Accuracy of the Clinical Diagnosis of Alzheimer Disease at National Institute on Aging Alzheimer Disease Centers, 2005–2010
Open accessAbstract
The neuropathologic examination is considered to provide the gold standard for Alzheimer disease (AD). To determine the accuracy of currently used clinical diagnostic methods, clinical and neuropathologic data from the National Alzheimer's Coordinating Center, which gathers information from the network of National Institute on Aging (NIA)-sponsored Alzheimer Disease Centers (ADCs), were collected as part of the National Alzheimer's Coordinating Center Uniform Data Set (UDS) between 2005 and 2010. A database search initially included all 1198 subjects with at least one UDS clinical assessment and who had died and been autopsied; 279 were excluded as being not demented or because critical data fields were missing. The final subject number was 919. Sensitivity and specificity were determined based on "probable" and "possible" AD levels of clinical confidence and 4 levels of neuropathologic confidence based on varying neuritic plaque densities and Braak neurofibrillary stages. Sensitivity ranged from 70.9% to 87.3%; specificity ranged from 44.3% to 70.8%. Sensitivity was generally increased with more permissive clinical criteria and specificity was increased with more restrictive criteria, whereas the opposite was true for neuropathologic criteria. When a clinical diagnosis was not confirmed by minimum levels of AD histopathology, the most frequent primary neuropathologic diagnoses were tangle-only dementia or argyrophilic grain disease, frontotemporal lobar degeneration, cerebrovascular disease, Lewy body disease and hippocampal sclerosis. When dementia was not clinically diagnosed as AD, 39% of these cases met or exceeded minimum threshold levels of AD histopathology. Neurologists of the NIA-ADCs had higher predictive accuracy when they diagnosed AD in subjects with dementia than when they diagnosed dementing diseases other than AD. The misdiagnosis rate should be considered when estimating subject numbers for AD studies, including clinical trials and epidemiologic studies.
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Claims the paper makes
21 of 46 cited sources checked · 4 supported · 1 flagged · accuracy not yet measured
- Premisecitation
The last diagnostic accuracy studies utilizing a complete ADC dataset were performed in 1998 and 1999.
“the last diagnostic accuracy studies utilizing a complete ADC dataset were performed in 1998 and 1999 (4, 23)”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [4] source
The Subjects section describes a diagnostic study using patients from 26 Alzheimer's disease centers, and the Results report diagnostic sensitivity and specificity. The Results also say complete information was available for only 2,188 of 3,177 patients. This 1998 paper does not establish that its dataset was complete or that the last such studies were performed in 1998 and 1999. (LLM, conf=0.83)
Experimental — accuracy not yet measured - cites [23] source
- Premisecitation
NIA-Reagan provides instructions for classification of only 3 of 25 possible combinations of CERAD neuritic plaque density and Braak stage.
“Because of 25 possible combinations of CERAD neuritic plaque density and Braak neurofibrillary stage, NIA-Reagan provides instructions for classification of only 3 (32, 38).”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [32] source
The Introduction (page unavailable) describes three NIA-Reagan likelihood categories and says off-diagonal plaque–tangle pairings are not clearly addressed. It does not support the count of 25 possible combinations: it describes four CERAD tiers and Braak stages 0–VI. The three categories also cover ranges of Braak stages, rather than just three individual combinations. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [38] source
- Interpretationcitation
Phenotype is not rigidly linked to etiology and may be moldable to a large extent by an individual's genetic and epigenetic background and/or total environmental exposure.
“These findings suggest that phenotype is not rigidly linked to etiology and may be moldable to a large extent by an individual's genetic and epigenetic background and/or total environmental exposure.”
Quote in the paperSubstantial claim3 of 4 sources checked- cites [44] source
The introductory passage following the Abstract conclusion says GRN-associated frontotemporal lobar degeneration is clinically heterogeneous even among relatives with the same mutation, and identifies nonmendelian genetic risk factors. This supports the suggestion that phenotype is not rigidly determined by the causal mutation, but the paper does not establish a large effect of epigenetic background or environmental exposure. Page numbers are unavailable in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [45] Larner, 2009, Genotype-phenotype relationships of presenilin-1 mutations in Alzheimer's disease: An update, J Alzheimer Dis source
- cites [46] source
The Comment section (page unavailable) reports marked clinical heterogeneity among family members likely to share a single disease-causing mutation, supporting the point that this disease’s phenotype is not fixed by its apparent etiology. The paper does not attribute that variation to genetic or epigenetic background or environmental exposure, nor establish how extensively those factors mold phenotype. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [47] Wszolek, 2009, Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), Orphanet J Rare Dis source
The Abstract and Genetic counseling sections (pages not supplied) report that the FTDP-17 phenotype can vary even among people with the same mutation, supporting the point that phenotype is not rigidly determined by etiology. Unresolved questions suggests that genetic modifiers and environmental factors may influence its expression, but does not mention epigenetic background, total environmental exposure, or influence 'to a large extent.' (LLM, conf=0.86)
Experimental — accuracy not yet measured
- Premisecitation
Correlation studies between molecular genetics and neuropathology indicate that for several autosomal dominant dementias, the presenting clinical phenotype may vary widely, from various dementia subtypes to parkinsonism to motor neuron disease-like, even among individuals with the same causative mutation.
“Correlation studies between molecular genetics and neuropathology also indicate that for several autosomal dominant dementias, the presenting clinical phenotype may vary widely, from various dementia subtypes to parkinsonism to motor neuron disease-like, even among individuals with the same causative mutation (44-47).”
Quote in the paperNot a substantial claim3 of 4 sources checked- cites [44] source
The introductory passage following the Abstract conclusion (page unavailable) says GRN-associated frontotemporal lobar degeneration is clinically heterogeneous even among family members with the same mutation. The Results report dementia and parkinsonian diagnoses, but describe motor neuron disease as uncommon and concomitant, not a typical presenting phenotype. This paper addresses GRN-associated disease, so it does not by itself establish the claim across several autosomal dominant dementias. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [45] Larner, 2009, Genotype-phenotype relationships of presenilin-1 mutations in Alzheimer's disease: An update, J Alzheimer Dis source
- cites [46] source
The Results (Clinical features) and Comment describe markedly different presentations—including FTD, ALS and Parkinsonism—within one family with autosomal dominant FTD/ALS. But the Genetics section identifies a shared chromosome 9p21 haplotype, not a causative mutation, and the paper does not establish this pattern across several autosomal dominant dementias. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [47] Wszolek, 2009, Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), Orphanet J Rare Dis source
The Abstract says FTDP-17 phenotypes vary even within families carrying the same mutation. The Clinical description (Phenotype-genotype correlations; Symptoms and signs) describes dementia-predominant and parkinsonism-predominant presentations and motor neuron dysfunction. The paper addresses FTDP-17, not several autosomal dominant dementias, and does not establish motor neuron disease-like illness as a presenting phenotype. (LLM, conf=0.85)
Experimental — accuracy not yet measured
- Premisecitation
The new NIA criteria use the same combination of moderate or frequent neuritic plaques and Braak stage III-VI as the minimum lesion density necessary for attributing the cause of dementia to AD.
“The new NIA criteria use the same combination of NPs and Braak stage as the minimum lesion density necessary for attributing the cause of dementia to AD (39, 40).”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [39] source
The Classification section defines moderate or frequent neuritic plaques and Braak stages III–VI as scores used by the new criteria. But it requires a third measure, Aβ plaque score, to classify AD neuropathologic change; the Reporting section says an intermediate or high overall level, rather than the stated two-measure combination alone, is an adequate explanation of dementia. Our copy provides no page numbers for these passages. (LLM, conf=0.87)
Experimental — accuracy not yet measured - cites [40] source
The Classification section says the new criteria use Braak stage and neuritic-plaque score, but also require an Aβ-plaque score as part of the ABC score. The Reporting section says intermediate or high AD neuropathologic change can adequately explain dementia; the passages do not establish moderate or frequent neuritic plaques plus Braak stage III–VI as the minimum sufficient combination. (LLM, conf=0.86)
Experimental — accuracy not yet measured
- Findingown data
The best sensitivity and specificity combination was 70.9% sensitivity and 70.8% specificity, achieved when clinical diagnosis was probable AD and neuropathological diagnosis was moderate or frequent neuritic plaques with Braak stage III-VI.
“When optimizing for sensitivity and specificity, the best result was 70.9% sensitivity and 70.8% specificity. This was achieved when the clinical diagnosis was defined as probable AD and the neuropathological diagnosis as moderate or frequent neuritic plaques with Braak stage III-VI.”
Quote in the paperSubstantial claim - Findingown data
The median scores for neuritic plaque density and Braak stage were significantly different, with progressively lower scores moving from probable AD through possible AD and not AD groups.
“The median scores for neuritic plaque density and Braak stage were significantly different, with progressively lower scores moving from probable AD through possible AD and not AD groups.”
Quote in the paperSubstantial claim - Findingown data
When non-demented controls were not included, 33% of subjects were not classifiable by NIA-Reagan criteria.
“here, we found that when non-demented controls were not included, 33% of subjects were not classifiable.”
Quote in the paperSubstantial claim - Findingown data
Of the 271 subjects clinically diagnosed as not having AD, 107 met a minimum histopathological threshold for AD.
