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Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature
Open accessAbstract
Clinicopathologic correlation studies are critically important for the field of Alzheimer disease (AD) research. Studies on human subjects with autopsy confirmation entail numerous potential biases that affect both their general applicability and the validity of the correlations. Many sources of data variability can weaken the apparent correlation between cognitive status and AD neuropathologic changes. Indeed, most persons in advanced old age have significant non-AD brain lesions that may alter cognition independently of AD. Worldwide research efforts have evaluated thousands of human subjects to assess the causes of cognitive impairment in the elderly, and these studies have been interpreted in different ways. We review the literature focusing on the correlation of AD neuropathologic changes (i.e. β-amyloid plaques and neurofibrillary tangles) with cognitive impairment. We discuss the various patterns of brain changes that have been observed in elderly individuals to provide a perspective for understanding AD clinicopathologic correlation and conclude that evidence from many independent research centers strongly supports the existence of a specific disease, as defined by the presence of Aβ plaques and neurofibrillary tangles. Although Aβ plaques may play a key role in AD pathogenesis, the severity of cognitive impairment correlates best with the burden of neocortical neurofibrillary tangles.
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TL;DR
This review synthesizes clinicopathologic correlation literature on Alzheimer disease (AD) and concludes that AD neuropathologic changes—Aβ plaques and neurofibrillary tangles—are strongly linked to cognitive impairment, with neocortical neurofibrillary tangle burden correlating best with severity. It argues that Aβ plaques alone are not sufficient for advanced AD dementia and that concomitant non-AD pathologies often weaken apparent correlations.
Key findings
- Evidence from many independent research centers supports AD as a specific disease defined by Aβ plaques and neurofibrillary tangles, but the severity of cognitive impairment correlates best with the burden of neocortical neurofibrillary tangles.
- Aβ plaques alone do not seem sufficient for advanced clinical AD dementia; neuritic plaques correlate with antemortem cognitive impairment better than diffuse Aβ plaques, and neocortical NFTs correlate more strongly than allocortical or subcortical NFTs.
- In a review of 11 studies comprising 555 subjects without dementia, 12 brains were Braak stage V (2.2%) and 3 were Braak stage VI (0.5%); among thousands of cases, there was no report of a thoroughly documented individual with truly “end-stage” neocortical NFT pathology who lacked antemortem cognitive impairment proximal to death.
- Concomitant pathologies are common and contribute noise: 75% to 90% of patients older than 90 years have some degree of cerebrovascular disease pathology, and hippocampal sclerosis affects up to 20% of individuals in advanced age and correlates with cognitive impairment independently of AD.
Methods
- Design: narrative literature review of clinicopathologic correlation (CPC) studies on AD neuropathologic changes and cognitive status, written from the perspective of neuropathologists and clinicians.
- Data/sample: human autopsy CPC studies, including more than 40 studies assessing Aβ plaques and numerous studies assessing NFTs; highlighted large autopsy series from at least 18 different research centers, with inclusion criteria of more than 40 patients, neuropathologic assessment of both NFTs and AβPs in cerebral neocortex, broad pathologic severity, and nondichotomous correlation with cognitive status.
- Main analysis: qualitative synthesis of study findings, discussion of sources of bias and variability, and comparison of correlations between Aβ plaques, neuritic plaques, NFTs, and antemortem cognitive impairment; no pooled meta-analysis is reported.
Limitations
- The paper states that CPC studies face numerous potential biases: autopsy selection bias, nonrandom clinic- or hospital-based samples, concentration on middle- and upper-income whites in advantaged countries, imperfect and evolving clinical and pathologic assessments, variable time between final clinical evaluation and autopsy, competing mortality risks, and high prevalence of concurrent diseases.
- The paper states that autopsy provides only cross-sectional data and cannot prove molecular mechanisms; pathologic assessments identify deviations from “normal” but do not prove that plaques or tangles are proximate to the ultimate neurotoxic species.
- The text makes evident that this is a narrative review rather than a systematic review or meta-analysis, and its highlighted large-series table uses selective inclusion criteria; the authors also note that not all AD cases fall within the same spatial continuum of NFT distributions and that Braak staging masks variability in lesion density within a given stage.
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In the paper
“In fact, there have been hints of some beneficial effects (clinical and biochemical) linked to human anti-Aβ immunotherapies (74-79).”
§ Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature > CONTROVERSIES IN AD CPC RESEARCH
What the sources say
Strength:hedged· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesNone of the sources cited for this claim have been checked yet.
In the paper
“On the other hand, the density of tau-positive NPs does correlate directly and statistically independently with some degree of cognitive impairment (105-107) (Fig. 2).”
§ Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature > LESS-PREVALENT PATTERNS OF CLINICAL AND PATHOLOGIC FEATURES FOUND IN HUMAN BRAINS > “Plaque-Only” Dementia
What the sources say
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In the paper
“We are aware of no reported case of truly intact cognition despite extremely severe AD pathologic changes (i.e. widespread neocortical NFTs) measured with quantitative pathologic analysis, although many persons with intact cognition have been assessed in autopsy series (33, 42, 54, 133, 142, 148, 151-166).”
§ Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature > LESS-PREVALENT PATTERNS OF CLINICAL AND PATHOLOGIC FEATURES FOUND IN HUMAN BRAINS > AβPs and NFTs But No Dementia
What the sources say
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In the paper
“Even in extreme old age, the presence of many neocortical NFTs correlates with antemortem cognitive decline (105, 188-191).”
§ Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature > LESS-PREVALENT PATTERNS OF CLINICAL AND PATHOLOGIC FEATURES FOUND IN HUMAN BRAINS > AD-Related Brain Pathology in Individuals Older Than 90 Years
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIn the paper
“Although the study designs were diverse in CPC studies involving AβPs, most studies confirm a significant correlation between antemortem cognitive impairment and neocortical AβPs, as demonstrated by Blessed et al (254) (Fig. 3).”
§ Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature > CLINICOPATHOLOGIC CORRELATION IN AD > Correlation Between AβPs and Cognitive Status
What the sources say
- Not checked yetcites [254] source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIn the paper
“A recent study with large numbers of subjects assessed with standardized antemortem cognitive testing found that the amyloid stage that has progressed to involve the striatum is highly predictive of dementia (263).”
§ Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature > CLINICOPATHOLOGIC CORRELATION IN AD > Correlation Between AβPs and Cognitive Status
What the sources say
- Not checked yetcites [263] Beach, 2012, Striatal amyloid plaque density predicts braak neurofibrillary stage and clinicopathological Alzheimer's disease: Implications for amyloid imaging, J Alzheimers Dis source
Strength:boosted· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesNone of the sources cited for this claim have been checked yet.
In the paper
“Subsequent studies have established that the densities of NPs correlate with antemortem cognitive impairment better than the densities of diffuse AβPs (45, 98, 106, 154, 189, 261).”
§ Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature > CLINICOPATHOLOGIC CORRELATION IN AD > Correlation Between AβPs and Cognitive Status
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesNone of the sources cited for this claim have been checked yet.
In the paper
“Duyckaerts et al (287) and Sabbagh et al (252) independently arrived at the conclusion that the density of NFTs in selected cerebral cortical fields significantly (p < 0.01) correlated with Blessed or Mini-Mental State Examination scores (297).”
§ Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature > CLINICOPATHOLOGIC CORRELATION IN AD > Correlation Between NFTs and Cognitive Status
What the sources say
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesNone of the sources cited for this claim have been checked yet.
In the paper
“At 40 years, all individuals studied by Braak and Del Tredici (39) and Braak et al (44) exhibited at least initial neurofibrillary pathology in the brainstem (Fig. 5).”
§ Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature > CLINICOPATHOLOGIC CORRELATION IN AD > Correlation Between NFTs and Cognitive Status
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIn the paper
“Similar results were obtained by Bennett et al (264) who found a strong correlation between global cognitive status and densities of neocortical tau-positive tangles.”
§ Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature > CLINICOPATHOLOGIC CORRELATION IN AD > Correlation Between NFTs and Cognitive Status
What the sources say
- Not checked yetcites [264] source
Strength:boosted· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
- Probably not a substantial claim. 21
- It may state two separate claims as one. 53
In the paper
“The findings reported by Tomlinson et al (38) in 1970 have been replicated many times: “[NFTs are] found in both controls and dements [demented subjects] in the hippocampus, but elsewhere in the cortex was only severe or widespread in the dements; severe generalized neurofibrillary change in the cortex was not seen in any control; it seems possible that its occurrence always indicates dementia.””
§ Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature > AβPS AND NEUROFIBRILLARY TANGLES: THE HISTOPATHOLOGIC HALLMARKS LINKED TO AD
What the sources say
- Not checked yetcites [38] source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. It may state two separate claims as one.
In the paper
“There were 58 subjects with dementia and AD changes, of which 40 had 2 or more neocortical tangles per high-magnification field in frontal, temporal, and parietal lobes; 18 had no neocortical NFTs.”
§ Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature > LESS-PREVALENT PATTERNS OF CLINICAL AND PATHOLOGIC FEATURES FOUND IN HUMAN BRAINS > “Plaque-Only” Dementia
What the sources say
- Not checked yetcites [101] source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“The cases did not differ in hippocampal tangle densities and had no significant differences in brain weights, neocortical thickness, or neocortical neuron counts.”
§ Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature > LESS-PREVALENT PATTERNS OF CLINICAL AND PATHOLOGIC FEATURES FOUND IN HUMAN BRAINS > “Plaque-Only” Dementia
What the sources say
- Not checked yetcites [101] source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“There have been cases in which individuals with mid- to late-stage clinical AD were administered anti-Aβ immunotherapy that partially cleared AβPs, but this clearance did not seem to mitigate NFT formation or the inexorable disease course (69-71).”
§ Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature > CONTROVERSIES IN AD CPC RESEARCH
What the sources say
Load-bearingStrength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Despite this, both groups were demented and did not differ significantly on the Blessed Dementia Scale.”
§ Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature > LESS-PREVALENT PATTERNS OF CLINICAL AND PATHOLOGIC FEATURES FOUND IN HUMAN BRAINS > “Plaque-Only” Dementia
What the sources say
- Not checked yetcites [101] source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Using data from the National Alzheimer’s Coordinating Center with inclusion and exclusion criteria, as described previously (282), NPs and NFTs tend to coexist (Table 4); this corroborates earlier observations (283).”
§ Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature > CLINICOPATHOLOGIC CORRELATION IN AD > Neuritic AβP (NP): A Pathologic Entity With Mechanistic Implications
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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
“In sum, both clinical and pathologic assessments are imperfect, variably applied, and constantly evolving.”
§ Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature > OVERVIEW OF CHALLENGES TO CPC STUDIES IN AD
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes? Checkable: unclear✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: Both clinical and pathologic assessments are imperfect, variably applied, and constantly evolving.
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
“Although Aβ plaques may play a key role in AD pathogenesis, the severity of cognitive impairment correlates best with the burden of neocortical neurofibrillary tangles.”
§ Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
“Studies on human subjects with autopsy confirmation entail numerous potential biases that affect both their general applicability and the validity of the correlations.”
§ Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature > Abstract
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✗ Based: failsProbably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Additional changes that may also occur in the brains of AD patients include amyloid angiopathy, age-related brain atrophy, synaptic pathology, white matter rarefaction, granulovacuolar degeneration, neuron loss, TDP-43 proteinopathy, and neuroinflammation (20-26), which may contribute to cognitive impairment; however, these are not considered pathognomonic features of AD (3).”
§ Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature > AβPS AND NEUROFIBRILLARY TANGLES: THE HISTOPATHOLOGIC HALLMARKS LINKED TO AD
What the sources say
- Not checked yetcites [20] source
- Not checked yetcites [21] source
- Not checked yetcites [22] Masliah, 1995, Mechanisms of synaptic dysfunction in Alzheimer's disease, Histol Histopathol
- Not checked yetcites [23] source
- Not checked yetcites [24] source
- Not checked yetcites [25] source
- Not checked yetcites [26] Scheff, 2006, Alzheimer's disease-related alterations in synaptic density: Neocortex and hippocampus, J Alzheimers Dis source
- Not checked yetcites [3] source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The tendency to dichotomize the disease (i.e. “demented vs nondemented”) and overreliance on ordinal variables may also obscure important relationships.”
§ Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature > OVERVIEW OF CHALLENGES TO CPC STUDIES IN AD
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Furthermore, CPC studies rarely are a random sample of the population and clinic- and hospital-based CPCs are subject to other potential biases.”
§ Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature > OVERVIEW OF CHALLENGES TO CPC STUDIES IN AD
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: CPC studies rarely are a random sample of the population.
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
“As such, neurofibrillary degeneration restricted to subcortical sites is often subclinical, whereas widespread neocortical NFTs are almost always associated with severe cognitive impairment in more than 1 disease state.”
§ Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature > AβPS AND NEUROFIBRILLARY TANGLES: THE HISTOPATHOLOGIC HALLMARKS LINKED TO AD
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“On the other hand, tau gene mutations can produce clinical dementia with NFTs; this indicates that, under some conditions, NFTs may be directly linked to the primary or at least proximal neurodegenerative changes (29, 31, 37).”
§ Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature > AβPS AND NEUROFIBRILLARY TANGLES: THE HISTOPATHOLOGIC HALLMARKS LINKED TO AD
What the sources say
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Neurofibrillary tangles are not specific for AD (29-32); indeed, they are found in almost every class of brain disease and are universal (yet topographically restricted) in normal aging subjects (33).”
§ Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature > AβPS AND NEUROFIBRILLARY TANGLES: THE HISTOPATHOLOGIC HALLMARKS LINKED TO AD
What the sources say
- Not checked yetcites [29] source
- Not checked yetcites [30] Arai, 2001, Distinct isoforms of tau aggregated in neurons and glial cells in brains of patients with Pick's disease, cor-ticobasal degeneration and progressive supranuclear palsy, Acta Neu-ropathol source
- Not checked yetcites [31] source
- Not checked yetcites [32] source
- Not checked yetcites [33] source
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“This subset of AβPs is a hallmark of the current diagnostic criteria for AD, although there is no universally accepted definition of a NP.”
§ Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature > AβPS AND NEUROFIBRILLARY TANGLES: THE HISTOPATHOLOGIC HALLMARKS LINKED TO AD
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“The concordance of genetics and Aβ deposition is aligned with CPC studies that indicate that AβPs may be a temporally “upstream” feature of the neocortical disease, with the caveats that brainstem and medial temporal lobe pretangles and NFTs are seen in subjects without Aβ deposition in all age categories (33, 39, 44).”
§ Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature > AβPS AND NEUROFIBRILLARY TANGLES: THE HISTOPATHOLOGIC HALLMARKS LINKED TO AD
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“In contrast to NFTs, AβPs are extracellular (45, 46) and are found in a high proportion of all elderly persons but are not universal (44, 47, 48).”
§ Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature > AβPS AND NEUROFIBRILLARY TANGLES: THE HISTOPATHOLOGIC HALLMARKS LINKED TO AD
What the sources say
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Both the density and the neuroanatomic localization of NFTs are important parameters in AD neuropathology.”
§ Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature > AβPS AND NEUROFIBRILLARY TANGLES: THE HISTOPATHOLOGIC HALLMARKS LINKED TO AD
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
“It must be acknowledged that a simplistic conceptualization of “plaques and tangles” does not adequately reflect the complexity of the biochemical changes in the brains of patients with AD.”
§ Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature > CONTROVERSIES IN AD CPC RESEARCH
Strength:plain· not yet calibratedTests✓ Asserted: passes✗ Checkable: fails✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. It may be too vague to check against evidence. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“It is clear, as mentioned previously, that AβPs, in the absence of any other neurodegenerative disease lesions or other pathologies, are not a sufficient substrate for severe dementia and thus do not constitute “advanced AD pathologic changes.””
§ Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature > CONTROVERSIES IN AD CPC RESEARCH
Load-bearingStrength:boosted· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“There are multiple reasons why these trials may have failed, including the late timing of the therapy. Thus, conclusions drawn from these trials may be premature (72, 73).”
§ Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature > CONTROVERSIES IN AD CPC RESEARCH
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
“As for Assertion 2, it is true that dementia, even one that may be clinically similar to probable AD, may be present without AD pathologic changes; this is simply not AD, but presumably one among many other diseases that cause dementia (e.g. hippocampal sclerosis or vascular dementia).”
§ Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature > CONTROVERSIES IN AD CPC RESEARCH
Load-bearingStrength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
“These patterns of brain changes indicate specific features that can be correlated with clinical parameters, modeled to understand disease mechanisms, and targeted for therapeutics.”
§ Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature > CONTROVERSIES IN AD CPC RESEARCH
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✗ Based: failsProbably not a substantial claim. The paper may give no 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
“Because autopsies provide only cross-sectional data, they cannot prove mechanism.”
§ Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature > CONTROVERSIES IN AD CPC RESEARCH
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Thus, AβPs and NFTs are the hallmark features of AD but do not develop in the human brain according to the same temporal or anatomic pattern (60, 61).”
§ Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature > AβPS AND NEUROFIBRILLARY TANGLES: THE HISTOPATHOLOGIC HALLMARKS LINKED TO AD
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
“Thus, peptides and higher-order aggregates derived from products of APP and MAPT genes can potentially lead to combinations of neuroprotective and toxic attributes.”
§ Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature > CONTROVERSIES IN AD CPC RESEARCH
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✗ Based: failsProbably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
In the paper
“In contrast, dense and extensive neocortical NFTs are very consistently associated with dementia and thus, according to new diagnostic criteria, these are required to constitute high burden of AD neuropathologic change (3).”
§ Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature > CONTROVERSIES IN AD CPC RESEARCH
What the sources say
- Not checked yetcites [3] source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“The toxicity of oligomeric forms of tau and Aβ peptides could be connected with biochemical changes that also produce NPs and NFTs; thus, the oligomeric species may be directly related to the neuropathology, although they are not exactly correlated (90-95).”
§ Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature > CONTROVERSIES IN AD CPC RESEARCH
What the sources say
- Not checked yetcites [90] source
- Not checked yetcites [91] Jin, 2011, Soluble amyloid {β}-protein dimers isolated from Alzheimer cortex directly induce Tau hyperphosphorylation and neuritic degeneration, Proc Natl Acad Sci U S A source
- Not checked yetcites [92] Gadad, 2011, Targeting oligomers in neurodegenerative disorders: lessons from alpha-synuclein, tau, and amyloid-β peptide, J Alzheimers Dis source
- Not checked yetcites [93] source
- Not checked yetcites [94] source
- Not checked yetcites [95] source
Strength:hedged· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Since both tau phosphorylation and Aβ peptide generation are seen in “normal” brains, some contend that there are probably beneficial and adaptive aspects to these molecular processes.”
§ Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature > CONTROVERSIES IN AD CPC RESEARCH
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“When modern pathologic methods are used, severe cognitive impairment associated only with diffuse AβPs in the brain at autopsy is rare and has an unknown relationship to AD.”
§ Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature > LESS-PREVALENT PATTERNS OF CLINICAL AND PATHOLOGIC FEATURES FOUND IN HUMAN BRAINS > “Plaque-Only” Dementia
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“The median life expectancy in Western countries is approximately 79 years (141).”
§ Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature > LESS-PREVALENT PATTERNS OF CLINICAL AND PATHOLOGIC FEATURES FOUND IN HUMAN BRAINS > AβPs and NFTs But No Dementia
What the sources say
- Not checked yetcites [141] Central Intelligence Agency. The World Factbook. Washington, DC: Central Intelligence Agency, 2008
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
In the paper
“There are also some individuals with intact or subtly diminished cognitive abilities whose brains harbor hippocampal and/or amygdala NFTs (Braak stages III–IV) with few or no AβPs; these represent approximately 5% of cases in some large autopsy series (41).”
§ Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature > LESS-PREVALENT PATTERNS OF CLINICAL AND PATHOLOGIC FEATURES FOUND IN HUMAN BRAINS > “Tangle-Only” or “Tangle-Predominant” Dementia and Other Non-AD Tauopathies
What the sources say
- Not checked yetcites [41] source
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“Subtle cognitive impairment may be associated with diffuse AβPs, indicating that these lesions may play a direct role in incipient AD (54), although a direct role of diffuse Aβ plaques without tau pathology has not been proven.”
§ Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature > LESS-PREVALENT PATTERNS OF CLINICAL AND PATHOLOGIC FEATURES FOUND IN HUMAN BRAINS > “Plaque-Only” Dementia
What the sources say
- Not checked yetcites [54] source
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Furthermore, diffuse AβPs may be associated with cerebral amyloid angiopathy, which could produce impairments separately (103, 104), although see Nelson et al (105).”
§ Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature > LESS-PREVALENT PATTERNS OF CLINICAL AND PATHOLOGIC FEATURES FOUND IN HUMAN BRAINS > “Plaque-Only” Dementia
What the sources say
Strength:hedged· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“The current revision of the National Institute on Aging–Alzheimer’s Association guidelines for the neuropathologic assessment of AD stipulate that subjects with moderately dense neuritic AβPs may be regarded as having an intermediate level of AD neuropathologic change and that other potential contributors to cognitive impairment and dementia should be sought (3).”
§ Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature > LESS-PREVALENT PATTERNS OF CLINICAL AND PATHOLOGIC FEATURES FOUND IN HUMAN BRAINS > “Plaque-Only” Dementia
What the sources say
- Not checked yetcites [3] source
Strength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Indeed, this is precisely the observation reported by one of the largest autopsy series to date (142) and is well supported by AD biomarker studies (143-145).”
§ Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature > LESS-PREVALENT PATTERNS OF CLINICAL AND PATHOLOGIC FEATURES FOUND IN HUMAN BRAINS > AβPs and NFTs But No Dementia
What the sources say
Strength:boosted· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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
“Thus, using these data, we can deduce confidently that an “average” person dying at age 79 has an approximately 15% likelihood of having been diagnosed clinically with ADD, but an approximately 30% to 40% chance of harboring significant AD neuropathologic changes (otherwise, the prevalence of ADD could not reach approximately 30%–40% by age 95).”
§ Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature > LESS-PREVALENT PATTERNS OF CLINICAL AND PATHOLOGIC FEATURES FOUND IN HUMAN BRAINS > AβPs and NFTs But No Dementia
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“In this condition, the NFTs comprise tau isoforms similar to those of classic AD, but these subjects do not have the same distribution of APOE genotypes as subjects with AD (118).”
§ Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature > LESS-PREVALENT PATTERNS OF CLINICAL AND PATHOLOGIC FEATURES FOUND IN HUMAN BRAINS > “Tangle-Only” or “Tangle-Predominant” Dementia and Other Non-AD Tauopathies
What the sources say
- Not checked yetcites [118] source
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“In most community-based autopsy series, non-AD tauopathies constitute approximately 1% of dementia cases (108-115) (but see Noda et al [116]).”
§ Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature > LESS-PREVALENT PATTERNS OF CLINICAL AND PATHOLOGIC FEATURES FOUND IN HUMAN BRAINS > “Tangle-Only” or “Tangle-Predominant” Dementia and Other Non-AD Tauopathies
What the sources say
- Not checked yetcites [108] source
- Not checked yetcites [109] source
- Not checked yetcites [110] source
- Not checked yetcites [111] Schneider, 2009, The neuropathology of older persons with and without dementia from community versus clinic cohorts, J Alzheimers Dis source
- Not checked yetcites [112] source
- Not checked yetcites [113] source
- Not checked yetcites [114] source
- Not checked yetcites [115] source
- Not checked yetcites [116] source
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“The prevalence of dementia due to AD, as judged by clinicians, doubles every half-decade after age 65; thus, approximately 30% to 40% of living 95-year-old patients receive the diagnosis of ADD (126-128).”
§ Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature > LESS-PREVALENT PATTERNS OF CLINICAL AND PATHOLOGIC FEATURES FOUND IN HUMAN BRAINS > AβPs and NFTs But No Dementia
What the sources say
- Not checked yetcites [126] source
- Not checked yetcites [127] Aronson, 1991, Dementia, Age-dependent incidence, prevalence, and mortality in the old old. Arch Intern Med
- Not checked yetcites [128] Katzman R Kawas C . The epidemiology of dementia and Alzheimer disease. In: Terry RD , ed. Alzheimer Disease. New York, NY: Raven Press, Ltd, 1994:105–22
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“A notable example of this is schizophrenia, which, in elderly patients, is associated with dementia, although the underlying basis of this dementia is enigmatic (174-176).”
§ Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature > LESS-PREVALENT PATTERNS OF CLINICAL AND PATHOLOGIC FEATURES FOUND IN HUMAN BRAINS > Dementia Cases Lacking AβPs, NFTs, or Other Pathologic Substrates
What the sources say
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Cerebrovascular disease (CVD) is the most prevalent non-AD pathologic diagnosis in the brains of the advanced aged and is directly relevant to any CPC study related to dementia.”
§ Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature > LESS-PREVALENT PATTERNS OF CLINICAL AND PATHOLOGIC FEATURES FOUND IN HUMAN BRAINS > AD-Related Brain Pathology in Individuals Older Than 90 Years
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“It is expected that many persons die with brains that exhibit AD neuropathologic change in the preclinical phase of AD; indeed, data support the modeled expectations (44, 142).”
§ Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature > LESS-PREVALENT PATTERNS OF CLINICAL AND PATHOLOGIC FEATURES FOUND IN HUMAN BRAINS > AβPs and NFTs But No Dementia
Load-bearingStrength:boosted· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Normal pressure hydrocephalus is another poorly understood cause of dementia that may lack AD pathologic changes (177, 178).”
§ Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature > LESS-PREVALENT PATTERNS OF CLINICAL AND PATHOLOGIC FEATURES FOUND IN HUMAN BRAINS > Dementia Cases Lacking AβPs, NFTs, or Other Pathologic Substrates
What the sources say
- Not checked yetcites [177] Leinonen V Koivisto AM Savolainen S . Post-mortem findings in 10 patients with presumed normal pressure hydrocephalus and review of the literature. [published online ahead of print February 10, 2012] Neuropathol Appl Neurobiol
- Not checked yetcites [178] source
Strength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“However, not all studies are in agreement on this point (185, 186); these “survivors” represent a small fraction of the human population with underrepresentation of APOE ε4 allele (187).”
§ Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature > LESS-PREVALENT PATTERNS OF CLINICAL AND PATHOLOGIC FEATURES FOUND IN HUMAN BRAINS > AD-Related Brain Pathology in Individuals Older Than 90 Years
What the sources say
- Not checked yetcites [187] source
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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
“In the same way, AβPs may be a key pathologic factor in AD without equating with the clinical features of ADD.”
§ Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature > CLINICOPATHOLOGIC CORRELATION IN AD > Correlation Between AβPs and Cognitive Status
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Owing in part to the scarcity of neocortical NFTs in the absence of AβPs, and the relatively modest apparent direct impact of AβPs on cognition, it has been suggested that the pathogenetic effect of AβP-related substances may be mediated by “seeding” neurofibrillary pathology (46, 88, 189, 264, 265).”
§ Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature > CLINICOPATHOLOGIC CORRELATION IN AD > Correlation Between AβPs and Cognitive Status
What the sources say
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“For this reason, the number of AβPs might plateau (or at least the rate of increase flatten out), leading to a “ceiling effect” relatively early in disease process that confounds linear correlations between plaque number and severity of cognitive change (253).”
§ Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature > CLINICOPATHOLOGIC CORRELATION IN AD > Correlation Between AβPs and Cognitive Status
What the sources say
- Not checked yetcites [253] source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Nevertheless, the profound impact of CVD on studies pertinent to cognition in the elderly seems to be underappreciated in dementia research (208-210).”
§ Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature > LESS-PREVALENT PATTERNS OF CLINICAL AND PATHOLOGIC FEATURES FOUND IN HUMAN BRAINS > AD-Related Brain Pathology in Individuals Older Than 90 Years
What the sources say
Strength:hedged· not yet calibratedTests✓ Asserted: passes✗ Checkable: fails✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. It may be too vague to check against evidence. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“In more advanced disease, the neuroanatomic distribution of NFTs correlates both with the location at which neurons die (302-305) and with the cognitive domains affected in patients with ADD.”
§ Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature > CLINICOPATHOLOGIC CORRELATION IN AD > Correlation Between NFTs and Cognitive Status
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“As AD progresses, the NFTs become numerous in locus coeruleus which may suggest the same pathogenetic process is becoming more severe (301).”
§ Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature > CLINICOPATHOLOGIC CORRELATION IN AD > Correlation Between NFTs and Cognitive Status
What the sources say
- Not checked yetcites [301] source
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“The abnormal NP-contacting dendrites and axons contain pathologic tau fibrils identical to those seen in NFTs (244, 273), with loss of adjacent synapses (274, 275).”
§ Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature > CLINICOPATHOLOGIC CORRELATION IN AD > Neuritic AβP (NP): A Pathologic Entity With Mechanistic Implications
What the sources say
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Dystrophic axons from completely different afferent sources, expressing distinct neurotransmitters, have been shown to be present in particular NPs (276, 277), which strongly implies that toxicity is directed from the (extracellular) plaque to the radially arranged intracellular neurites.”
§ Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature > CLINICOPATHOLOGIC CORRELATION IN AD > Neuritic AβP (NP): A Pathologic Entity With Mechanistic Implications
Strength:boosted· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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
“This process may be synergistic or identical to the stimuli that could promote NFTs in human brains.”
§ Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature > CLINICOPATHOLOGIC CORRELATION IN AD > Neuritic AβP (NP): A Pathologic Entity With Mechanistic Implications
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✗ Checkable: fails✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. It may be too vague to check against evidence. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, some evidence exists for NFT “turnover,” neuronal shrinkage, and/or non-NFT cell death mechanism(s).”
§ Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature > CLINICOPATHOLOGIC CORRELATION IN AD > Correlation Between NFTs and Cognitive Status
Load-bearingStrength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: Neurofibrillary tangles are quantified with certainty only at autopsy.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Concomitant pathologies are very common in aging brains.”
§ Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature > SUMMARY AND CONCLUSIONS
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✗ Based: failsProbably not a substantial claim. 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
“A patient lacking AD pathologic diagnosis at autopsy, despite “biomarker positivity,” is not an AD case and suggests the biomarker has imperfect specificity.”
§ Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature > EVOLVING CONCEPTS AND UNANSWERED QUESTIONS
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Neuritic plaques combine extracellular Aβ deposition and intracellular neurofibrillary (tau protein) pathology.”
§ Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature > SUMMARY AND CONCLUSIONS
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✗ Based: failsProbably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Indeed, there are still also no recognized biomarker-based criterion standards for a large number of other neurodegenerative tauopathies, synucleinopathies, and vascular brain changes.”
§ Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature > EVOLVING CONCEPTS AND UNANSWERED QUESTIONS
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably 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
“Pathologic assessments cannot prove molecular mechanisms; instead, they identify and describe deviations from what is recognized as “normal.””
§ Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature > EVOLVING CONCEPTS AND UNANSWERED QUESTIONS
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. 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
“Because cognitive impairment in aging may be attributed to many different conditions other than AD, current biomarkers for AD are limited to predicting which patients may become cognitively impaired with neocortical AβPs and NFTs, rather than just predicting cognitive impairment alone.”
§ Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature > EVOLVING CONCEPTS AND UNANSWERED QUESTIONS
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“However, until such a method becomes available, neuropathologic examination remains the criterion standard for disease definition.”
§ Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature > EVOLVING CONCEPTS AND UNANSWERED QUESTIONS
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“For example, hippocampal atrophy is visualized on magnetic resonance imaging in both AD and hippocampal sclerosis patients and is therefore not a distinct AD biomarker.”
§ Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature > EVOLVING CONCEPTS AND UNANSWERED QUESTIONS
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“This is an important consideration because up to 20% of individuals in advanced age are affected by hippocampal sclerosis that correlates with cognitive impairment independently of AD pathologic diagnosis (105, 211, 321-323).”
§ Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature > EVOLVING CONCEPTS AND UNANSWERED QUESTIONS
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
“Although the density of neocortical NFTs and neuritic AβPs on autopsy correlate with the severity of cognitive dysfunction, and the observed results align with a plausible hypothesis, this does not prove that these pathologic hallmarks are proximate to the ultimate neurotoxic species.”
§ Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature > EVOLVING CONCEPTS AND UNANSWERED QUESTIONS
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
The paper relies on this without support.
Autopsy is required for definitive AD diagnosis.
“Autopsy is required for definitive AD diagnosis, yet autopsy rates are generally low and autopsy inevitably confers a selection bias.”
The paper relies on this without support.
Autopsy rates are generally low.
“Autopsy is required for definitive AD diagnosis, yet autopsy rates are generally low and autopsy inevitably confers a selection bias.”
The paper relies on this without support.
CPC studies rarely are a random sample of the population.
“Furthermore, CPC studies rarely are a random sample of the population and clinic- and hospital-based CPCs are subject to other potential biases.”
The paper relies on this without support.
Most prior studies have concentrated on middle- and upper-income whites.
“Most prior studies have been performed in countries with the most advantageous socioeconomic conditions and have concentrated on middle- and upper-income whites.”
The paper relies on this without support.
Both clinical and pathologic assessments are imperfect, variably applied, and constantly evolving.
“In sum, both clinical and pathologic assessments are imperfect, variably applied, and constantly evolving.”
The paper relies on this without support.
Neurofibrillary tangles are quantified with certainty only at autopsy.
“As with AβPs, NFTs are quantified with certainty only at autopsy.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Numerous studies have linked tau pathology to cognitive decline, with some evidence suggesting it progresses more rapidly than Aβ accumulation and correlates with neuroinflammation, making it a valuable prognostic marker [20, 25–28].”
From Targeted Nanoparticles for Drug Delivery Across the Blood–Brain Barrier in Early and Late Stages of Alzheimer's Disease: A Review (2026) · cites this paper as [26]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“VEEV neuropathology shares similarities with AD, a widespread cognitive disorder of aging, including increased astrogliosis, glial nodules, and pathological indicators of neuroinflammation including perivascular cuffing (Nelson et al., 2012; Williams et al., 2023).”
From Arbovirus infection increases the risk for the development of neurodegenerative disease pathology in the murine model (2024) · cites this paper as Nelson et al., 2012
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“Variance in the distribution and burden of tauopathy in AD is closely associated with the clinical phenotype, 13 cognitive deficit, 14 and rate of cognitive decline. 15”
From Alzheimer's disease and its progression reduce pyramidal cell gain and connectivity (2025) · cites this paper as [14]
The cited source says what the claim attributes to it.
In the citing paper
“Histopathologically, AD is characterized by the formation of intraneuronal neurofibrillary tangles consisting of the hyperphosphorylated microtubule protein, tau, and extracellular deposits of plaques of amyloid-β (Aβ), a breakdown product of the transmembrane amyloid precursor protein (APP) [241]”
From Microglia and monocytes in inflammatory CNS disease: integrating phenotype and function (2022) · cites this paper as [241]
The cited source says what the claim attributes to it.
