveling the pathophysiology of the chronic changes.(60) Two animal models have been most helpful: 1) the bilateral occlusion of the common carotid arteries (BCAO) in the normotensive rat; and 2) the administration of the modifie…”
BackgroundMethodNeuropsychological assessment and cerebral vascular disease: The new standards
Godefroy, O., Leclercq, C., Bugnicourt, J., Roussel, M., Moroni, C., Quaglino, V., Beaunieux, H., Taillia, H., Nédélec-Ciceri, C., Bonnin, C. A., et al. (2013) · Revue Neurologique · doi:10.1016/j.neurol.2013.07.009 · Cited by 20
Postupna, N. O., Keene, C. D., Crane, P. K., Gonzalez‐Cuyar, L. F., Sonnen, J. A., Hewitt, J. L., Rice, S., Howard, K., Montine, K. S., Larson, E. B., et al. (2015) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0000000000000153 · Cited by 21
“Major findings from ACT study neuropathology investigations include the following: validation of the Honolulu-Asia Aging Study finding that microvascular brain injury (KVBI) is a common and strong contributor to dementia in older individuals (10); estimation of population-attributable risk for dementia from AD, Lewy b…”
BackgroundInfluentialSelf-citationHebert, P. L., McBean, A. M., O’Connor, H., Frank, B., Good, C., & Maciejewski, M. L. (2013) · Pharmacoepidemiology and Drug Safety · doi:10.1002/pds.3449 · Cited by 20
Yu, L., Huo, Z., Yang, J., Palma‐Gudiel, H., Boyle, P. A., Schneider, J. A., Bennett, D. A., & Zhao, J. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.765259 · Cited by 20
Seven-Tesla MRI and neuroimaging biomarkers for Alzheimer’s disease
Ali, R., Goubran, M., Choudhri, O., & Zeineh, M. (2015) · Neurosurgical FOCUS · doi:10.3171/2015.9.focus15326 · Cited by 20
Metadata
- 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)
- 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
- green
- www.ncbi.nlm.nih.gov
- 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
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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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