“Of these, 107 cases met a minimum histopathological threshold for AD, i.e. neuritic plaque density of moderate or frequent in combination with any Braak neurofibrillary tangle stage between III and VI, inclusive, despite their negative clinical diagnoses.”
Quote in the paperSubstantial claim - Findingown data
Neurologists of the NIA-ADCs had higher predictive accuracy when they diagnosed AD in demented subjects than when they diagnosed dementing diseases other than AD.
“Neurologists of the NIA-ADCs had higher predictive accuracy when they diagnosed AD in demented subjects than when they diagnosed dementing diseases other than AD.”
Quote in the paperSubstantial claim - Findingown data
When dementia was not clinically diagnosed as AD, 39% of these cases met or exceeded minimum threshold levels of AD histopathology.
“When dementia was not clinically diagnosed as AD, 39% of these cases met or exceeded minimum threshold levels of AD histopathology.”
- Also stated in: § Analysis of Mismatched Clinical and Neuropathological Diagnoses · plain
“Of these, 107 cases met a minimum histopathological threshold for AD, i.e. neuritic plaque density of moderate or frequent in combination with any Braak neurofibrillary tangle stage between III and VI, inclusive, despite their negative clinical diagnoses.”
Quote in the paperSubstantial claim- Rests on an assumption: The consensus of expert opinion has required that the clinically documented presence of dementia be part of the definition of AD.
- Rests on an assumption: It has been the common practice for both clinical and neuropathological diagnostic definitions of AD to require the presence of dementia.
- Rests on an assumption: Non-demented subjects are not generally classified as AD.
- Also stated in: § Analysis of Mismatched Clinical and Neuropathological Diagnoses · plain
- Findingown data
There were 271 subjects clinically diagnosed as not having either probable or possible AD.
“There were 271 subjects who were clinically diagnosed as not having either probable or possible AD (Table 5).”
Quote in the paperNot a substantial claim - Findingown data
The PPV for clinically probable AD was consistently approximately 16% higher than that resulting if all demented subjects were considered to have clinical AD.
“The PPV for clinically probable AD was consistently approximately 16% higher than that resulting if all demented subjects were considered to have clinical AD.”
Quote in the paperNot a substantial claim - Findingown data
The PPV for clinically probable AD was consistently about 4.5% to 5% higher than that for possible AD.
“The PPV for clinically probable AD was consistently about 4.5% to 5% higher than that for possible AD.”
Quote in the paperNot a substantial claim - Findingown data
Smaller numbers of cases were diagnosed as tangle-only dementia, argyrophilic grain disease, Pick disease, corticobasal degeneration, cerebrovascular disease, hippocampal sclerosis and amyotrophic lateral sclerosis.
“Smaller numbers of cases were diagnosed as tangle-only dementia, argyrophilic grain disease, Pick disease, corticobasal degeneration, cerebrovascular disease, hippocampal sclerosis and amyotrophic lateral sclerosis.”
Quote in the paperNot a substantial claim - Findingown data
There were 164 cases with clinical diagnoses other than AD that were confirmed neuropathologically in that minimum AD histopathology thresholds were not present.
“There were 164 cases that had clinical diagnoses other than AD and that were confirmed neuropathologically in that minimum AD histopathology thresholds were not present.”
Quote in the paperNot a substantial claim - Findingown data
The present results indicate that, when minimum neuropathological threshold is moderate/frequent neuritic plaques with Braak III-VI, the PPV of clinical diagnosis of probable AD is 83%.
“The present results indicate that, when the minimum neuropathological threshold for diagnosis is defined as moderate or frequent neuritic plaques together with Braak stage III-VI, the positive predictive value of the clinical diagnosis of probable AD is 83%, i.e. 83% of subjects with that clinical diagnosis were confirmed neuropathologically to have AD lesions sufficient to cause dementia.”
Quote in the paperSubstantial claim - Findingown data
When neurologists of NIA ADCs diagnose clinical AD, the PPV is approximately 16% more accurate than if they diagnosed all dementia subjects with AD.
“Additionally, when neurologists of the NIA ADCs diagnose clinical AD, the positive predictive value is approximately 16% more accurate than if they diagnosed all dementia subjects with AD.”
Quote in the paperSubstantial claim - Findingown data
Among cases not meeting the defined lower threshold for histopathological severity, the most frequent primary neuropathological diagnosis was AD, primary (NPPAD), assigned to 17 cases.
“The most frequent primary neuropathological diagnosis among these subjects was AD, primary (NACC database code NPPAD), assigned by the neuropathologist to 17 cases despite the relatively low levels of AD histopathology.”
Quote in the paperNot a substantial claim - Findingnone given
Between 2005 and 2010, the accuracy rate of the clinical diagnosis of AD at NIA ADCs varied depending on the exact clinical and neuropathological criteria used.
“In conclusion, between 2005 and 2010, the accuracy rate of the clinical diagnosis of AD at NIA ADCs varied depending on the exact clinical and neuropathological criteria used.”
Quote in the paperSubstantial claim - Findingnone given
Among demented subjects, ADC neurologists were more accurate when they diagnosed AD than when they diagnosed subjects with another dementing disease.
“Among demented subjects, ADC neurologists were more accurate when they diagnosed AD than when they diagnosed subjects with another dementing disease.”
Quote in the paperSubstantial claim - Findingreasoning
Neuropathologists not infrequently diagnosed AD in subjects clinically diagnosed as AD but not meeting a minimum histopathological threshold.
“Neuropathologists not infrequently diagnosed AD in subjects clinically diagnosed as AD but not meeting a minimum histopathological threshold.”
Quote in the paperSubstantial claim - Findingown data
Of subjects clinically diagnosed as not having either probable or possible AD, the most frequent primary neuropathological diagnosis was AD, accounting for 39% of the total.
“Of subjects clinically diagnosed as not having either probable or possible AD, the most frequent primary neuropathological diagnosis was AD, accounting for 39% of the total.”
Quote in the paperSubstantial claim - Study design and conductcitation
CERAD and Braak scoring methods have been shown to have a reasonably high level of reproducibility between observers and among research centers.
“These scoring methods have been shown to have a reasonably high level of reproducibility between observers and among research centers (34-37).”
Quote in the paperSubstantial claim0 of 4 sources checked - Interpretationcitation
These data agree with the median sensitivity (87%) and specificity (58%) calculated from a large set of previous publications.
“Comparisons with prior studies are difficult but these data agree with the median sensitivity (87%) and specificity (58%) calculated from a large set of previous publications (2-25).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites 2-25
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Premisecitation
The neuropathological criteria for AD used by all NIA ADCs since 1997 have been the NIA-Reagan criteria.
“The neuropathological criteria for AD used by all NIA ADCs since 1997 have been the NIA-Reagan criteria (30).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [30] source
- Premisecitation
The existing body of data on accuracy of current clinical AD diagnostic methods shows much variability among studies.
“The existing body of data on the accuracy of current clinical AD diagnostic methods shows much variability among studies (2-25).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites 2-25
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationreasoning
Therefore, for the foreseeable future, autopsy will still serve the role of 'gold standard' for determination of clinical diagnostic accuracy rates.
“Therefore, for the foreseeable future, autopsy will still serve the role of “gold standard” for the determination of clinical diagnostic accuracy rates.”
Quote in the paperNot a substantial claim- Rests on an assumption: Biopsy has long been contraindicated for AD due to a high risk/benefit ratio.
- Interpretationreasoning
The frequent diagnosis of AD by neuropathologists in clinically diagnosed AD subjects not meeting a minimum histopathological threshold is most likely due to the lack of a specified minimum histopathological threshold for the primary neuropathological diagnosis of AD in the 1997 NIA-Reagan criteria.
“This is most likely due to the lack of a specified minimum histopathological threshold for the primary neuropathological diagnosis of AD in the 1997 NIA-Reagan criteria.”
Quote in the paperSubstantial claim - Interpretationreasoning
Because large reported autopsy series are only done in tertiary care settings, it is not possible to know for certain whether differences in diagnostic accuracy between tertiary and other settings exist.
“Because large reported autopsy series are only done in tertiary care settings, it is not possible to know for certain whether such differences exist.”
Quote in the paperNot a substantial claim- Rests on an assumption: Large reported autopsy series are only done in tertiary care settings.
- Premisecitation
The clinical diagnosis of dementia is relatively nonspecific.
“First, as extensively previously documented, the clinical diagnosis of dementia is relatively nonspecific (2-25).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites 2-25
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- May combine two claims. 27
- Classified as probably not a substantial claim. 25
- The quote only partly states this claim. 1
May combine two claims.
PremisecitationOne study has reported no evident selection bias between autopsied and non-autopsied subjects among an incident community-diagnosed dementia series, suggesting that dementia case composition may not be substantially different in different settings.
“However, one study has reported no evident selection bias between autopsied and non-autopsied subjects among an incident community-diagnosed dementia series, suggesting that dementia case composition may not be substantially different in different settings (48).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [48] source
Split into 2 atoms — 0 confirmed, 1 partially supported, 1 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationThe shortcomings of the NIA-Reagan criteria have been recognized and a revised set of criteria are currently in press.
“The shortcomings of the NIA-Reagan criteria have been recognized and a revised set of criteria are currently in press (39, 40).”