In the citing paper
“Recent studies suggest that NFT pathology closely correlates with neurodegeneration and cognitive decline [1, 2].”
From Selective suppression of the α isoform of p38 MAPK rescues late-stage tau pathology (2016) · cites this paper as [2]
In the citing paper
“For example, there is minimal correlation between phases of amyloid deposition and degree of cognitive decline”
From Alzheimer Disease: An Update on Pathobiology and Treatment Strategies (2019) · cites this paper as Nelson et al., 2012
In the citing paper
“Unlike Aβ, the stage of tau pathology correlates well with progression of cognitive impairment”
From Alzheimer Disease: An Update on Pathobiology and Treatment Strategies (2019) · cites this paper as Nelson et al., 2012
In the citing paper
“Its tendency to accumulate for years without causing symptomatic disease (i.e., asymptomatic AD or AsymAD) supports this conclusion [35, 36].”
From Systems-based proteomics to resolve the biology of Alzheimer’s disease beyond amyloid and tau (2021) · cites this paper as [35]
In the citing paper
“Compared with cortical Aβ plaque, the density and distribution of phosphorylated tau aggregated in NFTs correlate more closely with AD-associated cognitive impairment and neurodegeneration.12,13,14”
From Positron Emission Tomography Imaging With [ 18 F]flortaucipir and Postmortem Assessment of Alzheimer Disease Neuropathologic Changes (2020) · cites this paper as [14]
In the citing paper
“given that tangle burden is more closely correlated with cortical atrophy and cognitive decline [46]”
From Deep proteomic network analysis of Alzheimer’s disease brain reveals alterations in RNA binding proteins and RNA splicing associated with disease (2018) · cites this paper as [46]
In the citing paper
“The close correlation between tau deposition and cognitive decline (3)”
From Tau reduction prevents neuronal loss and reverses pathological tau deposition and seeding in mice with tauopathy (2017) · cites this paper as [3]
In the citing paper
“In AD, tau burden appears to directly correlate with disease progression and cognitive decline (3).”
From Tau reduction prevents neuronal loss and reverses pathological tau deposition and seeding in mice with tauopathy (2017) · cites this paper as [3]
Citations
Cites
Items 201–359 of 359
Dementia. Age-dependent incidence, prevalence, and mortality in the old old
Aronson, M. K. (1991) · Archives of Internal Medicine · doi:10.1001/archinte.151.5.989 · Cited by 154
Role of the neuropathology of Alzheimer disease in dementia in the oldest-old
Haroutunian, V., Schnaider-Beeri, M., Schmeidler, J., Wysocki, M., Purohit, D. P., Perl, D. P., Libow, L. S., Lesser, G. T., Maroukian, M., & Grossman, H. T. (2008) · Archives of Neurology · doi:10.1001/archneur.65.9.1211 · Cited by 154
Self-citationCrystal, H. A., Dickson, D., Davies, P., Masur, D., Grober, E., & Lipton, R. B. (2000) · Archives of Neurology · doi:10.1001/archneur.57.5.713 · Cited by 152
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The key role of mitochondria in Alzheimer's disease
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“Numerous CPC studies have assessed the association between NFTs and cognitive status (38, 98, 154, 158, 162, 185, 188, 189, 191, 223 Y 232, 235 Y 240, 244, 250 Y 252, 258, 261, 264, 287 Y 296).”
ResultInfluentialSelf-citationNeurodegeneration in Normal Brain Aging and Disease
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“…of no reported case of truly intact cognition despite extremely severe AD pathologic changes (i.e. widespread neocortical NFTs) measured with quantitative pathologic analysis, although many persons with intact cognition have been assessed in autopsy series (33, 42, 54, 133, 142, 148, 151 Y 166).”
Self-citationSenile Dementia with Tangles (Tangle Predominant Form of Senile Dementia)
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Self-citationOskar Fischer and the study of dementia
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“Numerous CPC studies have assessed the association between NFTs and cognitive status (38, 98, 154, 158, 162, 185, 188, 189, 191, 223 Y 232, 235 Y 240, 244, 250 Y 252, 258, 261, 264, 287 Y 296).”
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“Neurofibrillary pathology is observed in the human brain long before A A plaques develop (39, 44, 300).”
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“The abnormal NP-contacting dendrites and axons contain pathologic tau fibrils identical to those seen in NFTs (244, 273), with loss of adjacent synapses (274, 275).”
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Self-citationRe-Evaluation of the Structural Organization of Neuritic Plaques in Alzheimerʼs Disease
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Self-citationHippocampal sclerosis dementia differs from hippocampal sclerosis in frontal lobe degeneration
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“Numerous CPC studies have assessed the association between NFTs and cognitive status (38, 98, 154, 158, 162, 185, 188, 189, 191, 223 Y 232, 235 Y 240, 244, 250 Y 252, 258, 261, 264, 287 Y 296).”
Self-citationHippocampal Sclerosis in the Elderly
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APOE related alterations in cerebral activation even at college age
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Self-citationNeuropathology of preclinical and clinical lateonset Alzheimer's disease
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Self-citationHealthy ageing in the Nun Study: definition and neuropathologic correlates
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“Some, but not all, studies have indicated that more neurons disappear in brains of demented subjects than can be explained directly by the number of NFTs and ‘‘ghost tangles’’ observed at autopsy (285, 304, 307Y310) (but see [305]).”
ResultSelf-citationNeocortical and hippocampal amyloid-β and tau measures associate with dementia in the oldest-old
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“Even in extreme old age, the presence of many neocortical NFTs correlates with antemortem cognitive decline (105, 188 Y 191).”
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Self-citationIncidence and Causes of Nondegenerative Nonvascular Dementia
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γ-Secretase-dependent amyloid-β is increased in Niemann-Pick type C
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The widespread alteration of neurites in Alzheimer's disease may be unrelated to amyloid deposition
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“Numerous CPC studies have assessed the association between NFTs and cognitive status (38, 98, 154, 158, 162, 185, 188, 189, 191, 223 Y 232, 235 Y 240, 244, 250 Y 252, 258, 261, 264, 287 Y 296).”