Quote in the paperNot a substantial claim2 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIn a recent multivariate analysis, approximately two-thirds of the variation in cognitive ability of elderly subjects was accounted for by variation in CERAD neuritic plaque density and Braak stage.
“In a recent multivariate analysis, approximately two-thirds of the variation in cognitive ability of elderly subjects was accounted for by variation in CERAD neuritic plaque density and Braak stage (41).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [41] source
The Results section (page not provided) says that more than two-thirds of MMSE-score variability in the elderly autopsy cohort was associated with Alzheimer-type pathology, specifically neurofibrillary tangles and neuritic plaques. It does not attribute that figure to CERAD neuritic plaque density and Braak stage as the two measures in the claim; the Discussion describes its findings as compatible with Braak staging. (LLM, conf=0.89)
Experimental — accuracy not yet measured
May combine two claims.
InterpretationcitationThere is relatively close agreement with the last 2 prior assessments using total NIA-ADC dataset: Mayeux et al estimated sensitivity 93% and specificity 55% and Tsuang et al reported sensitivity 84% and specificity 50%.
“There is also relatively close agreement with the last 2 prior assessments of diagnostic accuracy using the total NIA-ADC dataset: Mayeux et al estimated a sensitivity of 93% and a specificity of 55% (4) and Tsuang et al reported a sensitivity of 84% and a specificity of 50% (23).”
Quote in the paperNot a substantial claim1 of 2 sources checkedClassified as probably not a substantial claim.
Study design and conductcitationDue to idiosyncratic assignment of NIA-Reagan categories from case to case, we instead stratified by all relevant combinations of CERAD neuritic plaque density and Braak stage.
“Due to the idiosyncratic assignment of these categories from case to case (32), we instead stratified by all relevant combinations of the deterministic histopathological scores, consisting of the CERAD-defined neuritic plaque density score (29) and the Braak neurofibrillary tangle stage (33).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [32] source
The Results report relatively low consistency in NIA-Reagan category assignments for cases outside the guidelines, supporting the concern behind the citing authors’ choice. But they also report high consistency for cases that match the guidelines, so the source does not support describing assignments as idiosyncratic across cases generally. The decision to stratify by CERAD and Braak scores is the citing authors’ own method, not a finding attributed to this source. (LLM, conf=0.83)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationMeasures of all biomarkers studied to date have considerable overlap with those found in other types of dementia and cognitively normal elderly, making it difficult to determine whether cognitive impairment is due to AD or another process.
“because measures of all biomarkers studied to date have considerable overlap with those found other types of dementia (as well the cognitively normal elderly population), it remains difficult to determine whether or not cognitive impairment is due to AD or another more dominant and concurrent process.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [1] source
The section ‘Biomarker abnormalities precede clinical symptoms’ (page not provided) reports amyloid-biomarker abnormalities in 20–40% of cognitively normal elderly people, and ‘AD clinical features and pathological changes’ notes that dementia in older patients often has multiple underlying pathologies. The ‘Biomarkers of neurodegeneration’ section also says CSF tau is not specific to AD. These passages support diagnostic ambiguity, but not the broader assertion that all biomarkers studied have considerable overlap with both other dementias and cognitively normal elderly people. (LLM, conf=0.84)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIn the revision of the 1997 criteria, combinations of plaque and tangle pathologies considered sufficient to cause dementia and qualify for the neuropathological diagnosis of AD are explicitly stated.
“In the revision of the 1997 criteria, combinations of plaque and tangle pathologies considered sufficient to cause dementia and qualify for the neuropathological diagnosis of AD are explicitly stated (40, 41).”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [40] source
- cites [41] source
The Neuropathology section describes how the study counted plaques and tangles, but does not state what combinations qualify for an AD diagnosis or are sufficient to cause dementia. Searches for the 1997 criteria, their revision, and diagnostic thresholds found no passage addressing that claim in our copy; the other relevant matches were in the References section. (LLM, conf=0.72)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationNew clinical diagnostic consensus criteria have now been finalized under the auspices of the NIA and Alzheimer's Association, with novel features including recognition of a preclinical stage of AD and the incorporation of imaging and laboratory-based cerebrospinal fluid biomarkers.
“New clinical diagnostic consensus criteria have now been finalized under the auspices of the NIA and Alzheimer's Association (52), with novel features including recognition of a preclinical stage of AD and the incorporation of imaging and laboratory-based cerebrospinal fluid biomarkers.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [52] source
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationAmyloid staging may be of immediate clinical diagnostic utility when used to guide amyloid imaging as the progression of amyloid plaques beyond the cortex appears to be a useful marker of higher Braak tangle stage and of the presence of dementia.
“Amyloid staging may be of immediate clinical diagnostic utility when used to guide amyloid imaging as the progression of amyloid plaques beyond the cortex appears to be a useful marker of higher Braak tangle stage and of the presence of dementia (49, 50).”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [49] Thal, 2002, Phases of A beta-deposition in the human brain and its relevance for the development of AD, Neurology source
- cites [50] Beach, 2012, Striatal amyloid plaque density predicts Braak neurofibrillary stage and clinicopathological Alzheimer's disease: Implications for amyloid imaging, J Alzheimer Dis source
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measured
May combine two claims.
Findingown dataThe most frequent primary neuropathological diagnoses in these 164 cases were frontotemporal lobar degeneration (60), Lewy body disease (39), Creutzfeldt-Jakob disease (20), and progressive supranuclear palsy (18).
“The most frequent primary neuropathological diagnoses in these cases were frontotemporal lobar degeneration (60 cases), followed by Lewy body disease (39 cases), Creutzfeldt-Jakob disease (20 cases) and progressive supranuclear palsy (18 cases).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataThe mean age of the 'not AD' group was significantly lower than that of the probable or possible AD groups (72.8, 81.2 and 83.2 years, respectively).
“The mean age of the “not AD” group was significantly lower than that of the probable or possible AD groups (72.8, 81.2 and 83.2 years, respectively).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataSensitivity of clinical diagnosis of Alzheimer disease ranged from 70.9% to 87.3% and specificity ranged from 44.3% to 70.8% across stratified clinical and neuropathological criteria.
“Sensitivity ranged from 70.9% to 87.3%; specificity ranged from 44.3% to 70.8%.”
- Also stated in: § Diagnostic Classification Comparison · plain
“Sensitivity ranged from 70.9% to 87.3% and specificity ranged from 44.3% to 70.8%.”
- Also stated in: § Discussion · plain
“We found that sensitivity for AD diagnosis ranged from 70.9% to 87.3% whereas specificity ranged from 44.3% to 70.8%.”
Quote in the paperSubstantial claim- Also stated in: § Diagnostic Classification Comparison · plain
May combine two claims.
Findingown dataThe positive predictive value for clinical diagnosis of AD ranged from 46.0% to 83.3%, with best result for probable AD and moderate/frequent neuritic plaques with Braak stage III-VI.
“The PPV for the clinical diagnosis of AD ranged from 46.0% to 83.3%, with the best result achieved when the clinical diagnosis was defined by probable AD and the neuropathological diagnosis as moderate or frequent neuritic plaques with Braak stage III-VI (the prevalence of subjects at or above this histopathological threshold was 67.2%).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataFor the set of minimum neuropathological criteria (CERAD moderate/frequent and Braak III-VI), sensitivity and specificity of clinical diagnosis of probable AD were each approximately 71%, whereas for combined probable and possible AD sensitivity was about 83% with specificity about 55%.
“For the set of minimum neuropathological criteria that are perhaps most commonly used to define AD (i.e. CERAD neuritic plaque density of ‘moderate” or “frequent” and Braak stage III-VI), the sensitivity and specificity of the clinical diagnosis of “probable AD” were each approximately 71%, whereas for “combined “probable” and possible AD” sensitivity was about 83% with specificity about 55%.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataSensitivity generally increased with more permissive clinical criteria and specificity increased with more restrictive clinical criteria, whereas the opposite was true for neuropathological criteria.
“Sensitivity was generally increased with more permissive clinical criteria and specificity was increased with more restrictive criteria, whereas the opposite was true for neuropathological criteria.”
- Also stated in: § Diagnostic Classification Comparison · plain
“In general, sensitivity was increased with more permissive clinical criteria and specificity was increased with more restrictive clinical criteria, whereas the opposite was true for neuropathological criteria.”
Quote in the paperSubstantial claim- Also stated in: § Diagnostic Classification Comparison · plain
May combine two claims.
Findingown dataOf 526 subjects diagnosed as clinically probable AD, 438 were confirmed as neuropathological AD and 88 did not meet neuropathological criteria.
“Of the 526 subjects diagnosed as clinically probable AD, 438 were confirmed as neuropathological AD, as defined above, and 88 did not meet neuropathological criteria.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataA small number of cases received primary neuropathological diagnoses of progressive supranuclear palsy (3), corticobasal degeneration (2), neuroaxonal dystrophy/Hallervorden-Spatz-like disease (2), and several miscellaneous diagnoses (1 each).
“A small number of cases received primary neuropathological diagnoses of progressive supranuclear palsy (3 cases), corticobasal degeneration (2 cases) and neuroaxonal dystrophy/Hallervorden-Spatz-like disease (2 cases); there were several other miscellaneous neuropathological diagnoses (1 case each) (Table 4).”
Quote in the paperNot a substantial claimThe quote only partly states this claim.
Findingown dataWhen a clinical diagnosis was not confirmed by minimum levels of AD histopathology, the most frequent primary neuropathological diagnoses were tangle-only dementia or argyrophilic grain disease, frontotemporal lobar degeneration, cerebrovascular disease, Lewy body disease and hippocampal sclerosis.
“When a clinical diagnosis was not confirmed by minimum levels of AD histopathology, the most frequent primary neuropathological diagnoses were tangle-only dementia or argyrophilic grain disease, frontotemporal lobar degeneration, cerebrovascular”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataMany cases had contributing neuropathological diagnoses in addition to their primary diagnosis; the most frequent contributing diagnoses were similar to the most frequent primary diagnoses.
“Many cases had contributing neuropathological diagnoses in addition to their primary diagnosis; the most frequent contributing diagnoses were similar to the most frequent primary diagnoses.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingnone givenThere was a high rate of multiple neuropathological diagnoses in demented subjects, whereas clinicians rarely assign more than one diagnosis.
“While not formally analyzed here, we did note a high rate of multiple neuropathological diagnoses in demented subjects whereas clinicians rarely assign more than one diagnosis.”
Quote in the paperNot a substantial claimMay combine two claims.
Study design and conductown dataThe excluded subjects significantly differed from the 919 included subjects in terms of age, gender distribution and AD-related histopathological scores, but not in the mean interval last clinical assessment and death.
“The excluded subjects significantly differed from the 919 included subjects in terms of age, gender distribution and AD-related histopathological scores, but not in the mean interval last clinical assessment and death.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
PremisecitationThere have been several changes in neuropathological diagnostic criteria, including Khachaturian 1985, Tierney 1988, CERAD 1991, NIA-Reagan 1997.
“there have been several changes in neuropathological diagnostic criteria, including the “Khachaturian criteria” of 1985 (27), the “Tierney” criteria of 1988 (28), The Consortium to Establish a Registry for Alzheimer's Disease (CERAD) criteria in 1991 (29), and the National Institute on Aging (NIA)-Reagan criteria in 1997 (30).”
Quote in the paperSubstantial claim0 of 4 sources checkedClassified as probably not a substantial claim.
PremisereasoningNeuropathological examination is considered to provide the gold standard for Alzheimer disease.
“The neuropathological examination is considered to provide the gold standard for Alzheimer disease (AD).”
- Also stated in: § Introduction · boosted
“it is generally accepted that histological examination is the best indicator of AD diagnosis.”
Quote in the paperSubstantial claim- Also stated in: § Introduction · boosted
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe NIA-Reagan criteria are the most current guidelines for neuropathological diagnosis of AD.
“For the neuropathological diagnosis of AD, the NIA-Reagan criteria (30) are the most current guidelines”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [30] source
Probably not a substantial claim: may not pass S4 (based). May combine two claims.
Premisenone givenIn most studies, sensitivity is relatively high while specificity is low and many studies have reported only sensitivity or positive predictive value, which has led to a false impression that the clinical diagnosis of AD is extremely accurate.
“In most studies, sensitivity is relatively high while specificity is low and many studies have reported only sensitivity or positive predictive value, which has led to a false impression that the clinical diagnosis of AD is extremely accurate.”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationreasoningWith an estimated response rate to a trial medication of 50%, a 20% misdiagnosis rate would lower the actual response rate to 40% (if non-AD dementia subjects do not respond to the medication), which would require an approximate doubling of subject recruitment to maintain statistical power.
“For example, with an estimated response rate to a trial medication of 50%, a 20% misdiagnosis rate would lower the actual response rate to 40% (if non-AD dementia subjects do not respond to the medication), which would require an approximate doubling of subject recruitment to maintain statistical power.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.
Premisenone givenWhile the clinical diagnosis of AD often is validated by neuropathological examination, a clinical diagnosis of a non-AD dementia is often not verified by neuropathology.
“While the clinical diagnosis of AD often is validated by neuropathological examination, a clinical diagnosis of a non-AD dementia is often not verified by neuropathology.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S2 (checkable).
InterpretationreasoningIt is important, for current research and clinical usage, to obtain more appropriate figures.
“it is important, for current research and clinical usage, to obtain more appropriate figures.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S2 (checkable).
PremisereasoningBecause many studies have reported only sensitivity or positive predictive value, a general impression has arisen that the clinical diagnosis of AD is extremely accurate.
“Because many studies have reported only sensitivity or positive predictive value, a general impression has arisen that the clinical diagnosis of AD is extremely accurate.”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationcitationThe data analyzed in this study have been collected as part of NACC UDS since 2005 and thus represent the most current research practices.
“The data analyzed in this study have been collected as part of the NACC Uniform Data Set (UDS) since 2005 (31) and thus represent the most current research practices.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [31] source
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataThe 3 groups did not significantly differ in the mean interval between last clinical assessment and death.
“The 3 groups did not significantly differ in the mean interval between last clinical assessment and death.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationSensitivity estimates have ranged between 41% and 100% (median 87%), while specificity has ranged between 37% and 100% (median 58%).
“Sensitivity estimates have ranged between 41% and 100% (median of 87%), while specificity has ranged between 37% and 100% (median of 58%).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites 2-25
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
InterpretationreasoningA large fraction of subjects are not classifiable by NIA-Reagan criteria and the neuropathologist is left to make an arbitrary assignment.
“Thus, a large fraction of subjects are not classifiable by NIA-Reagan criteria and the neuropathologist is left to make an arbitrary assignment.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductown dataThe gender distribution was generally skewed towards more males but did not significantly differ among groups.
“The gender distribution was generally skewed towards more males but did not significantly differ among groups.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim. May combine two claims.
PremisereasoningThe NIA-Reagan criteria do not give entirely specific guidelines for making the diagnosis, but rather set probability levels.
“These, however, do not give entirely specific guidelines for making the diagnosis, but rather set probability levels, given threshold levels of histopathological severity (CERAD neuritic plaque density and Braak neurofibrillary stage) for when dementia may be due to AD.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim. May combine two claims.
InterpretationreasoningEven a modest level of diagnostic misclassification could have a significant effect on clinical trial calculations for minimum subject number and thus should be considered in clinical trial planning.
“However, even a modest level of diagnostic misclassification could have a significant effect on clinical trial calculations for minimum subject number and thus should be considered in clinical trial planning.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationNelson et al estimated that 18% of subjects with dementia fell outside of the NIA-Reagan guidelines.
“In a recent examination of NACC data, Nelson et al estimated that 18% of subjects with dementia fell outside of the NIA-Reagan guidelines (34);”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [34] source
Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.
InterpretationreasoningIt is likely that individual subjects will vary in their ability to withstand a given lesion density (perhaps due to cognitive reserve), differences in genetic background or differences in environmental exposures.
“It is likely that, just as some subjects with 90% coronary artery stenosis suffer myocardial infarctions and some do not, individual subjects will vary in their ability to withstand a given lesion density (perhaps due to “cognitive reserve”), differences in genetic background or differences in environmental exposures.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S4 (based).
InterpretationreasoningFor selecting subjects for clinical trials, the relatively high sensitivity is somewhat reassuring because it means that a relatively small percentage of non-AD subjects will be included in clinical trials.
“For selecting subjects for clinical trials, the relatively high sensitivity is somewhat reassuring because it means that a relatively small percentage of non-AD subjects will be included in clinical trials.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
InterpretationreasoningBecause ADCs are tertiary referral centers, diagnostic accuracy rates may differ from those achieved in secondary or primary care settings.
“Because ADCs are tertiary referral centers, diagnostic accuracy rates may differ from those that may be achieved in secondary or primary care settings.”
Quote in the paperNot a substantial claim- Rests on an assumption: Patients with a more complex clinical syndrome are more likely to be referred to a tertiary care center.
- Rests on an assumption: The greater level of neurological expertise at tertiary care centers contributes to more accurate diagnoses.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisereasoningDefinitive recommendations on which of the 3 NIA-Reagan levels should be attained to justify conclusion that dementia is due primarily to AD have not been defined.
“Thus there are “low,” “intermediate” and “high” probability designations for classifying autopsy subjects although definitive recommendations on which of these 3 levels should be attained to justify the conclusion that dementia is due primarily to AD have not been defined.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationAlthough neuropathological consensus criteria for AD have changed several times over the last 3 decades, the clinical criteria have remained virtually unchanged since the NINCDS-ADRDA-sponsored criteria published in 1984.
“Although neuropathological consensus criteria for AD have changed several times over the last 3 decades, the clinical criteria have remained virtually unchanged since the NINCDS-ADRDA-sponsored criteria published in 1984 (6).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [6] McKeel, 2004, Neuropathologic criteria for diagnosing Alzheimer disease in persons with pure dementia of Alzheimer type, J Neuropathol Exp Neurol source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationAD has generally been attributed to be the neuropathological cause in between 65% and 75% of dementia cases.
“AD has generally been attributed to be the neuropathological cause in between 65% and 75% of dementia cases (42, 43).”
Quote in the paperNot a substantial claim0 of 2 sources checked
The paper relies on this without support.