Self-citationAbundant neurofibrillary tangles without senile plaques in a subset of patients with senile dementia
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Self-citationCauses versus effects: the increasing complexities of Alzheimer’s disease pathogenesis
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Self-citationPreclinical AD Workgroup staging: Pathological correlates and potential challenges
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“In the same way, A A Ps may be a key pathologic factor in AD without equating with the clinical features of ADD.”
BackgroundInfluentialSelf-citationAge, Alzheimer's disease and dementia in the Baltimore Longitudinal Study of Ageing
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“Even in extreme old age, the presence of many neocortical NFTs correlates with antemortem cognitive decline (105, 188 Y 191).”
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Self-citationAn Anatomic Substrate for Visual Disconnection in Alzheimer's Diseasea
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“The characteristic anatomic distribution of NPs and NFTs supports additional hypotheses in relation to their formation that are outside the scope of this review (33, 39, 284 Y 286).”
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Self-citationDementia incidence may increase more slowly after age 90: Results from the Bronx Aging Study
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“A A Ps being possibly reabsorbed during life so that they would not be ‘‘counted’’ at autopsy), which seems to occur in some subjects (70, 270).”
BackgroundSelf-citationClinical Validity of Aß-Protein Deposition Staging in Brain Aging and Alzheimer Disease
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Self-citationAmyloid‐β in Alzheimer's disease: the horse or the cart? Pathogenic or protective?
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“Dystrophic axons from completely different afferent sources, expressing distinct neuro-transmitters, have been shown to be present in particular NPs (276, 277), which strongly implies that toxicity is directed from the (extracellular) plaque to the radially arranged intracellular neurites.”
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Metadata
- Authors
- 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., Duyckaerts, C., Frosch, M. P., Haroutunian, V., Hof, P. R., Hulette, C. M., Hyman, B. T., Iwatsubo, T., Jellinger, K. A., Jicha, G. A., Kövari, E., Kukull, W. A., Leverenz, J. B., Love, S., Mackenzie, I. R., Mann, D. M., Masliah, E., McKee, A. C., Montine, T. J., Morris, J. C., Schneider, J. A., Sonnen, J. A., Thal, D. R., Trojanowski, J. Q., Troncoso, J. C., Wisniewski, T., Woltjer, R. L., & Beach, T. G.
- Affiliations
- University of Kentucky (US)
- Uppsala University (SE)
- Northwestern University (US)
- University of Geneva (CH)
- University of Maryland, Baltimore (US)
- University of British Columbia (CA)
- Albert Einstein College of Medicine (US)
- Harvard University (US)
- Boston University (US)
- Rush University Medical Center (US)
- Corresponding author
- Nelson, Peter T.
- ORCID
- Nelson, Peter T.
- Alafuzoff, Irina
- Bigio, Eileen H.
- Braak, Heiko
- Castellani, Rudolph J.
- Davies, Peter
- Tredici, Kelly Del
- Duyckaerts, Charles
- Frosch, Matthew P.
- Haroutunian, Vahram
- Hof, Patrick R.
- Hyman, Bradley T.
- Iwatsubo, Takeshi
- Jellinger, Kurt A.
- Jicha, Gregory A.
- Kukull, Walter A.
- Leverenz, James B.
- Love, Seth
- Mackenzie, Ian R.
- Mann, David M.
- Masliah, Eliezer
- McKee, Ann C.
- Montine, Thomas J.
- Morris, John C.
- Schneider, Julie A.
- Sonnen, Joshua A.
- Thal, Dietmar R.
- Trojanowski, John Q.
- Troncoso, Juan C.
- Woltjer, Randall L.
- Beach, Thomas G.
- Venue
- Journal of Neuropathology & Experimental Neurology
- Publisher
- Oxford University Press (OUP)
- Published
- 2012-05
- Volume
- 71
- Issue
- 5
- Pages
- 362-381
- ISSN
- 0022-3069 (ISSN-L)
- 1554-6578
- PMC
- PMC3560290
- OpenAlex
- W2074274706
- Semantic Scholar
- bce678baa6d56ad7c06197507d7903b6c7619507
- Cited by
- 2,050
- References
- 369
- Citations by year
- 2026: 115 · 2025: 153 · 2024: 166 · 2023: 161 · 2022: 213 · 2021: 205 · 2020: 194 · 2019: 179 · 2018: 139 · 2017: 134 · 2016: 108 · 2015: 95 · 2014: 98 · 2013: 72 · 2012: 17
- FWCI
- 12.22
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuropathology & Experimental Neurology (publishedVersion)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion)
- Archive ouverte UNIGE (University of Geneva) (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Bristol Research (University of Bristol) (submittedVersion)
- Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
- Funders
- Alzheimer's Association
- Alzheimer Forschung Initiative
- Alzheimer's Society
- Deutsche Forschungsgemeinschaft
- Medical Research Council
- National Institute on Aging (AG-028383, AG 016976, AG-15819, AG13854, AG 10161, R01AG035071, AG-02219, AG 05136, P30AG028383, AG008017, U01AG006781, AG 05138, U01AG016976, P50AG005138, AG-06647, AG035071, P30AG010124, AG 05681, R01AG015819, P30AG008017, AG-10124, P30AG010161, R37AG022102, R01AG006647, P30AG008051, AG 08051, P50AG005681, R01AG022102, P50AG005136, P30AG013854, U19AG010483, R37AG006647, R01AG020245, P01AG002219, RF1AG015819)
- National Institute of Neurological Disorders and Stroke (R01NS073502)
- 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 › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, clinicopathological correlation, cognitive impairment, amyloid plaques, neurofibrillary tangles, disease severity
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Brain, Cognition Disorders, Humans, Statistics as Topic, Amyloid beta-Peptides, Neurofibrillary Tangles, Plaque, Amyloid
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-10, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-10 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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