Biopsy has long been contraindicated for AD due to a high risk/benefit ratio.
“For many disorders this is possible during life through biopsy but biopsy has long been contraindicated for AD due to a high risk/benefit ratio.”
The paper relies on this without support.
The consensus of expert opinion has required that the clinically documented presence of dementia be part of the definition of AD.
“Indeed, until the present time the consensus of expert opinion has required that the clinically documented presence of dementia be part of the definition of AD.”
The paper relies on this without support.
It has been the common practice for both clinical and neuropathological diagnostic definitions of AD to require the presence of dementia.
“Subjects without dementia were excluded because it has been the common practice for both clinical and neuropathological diagnostic definitions of AD to require the presence of dementia.”
The paper relies on this without support.
Non-demented subjects are not generally classified as AD.
“Therefore, non-demented subjects are not generally classified as AD.”
The paper relies on this without support.
The available body of knowledge does not allow neuropathologists to be dogmatic about exactly how much plaque and tangle pathology is necessary to cause dementia.
“We feel that our approach here has been cautious as the available body of knowledge does not allow neuropathologists to be dogmatic about exactly how much plaque and tangle pathology is necessary to cause dementia.”
The paper relies on this without support.
The clinical methods for diagnosing AD have not changed substantially since the introduction of NINDS-ADRDA criteria in 1984.
“whereas the clinical methods for diagnosing AD have not changed substantially since the introduction of the National Institute of Neurological Disorders and Stroke-Alzheimer's Disease and Related Disorders Association (NINDS-ADRDA) criteria in 1984 (26)”
The paper relies on this without support.
A large fraction of cognitively unimpaired elderly possesses sparse neuritic plaques and/or Braak stages 0-II.
“Lowering the lesion density threshold further (e.g. allowing sparse neuritic plaques and/or Braak stages 0-II) seemed counterintuitive because a large fraction of cognitively unimpaired elderly possesses such attributes.”
The paper relies on this without support.
Patients with a more complex clinical syndrome are more likely to be referred to a tertiary care center.
“For example, patients with a more complex clinical syndrome are more likely to be referred to a tertiary care center.”
The paper relies on this without support.
The greater level of neurological expertise at tertiary care centers contributes to more accurate diagnoses.
“On the other hand, the greater level of neurological expertise at these centers would presumably contribute to more accurate diagnoses.”
The paper relies on this without support.
Large reported autopsy series are only done in tertiary care settings.
“Because large reported autopsy series are only done in tertiary care settings, it is not possible to know for certain whether such differences exist.”
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?
Physicians struggle with accurate and reliable diagnostics even when multimodality is present, as proven by histopathological correlation.
“while physicians struggle with accurate and reliable diagnostics even when multimodality is present, as proven by histopathological correlation42.”
From Fusion of medical imaging and electronic health records using deep learning: a systematic review and implementation guidelines (2020) · cites this paper as [42]
The Results (Diagnostic Classification Comparison; page unavailable) show imperfect agreement between clinical Alzheimer disease diagnoses and neuropathological findings, supporting the point that clinicians can have difficulty diagnosing AD accurately against a histopathological standard. The Materials and Methods (Analysis Strategy; page unavailable) do not establish that the clinical diagnoses used multiple diagnostic modalities, and the study does not assess diagnostic reliability. Its findings concern AD at participating disease centers, not physicians’ diagnostics generally. (LLM, conf=0.88)
Experimental — accuracy not yet measuredCommon non-AD dementias such as vascular dementia, Lewy body dementia, and frontotemporal dementia widen the differential diagnosis of neurodegenerative conditions and contribute to variability in diagnostic sensitivity and specificity.
“common causes of dementias outside of AD such as vascular dementia (VD), Lewy body dementia (LBD), and frontotemporal dementia (FTD) widen the differential diagnosis of neurodegenerative conditions and contribute to variability in diagnostic sensitivity and specificity12.”
From Multimodal deep learning for Alzheimer's disease dementia assessment (2022) · cites this paper as [12]
The Results (Analysis of Mismatched Clinical and Neuropathological Diagnoses; page unavailable) identify frontotemporal lobar degeneration, Lewy body disease, and cerebrovascular disease among non-AD findings. The Discussion says alternate causes make dementia diagnosis relatively nonspecific and reports varying sensitivity and specificity, but attributes those measured ranges to changes in diagnostic criteria, not specifically to the three named conditions. (LLM, conf=0.83)
Experimental — accuracy not yet measuredBeach et al found that sensitivity of clinical AD diagnosis ranged from 70.9% to 87.3% and specificity from 44.3% to 70.8%.
“Beach et al (6) found that sensitivity ranged from 70.9% to 87.3% and specificity from 44.3% to 70.8%.”
From Concordance of Clinical Alzheimer Diagnosis and Neuropathological Features at Autopsy (2020) · cites this paper as [6]
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Beach, T. G., Sue, L. I., Walker, D. G., Sabbagh, M. N., Serrano, G., Dugger, B. N., Mariner, M., Yantos, K., Henry-Watson, J., Chiarolanza, G., et al. (2012) · Journal of Alzheimer s Disease · doi:10.3233/jad-2011-111340 · Cited by 74 · cited 1× · see citing works
“Amyloid staging may be of immediate clinical diagnostic utility when used to guide amyloid imaging as the progression of amyloid plaques beyond the cortex appears to be a useful marker of higher Braak tangle stage and of the presence of dementia (49, 50).”
BackgroundSelf-citationMcKeel, D. W., Price, J. L., Miller, J. P., Grant, E. A., Xiong, C., Berg, L., & Morris, J. C. (2004) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/63.10.1028 · Cited by 68 · cited 1× · see citing works
“Although neuropathologic consensus criteria for AD have changed several times over the last 3 decades, the clinical criteria have remained virtually unchanged since the NINDS-ADRDA-sponsored criteria published in 1984 (6).”
BackgroundGenotype-phenotype relationships of presenilin-1 mutations in Alzheimer's disease: An update
Larner, A. J., & Doran, M. (2008) · Journal of Alzheimer's Disease · doi:10.3233/jad-2009-1042 · Cited by 67 · see citing works
Halliday, G., Ng, T., Rodriguez, M., Harding, A., Blumbergs, P., Evans, W., Fabian, V., Fryer, J., Gonzales, M., Harper, C., et al. (2002) · Acta Neuropathologica · doi:10.1007/s00401-002-0529-5 · Cited by 57 · see citing works
Hogervorst, E., Barnetson, L. P. D., Jobst, K. A., Nagy, Z., Combrinck, M. I., & Smith, A. D. (2000) · Dementia and Geriatric Cognitive Disorders · doi:10.1159/000017222 · Cited by 55 · see citing works
Nagy, Z., Yilmazer-Hanke, D. M., Braak, H., Braak, E., Schultz, C., & Hanke, J. (1998) · Dementia and Geriatric Cognitive Disorders · doi:10.1159/000017038 · Cited by 51 · see citing works
Staging of Alzheimer-Type Pathology: An Interrater-Intrarater Study
Nagy, Z., Vatter-Bittner, B., Braak, H., Braak, E., Yilmazer, D. M., Schultz, C., & Hanke, J. (1997) · Dementia and Geriatric Cognitive Disorders · doi:10.1159/000106639 · Cited by 45 · see citing works
Tsuang, D., Larson, E. B., Bowen, J., McCormick, W., Teri, L., Nochlin, D., Leverenz, J. B., Peskind, E. R., Lim, A., Raskind, M. A., et al. (1999) · Archives of Neurology · doi:10.1001/archneur.56.12.1489 · Cited by 42 · cited 2× · see citing works
“Because the last diagnostic accuracy studies using a complete ADC data set were performed in 1998 and 1999 (4, 23), it is important, for current research and clinical use, to obtain more appropriate figures.”
MethodResultSelf-citationNelson, P. T., Kukull, W. A., & Frosch, M. P. (2010) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e3181d8db07 · Cited by 37 · cited 3× · see citing works
“In a recent examination of NACC data, Nelson et al estimated that 18% of subjects with dementia fell outside of the NIA-Reagan guidelines (32); here, we found that when controls with no dementia were not included, 33% of subjects were not classifiable.”
BackgroundMethodSelf-citationEvaluation of Selection Bias in an Incident-Based Dementia Autopsy Case Series
Tsuang, D., Simpson, K. L., Li, G., Barnhart, R. L., Edland, S. D., Bowen, J., McCormick, W., Teri, L., Nochlin, D., Larson, E. B., et al. (2005) · Alzheimer Disease & Associated Disorders · doi:10.1097/01.wad.0000165507.67993.47 · Cited by 37 · cited 1× · see citing works
“However, one study has reported no evident selection bias between autopsied and nonautopsied subjects among an incident community-diagnosed dementia series, suggesting that dementia case composition may not be substantially different in different settings (48).”
BackgroundGay, B. E., Taylor, K. I., Hohl, U., Tolnay, M., & Staehelin, H. B. (2008) · The journal of nutrition health & aging · doi:10.1007/bf02982566 · Cited by 16 · see citing works
Neuropathology-Based Risk Scoring for Dementia Diagnosis in the Elderly
Haneuse, S., Larson, E., Walker, R., Montine, T., & Sonnen, J. (2009) · Journal of Alzheimer's Disease · doi:10.3233/jad-2009-1105 · Cited by 15 · see citing works
Accuracy of clinical criteria for AD in the Honolulu–Asia Aging Study, a population-based study
Jellinger, K. A. (2002) · Neurology · doi:10.1212/wnl.58.6.989 · Cited by 7 · see citing works
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Knopman, D. S., Amieva, H., Petersen, R. C., Chételat, G., Holtzman, D. M., Hyman, B. T., Nixon, R. A., & Jones, D. T. (2021) · Nature Reviews Disease Primers · doi:10.1038/s41572-021-00269-y · Cited by 2,606 · see citing works
Pathology of Neurodegenerative Diseases
Dugger, B. N., & Dickson, D. W. (2017) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a028035 · Cited by 1,665 · see citing works
“Studying disease heterogeneity at autopsy is key to understanding discrepancies between clinical and pathological diagnoses (Hughes et al. 1992; Josephs and Dickson 2003; Beach et al. 2012; Adler et al. 2014).”
BackgroundJanelidze, S., Mattsson, N., Palmqvist, S., Smith, R., Beach, T. G., Serrano, G. E., Chai, X., Proctor, N. K., Eichenlaub, U., Zetterberg, H., et al. (2020) · Nature Medicine · doi:10.1038/s41591-020-0755-1 · Cited by 1,247 · see citing works
Self-citationBiomarkers for neurodegenerative diseases
Hansson, O. (2021) · Nature Medicine · doi:10.1038/s41591-021-01382-x · Cited by 1,159 · see citing works
Biomarkers for Alzheimer's disease: current status and prospects for the future
Blennow, K., & Zetterberg, H. (2018) · Journal of Internal Medicine · doi:10.1111/joim.12816 · Cited by 1,000 · see citing works
“diagnostic criteria for AD have poor accuracy, with sensitivity and specificity figures of around 7080% when related to neuropathology (21, 22).”
BackgroundDefining imaging biomarker cut points for brain aging and Alzheimer's disease
Jack, C. R., Wiste, H. J., Weigand, S. D., Therneau, T. M., Lowe, V. J., Knopman, D. S., Gunter, J. L., Senjem, M. L., Jones, D. T., Kantarci, K., et al. (2017) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2016.08.005 · Cited by 931 · see citing works
“Of individuals with clinically diagnosed AD dementia, 10%–30% do not have AD at autopsy [18] or have no biomarker evidence of amyloidosis [19,20].”
Huang, S.-C., Pareek, A., Seyyedi, S., Banerjee, I., & Lungren, M. P. (2020) · npj Digital Medicine · doi:10.1038/s41746-020-00341-z · Cited by 934 · see citing works
“Leveraging deep learning fusion techniques consistently showed improvements in performance for Alzheimer ’ s disease diagnosis, while physicians struggle with accurate and reliable diagnostics even when multimodality is present, as proven by histopathological correlation 42 .”
MethodToledo, J. B., Arnold, S. E., Raible, K., Brettschneider, J., Xie, S. X., Grossman, M., Monsell, S. E., Kukull, W. A., & Trojanowski, J. Q. (2013) · Brain · doi:10.1093/brain/awt188 · Cited by 849 · see citing works
“For instance, 40% of patients with clinically diagnosed FTD are found to have a neuropathological diagnosis of Alzheimer’s disease on post-mortem examination (Beach et al., 2012; Nelson et al., 2012; Toledo et al., 2012b).”
BackgroundSelf-citationHansson, O., Seibyl, J., Stomrud, E., Zetterberg, H., Trojanowski, J. Q., Bittner, T., Lifke, V., Corradini, V., Eichenlaub, U., Batrla, R., et al. (2018) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2018.01.010 · Cited by 808 · see citing works
“It is well established, from combined clinical and neuropathologic studies [5,6], and clinical trials using amyloid-b PET scans [7], that the accuracy of clinical criteria is suboptimal.”
BackgroundPrevalence of Amyloid PET Positivity in Dementia Syndromes: A Meta-analysis
Ossenkoppele, R., Jansen, W. J., Rabinovici, G. D., Knol, D. L., van der Flier, W. M., van Berckel, B. N. M., Scheltens, P., Visser, P. J., Verfaillie, S. C. J., Zwan, M. D., et al. (2015) · JAMA · doi:10.1001/jama.2015.4669 · Cited by 677 · see citing works
Rabinovici, G. D., Gatsonis, C., Apgar, C., Chaudhary, K., Gareen, I., Hanna, L., Hendrix, J., Hillner, B. E., Olson, C., Lesman-Segev, O. H., et al. (2019) · JAMA · doi:10.1001/jama.2019.2000 · Cited by 674 · see citing works
“The most common reported causes of death were cardiac (12), unknown (9), infection (5), and pulmonary (4).”
BackgroundFlorbetaben PET imaging to detect amyloid beta plaques in Alzheimer's disease: Phase 3 study
Sabri, O., Sabbagh, M. N., Seibyl, J., Barthel, H., Akatsu, H., Ouchi, Y., Senda, K., Murayama, S., Ishii, K., Takao, M., et al. (2015) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2015.02.004 · Cited by 602 · see citing works
“Consistent with previous studies, only 44 of 57 (77%) patients with a clinical diagnosis of AD in the present study were actually found to have brain b-amyloid [21].”
ResultSelf-citationOvod, V., Ramsey, K. N., Mawuenyega, K. G., Bollinger, J. G., Hicks, T., Schneider, T., Sullivan, M., Paumier, K., Holtzman, D. M., Morris, J. C., et al. (2017) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2017.06.2266 · Cited by 585 · see citing works
“3%, respectively, when confirmed by postmortem histopathology [4].”
BackgroundHansson, O., Edelmayer, R. M., Boxer, A. L., Carrillo, M. C., Mielke, M. M., Rabinovici, G. D., Salloway, S., Sperling, R., Zetterberg, H., & Teunissen, C. E. (2022) · Alzheimer's & Dementia · doi:10.1002/alz.12756 · Cited by 607 · see citing works
“(3) In non-AD trials, BBMs (especially plasma Aβ42/Aβ40 and p-tau assays with established thresholds) can be used to exclude patients likely having AD co-pathology.”
BackgroundMethodInfluentialOssenkoppele, R., Pijnenburg, Y. A. L., Perry, D. C., Cohn-Sheehy, B. I., Scheltens, N. M. E., Vogel, J. W., Kramer, J. H., van der Vlies, A. E., Joie, R. L., Rosen, H. J., et al. (2015) · Brain · doi:10.1093/brain/awv191 · Cited by 548 · see citing works
“, 2013a) or post-mortem evaluation (Varma et al., 1999; Forman et al., 2006; Alladi et al., 2007; Beach et al., 2012).”
ResultChételat, G., Arbizu, J., Barthel, H., Garibotto, V., Law, I., Morbelli, S., van de Giessen, E., Agosta, F., Barkhof, F., Brooks, D. J., et al. (2020) · The Lancet Neurology · doi:10.1016/s1474-4422(20)30314-8 · Cited by 526 · see citing works
Ossenkoppele, R., Rabinovici, G. D., Smith, R., Cho, H., Schöll, M., Strandberg, O., Palmqvist, S., Mattsson, N., Janelidze, S., Santillo, A., et al. (2018) · JAMA · doi:10.1001/jama.2018.12917 · Cited by 472 · see citing works
Biobank, O. B. O. D. P. U. A. U., Wilkinson, T., Schnier, C., Bush, K., Rannikmäe, K., Henshall, D. E., Lerpiniere, C., Allen, N. E., Flaig, R., Russ, T. C., et al. (2019) · European Journal of Epidemiology · doi:10.1007/s10654-019-00499-1 · Cited by 452 · see citing works
Qiu, S., Joshi, P. S., Miller, M. I., Xue, C., Zhou, X., Karjadi, C., Chang, G. H., Joshi, A. S., Dwyer, B., Zhu, S., et al. (2020) · Brain · doi:10.1093/brain/awaa137 · Cited by 472 · see citing works
Beach, T. G., Adler, C. H., Sue, L. I., Serrano, G., Shill, H. A., Walker, D. G., Lue, L., Roher, A. E., Dugger, B. N., Maarouf, C., et al. (2015) · Neuropathology · doi:10.1111/neup.12189 · Cited by 460 · see citing works
“Therefore the numerous CSF studies that claim 80–90% sensitivity and specificity as compared to the clinical diagnosis of AD are misleading in that they actually represent only at most 70% accuracy with respect to the true neuropathological diagnosis.(55) The usage of post-mortem CSF in conjunction with neuropathologi…”
BackgroundSelf-citationClinical utility of cerebrospinal fluid biomarkers in the diagnosis of early Alzheimer's disease
Blennow, K., Dubois, B., Fagan, A. M., Lewczuk, P., de Leon, M. J., & Hampel, H. J. (2014) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2014.02.004 · Cited by 455 · see citing works
“The accuracy of current clinical AD diagnostic methods to predict pathologic diagnoses (in the absence of biomarker information) is generally low; sensitivities have been reported to range from 71% to 88% and specificities from 44% to 71%, depending on the specific histopathologic diagnostic criteria used [17].”
BackgroundLongitudinal Change in CSF Biomarkers in Autosomal-Dominant Alzheimer’s Disease
Fagan, A. M., Xiong, C., Jasielec, M. S., Bateman, R. J., Goate, A. M., Benzinger, T. L. S., Ghetti, B., Martins, R. N., Masters, C. L., Mayeux, R., et al. (2014) · Science Translational Medicine · doi:10.1126/scitranslmed.3007901 · Cited by 434 · see citing works
“Suboptimal clinical diagnostic accuracy (1) and the existence of a long preclinical phase dur-”
BackgroundMethodImaging tau and amyloid-β proteinopathies in Alzheimer disease and other conditions
Villemagne, V. L., Doré, V., Burnham, S. C., Masters, C. L., & Rowe, C. C. (2018) · Nature Reviews Neurology · doi:10.1038/nrneurol.2018.9 · Cited by 440 · see citing works
Multimodal deep learning for Alzheimer's disease dementia assessment
Qiu, S., Miller, M. I., Joshi, P. S., Lee, J. C., Xue, C., Ni, Y., Wang, Y., De Anda-Duran, I., Hwang, P. H., Cramer, J. A., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-31037-5 · Cited by 420 · see citing works
Janelidze, S., Berron, D., Smith, R. A., Strandberg, O. T., Proctor, N. K., Dage, J. L., Stomrud, E., Palmqvist, S., Mattsson, N., & Hansson, O. (2020) · JAMA Neurology · doi:10.1001/jamaneurol.2020.4201 · Cited by 390 · see citing works
“According to the present results, plasma P-tau217 could serve as a tool in clinical trials for (1) selection of individuals with preclinical AD who harbor early stage tau pathology before insoluble tau aggregates are prevalent and detectable by tau-PET and (2) monitoring target engagement of certain anti-tau drugs (gi…”
MethodThe neurobiological basis of cognitive impairment in Parkinson's disease
Halliday, G. M., Leverenz, J. B., Schneider, J. S., & Adler, C. H. (2014) · Movement Disorders · doi:10.1002/mds.25857 · Cited by 366 · see citing works
“Hippocampal sclerosis (HS), the loss of neurons and presence of gliosis in the CA1 region of the hippocampus and subiculum,(29) may be found in 10% of AD cases.(30) In PDD, one study found HS in only 1 of 17 cases,(20) a second study found no correlation between HS and PDD,(12) and a third study found 4.”
BackgroundSpectral-Domain OCT Measurements in Alzheimer’s Disease
Chan, V. T. T., Sun, Z., Tang, S., Chen, L. J., Wong, A., Tham, C. C. Y., Wong, T. Y., Chen, C., Ikram, M. K., Whitson, H. E., et al. (2018) · Ophthalmology · doi:10.1016/j.ophtha.2018.08.009 · Cited by 361 · see citing works
Blood‐based biomarkers for Alzheimer's disease
Leuzy, A., Mattsson, N., Palmqvist, S., Janelidze, S., Dage, J. L., & Hansson, O. (2021) · EMBO Molecular Medicine · doi:10.15252/emmm.202114408 · Cited by 352 · see citing works
“For P-tau 231 ADx , the inverted V symbol represents a biotin-conjugated N-terminal anti-tau mouse monoclonal antibody, as detailed in Ashton et al ( 2021 c). neurodegenerative disorders early on in the disease course (Beach et al , 2012; Salloway et al , 2014).”
Lantero Rodriguez, J., Karikari, T. K., Suárez-Calvet, M., Troakes, C., King, A., Emersic, A., Aarsland, D., Hye, A., Zetterberg, H., Blennow, K., et al. (2020) · Acta Neuropathologica · doi:10.1007/s00401-020-02195-x · Cited by 350 · see citing works
Curtis, C., Gamez, J. E., Singh, U., Sadowsky, C. H., Villena, T., Sabbagh, M. N., Beach, T. G., Duara, R., Fleisher, A. S., Frey, K. A., et al. (2015) · JAMA Neurology · doi:10.1001/jamaneurol.2014.4144 · Cited by 332 · see citing works
“39) [0-30] 8.”
Self-citationKarikari, T. K., Benedet, A. L., Ashton, N. J., Lantero‐Rodriguez, J., Snellman, A., Suárez‐Calvet, M., Saha‐Chaudhuri, P., Lussier, F. Z., Kvartsberg, H., Moscoso, A., et al. (2020) · Molecular Psychiatry · doi:10.1038/s41380-020-00923-z · Cited by 348 · see citing works
“Firstly, the clinical identification of AD dementia could be greatly aided by plasma p-tau181 in primary care, which is important given that discrepancies are common between the clinical diagnosis of AD [34].”
Blood phospho-tau in Alzheimer disease: analysis, interpretation, and clinical utility
Karikari, T. K., Ashton, N. J., Brinkmalm, G., Brum, W. S., Benedet, A. L., Montoliu‐Gaya, L., Lantero‐Rodriguez, J., Pascoal, T. A., Suárez‐Calvet, M., Rosa‐Neto, P., et al. (2022) · Nature Reviews Neurology · doi:10.1038/s41582-022-00665-2 · Cited by 327 · see citing works
Chatterjee, P., Pedrini, S., Doecke, J. D., Thota, R. N., Villemagne, V. L., Doré, V., Singh, A. K., Wang, P., Rainey‐Smith, S. R., Fowler, C. J., et al. (2022) · Alzheimer s & Dementia · doi:10.1002/alz.12724 · Cited by 317 · see citing works
Jack, C. R., Therneau, T. M., Weigand, S. D., Wiste, H. J., Knopman, D. S., Vemuri, P., Lowe, V. J., Mielke, M. M., Roberts, R. O., Machulda, M. M., et al. (2019) · JAMA Neurology · doi:10.1001/jamaneurol.2019.1971 · Cited by 300 · see citing works
Improving dementia care: The role of screening and detection of cognitive impairment
Soo Borson, B., Frank, L. B., Bayley, P. J., Boustani, M. A., Dean, M., Lin, P., McCarten, J. R., Morris, J. C., Salmon, D. P., Schmitt, F. A., et al. (2013) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2012.08.008 · Cited by 287 · see citing works
“8% [39].”
Shaw, L. M., Arias, J., Blennow, K., Galasko, D., Molinuevo, J. L., Salloway, S., Schindler, S., Carrillo, M. C., Hendrix, J. A., Ross, A., et al. (2018) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2018.07.220 · Cited by 266 · see citing works
“[122] Beach TG, Monsell SE, Phillips LE, Kukull W.”
BackgroundInfluentialCerebrospinal fluid biomarkers measured by Elecsys assays compared to amyloid imaging
Schindler, S. E., Gray, J. D., Gordon, B. A., Xiong, C., Batrla‐Utermann, R., Quan, M., Wahl, S., Benzinger, T. L. S., Holtzman, D. M., Morris, J. C., et al. (2018) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2018.01.013 · Cited by 284 · see citing works
“As demonstrated by clinicopathological series, the clinical diagnosis of AD can be incorrect [13], so biomarkers may be helpful in establishing an accurate diagnosis.”
MRI visual rating scales in the diagnosis of dementia: evaluation in 184 post-mortem confirmed cases
Harper, L., Fumagalli, G. G., Barkhof, F., Scheltens, P., O’Brien, J. T., Bouwman, F., Burton, E. J., Rohrer, J. D., Fox, N. C., Ridgway, G. R., et al. (2016) · Brain · doi:10.1093/brain/aww005 · Cited by 264 · see citing works
“Post-mortem examination of brain tissue, therefore, currently remains the diagnostic gold standard (Beach et al., 2012).”
BackgroundCheung, C. Y.-L., Ran, A. R., Wang, S., Chan, V. T. T., Sham, K., Hilal, S., Venketasubramanian, N., Cheng, C., Sabanayagam, C., Tham, Y. C., et al. (2022) · The Lancet Digital Health · doi:10.1016/s2589-7500(22)00169-8 · Cited by 272 · see citing works
Kunkle, B. W., Schmidt, M. A., Klein, H., Naj, A. C., Hamilton‐Nelson, K. L., Larson, E. B., Evans, D. A., Jager, P. L. D., Crane, P. K., Buxbaum, J. D., et al. (2020) · JAMA Neurology · doi:10.1001/jamaneurol.2020.3536 · Cited by 254 · see citing works
Young, J., Modat, M., Cardoso, M. J., Mendelson, A., Cash, D., & Ourselin, S. (2013) · NeuroImage Clinical · doi:10.1016/j.nicl.2013.05.004 · Cited by 249 · see citing works
“(Beach et al., 2012).”
Ossenkoppele, R., Cohn‐Sheehy, B. I., La Joie, R., Vogel, J. W., Möller, C., Lehmann, M., van Berckel, B. N. M., Seeley, W. W., Pijnenburg, Y. A., Gorno‐Tempini, M. L., et al. (2015) · Human Brain Mapping · doi:10.1002/hbm.22927 · Cited by 243 · see citing works
“Possibly due to the young age and atypical presentation, diagnostic accuracy is particularly low in earlyonset and nonamnestic variants of AD [Alladi et al., 2007; Beach et al., 2012], and the diagnosis is often delayed or entirely missed during life [Crutch et al., 2012; van Vliet et al., 2011].”
BackgroundMachine Learning and Novel Biomarkers for the Diagnosis of Alzheimer’s Disease
Chang, C.-H., Lin, C.-H., & Lane, H.-Y. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22052761 · Cited by 257 · see citing works
Leuzy, A., Smith, R., Ossenkoppele, R., Santillo, A., Borroni, E., Klein, G., Ohlsson, T., Jögi, J., Palmqvist, S., Mattsson-Carlgren, N., et al. (2020) · JAMA Neurology · doi:10.1001/jamaneurol.2020.0989 · Cited by 222 · see citing works
Mild Cognitive Impairment: the Manchester consensus
Dunne, R. A., Aarsland, D., O'Brien, J. T., Ballard, C. G., Banerjee, S., Fox, N. C., Isaacs, J. D., Underwood, B. R., Perry, R. J., Chan, D., et al. (2020) · Age and Ageing · doi:10.1093/ageing/afaa228 · Cited by 222 · see citing works
Morris, G. P., Clark, I. A., & Vissel, B. (2018) · Acta Neuropathologica · doi:10.1007/s00401-018-1918-8 · Cited by 212 · see citing works
El-Hayek, Y. H., Wiley, R. E., Khoury, C. P., Daya, R. P., Ballard, C., Evans, A. R., Karran, M., Molinuevo, J. L., Norton, M., & Atri, A. (2019) · Journal of Alzheimer's Disease · doi:10.3233/jad-190426 · Cited by 216 · see citing works
Jack, C. R., Wiste, H. J., Botha, H., Weigand, S. D., Therneau, T. M., Knopman, D. S., Graff-Radford, J., Jones, D. T., Ferman, T. J., Boeve, B. F., et al. (2019) · Brain · doi:10.1093/brain/awz268 · Cited by 200 · see citing works
“indicator of underlying aetiology (Beach et al., 2012; Jagust et al., 2019).”
Designing the next-generation clinical care pathway for Alzheimer’s disease
Hampel, H., Au, R., Mattke, S., van der Flier, W. M., Aisen, P., Apostolova, L., Chen, C., Cho, M., De Santi, S., Gao, P., et al. (2022) · Nature Aging · doi:10.1038/s43587-022-00269-x · Cited by 191 · see citing works
Molinuevo, J. L., Blennow, K., Dubois, B., Engelborghs, S., Lewczuk, P., Perret‐Liaudet, A., Teunissen, C. E., & Parnetti, L. (2014) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2014.03.003 · Cited by 198 · see citing works
“[23] Beach TG, Monsell SE, Phillips LE, Kukull W.”
BackgroundBiomarker-based staging of Alzheimer disease: rationale and clinical applications
Therriault, J., Schindler, S. E., Salvadó, G., Pascoal, T. A., Benedet, A. L., Ashton, N. J., Karikari, T. K., Apostolova, L. G., Murray, M. E., Verberk, I. M. W., et al. (2024) · Nature Reviews Neurology · doi:10.1038/s41582-024-00942-2 · Cited by 206 · see citing works
“However, studies have shown that 15–30% of individuals with a clinical diagnosis of probable AD dementia (without AD biomarker support) have insufficient levels of Aβ plaques and NFTs at autopsy 5 or on PET imaging 6 to fulfil the criteria for AD, even when the diagnoses were made at expert centres.”
Androgen Deprivation Therapy and Future Alzheimer’s Disease Risk
Nead, K. T., Gaskin, G., Chester, C., Swisher-McClure, S. D., Dudley, J. T., Leeper, N. J., & Shah, N. H. (2015) · Journal of Clinical Oncology · doi:10.1200/jco.2015.63.6266 · Cited by 198 · see citing works
Metabolomics of Human Brain Aging and Age-Related Neurodegenerative Diseases
Jové, M., Portero-Otín, M., Naudí, A., Ferrer, I., & Pamplona, R. (2014) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0000000000000091 · Cited by 195 · see citing works
Korolev, I. O., Symonds, L. L., Bozoki, A., & Initiative, A. D. N. (2016) · PLoS ONE · doi:10.1371/journal.pone.0138866 · Cited by 192 · see citing works
“The clinical diagnosis of probable AD has an accuracy of 70–90% relative to the pathological diagnosis [82] The implication of this is that models developed to predict progression fromMCI to clinicallydiagnosed AD can only be as accurate as the clinical diagnosis itself.”
BackgroundThomson, K. L., Yeo, J. M., Waddell, B., Cameron, J. R., & Pal, S. (2015) · Alzheimer s & Dementia Diagnosis Assessment & Disease Monitoring · doi:10.1016/j.dadm.2015.03.001 · Cited by 193 · see citing works
Total Aβ 42 /Aβ 40 ratio in plasma predicts amyloid-PET status, independent of clinical AD diagnosis
Doecke, J. D., Pérez‐Grijalba, V., Fandos, N., Fowler, C. J., Villemagne, V. L., Masters, C. L., Pesini, P., & Sarasa, M. (2020) · Neurology · doi:10.1212/wnl.0000000000009240 · Cited by 190 · see citing works
Pathophysiological subtypes of Alzheimer’s disease based on cerebrospinal fluid proteomics
Tijms, B. M., Gobom, J., Reus, L. M., Jansen, I. E., Hong, S., Dobričić, V., Kilpert, F., ten Kate, M., Barkhof, F., Tsolaki, M., et al. (2020) · Brain · doi:10.1093/brain/awaa325 · Cited by 192 · see citing works
“Another point of consideration is that with older age co-pathology often occurs, which may influence proteomic subtype definitions (Beach et al., 2012).”
BackgroundAmyloid blood biomarker detects Alzheimer's disease
Nabers, A., Perna, L., Lange, J., Mons, U., Schartner, J., Güldenhaupt, J., Saum, K., Janelidze, S., Holleczek, B., Rujescu, D., et al. (2018) · EMBO Molecular Medicine · doi:10.15252/emmm.201708763 · Cited by 185 · see citing works
“At these later stages, clinical diagnoses are more accurate even without neurochemical marker assessment and PET scanning (Beach et al, 2012; Martinelli et al, 2014).”
BackgroundIs Alzheimer disease a disease?
Korczyn, A. D., & Grinberg, L. T. (2024) · Nature Reviews Neurology · doi:10.1038/s41582-024-00940-4 · Cited by 192 · see citing works
“Second, AD neuropathological changes, particularly amyloid-β deposition, occur frequently in older individuals with normal cognition 5,9 , referred to as resilience to AD changes 10 .”
Fandos, N., Pérez‐Grijalba, V., Pesini, P., Olmos, S., Bossa, M., Villemagne, V. L., Doecke, J., Fowler, C., Masters, C. L., Sarasa, M., et al. (2017) · Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring · doi:10.1016/j.dadm.2017.07.004 · Cited by 187 · see citing works
“8 [27], which could seriously skew the results of any test and is almost certainly a relevant source of variability between studies.”
BackgroundDuara, R., & Barker, W. (2022) · Neurotherapeutics · doi:10.1007/s13311-022-01185-z · Cited by 187 · see citing works
Serrano‐Pozo, A., Qian, J., Monsell, S. E., Betensky, R. A., & Hyman, B. T. (2015) · Annals of Neurology · doi:10.1002/ana.24369 · Cited by 176 · see citing works
“This is of critical importance, because up to 30% of subjects diagnosed with probable AD in US NIA-funded ADCs have other neuropathological diagnoses causing or contributing to their cognitive deficits, or insufficient AD neuropathological changes at autopsy to fulfill current AD neuropathological diagnostic criteria.…”
BackgroundSelf-citationPlasma biomarkers and genetics in the diagnosis and prediction of Alzheimer’s disease
Stevenson‐Hoare, J. O., Heslegrave, A., Leonenko, G., Fathalla, D., Bellou, E., Luckcuck, L., Marshall, I. J., Sims, R., Morgan, B. P., Hardy, J., et al. (2022) · Brain · doi:10.1093/brain/awac128 · Cited by 185 · see citing works
“ple with clinical AD do not have underlying pathology at autopsy, and many people who have not yet developed AD-type dementia have incipient pathology, the prevalence of which increases with age.(1) Detecting AD at the earliest possible stage remains essential to combating its effects and to further our understanding…”
BackgroundFluid Biomarkers for Synaptic Dysfunction and Loss
Camporesi, E., Nilsson, J., Brinkmalm, A., Becker, B., Ashton, N. J., Blennow, K., & Zetterberg, H. (2020) · Biomarker Insights · doi:10.1177/1177271920950319 · Cited by 165 · see citing works
Longitudinal change in CSF Tau and Aβ biomarkers for up to 48 months in ADNI
Toledo, J. B., Xie, S. X., Trojanowski, J. Q., & Shaw, L. M. (2013) · Acta Neuropathologica · doi:10.1007/s00401-013-1151-4 · Cited by 180 · see citing works
“These studies mainly compared changes based on clinical diagnosis; however, the use of clinical diagnosis that is not neuropathologically validated might be prone to false positive results because of the assumption that all MCI and AD cases will have only AD pathology, but this assumption is incorrect in 7–17 % of AD…”
Beta-amyloid imaging with florbetaben
Sabri, O., Seibyl, J., Rowe, C., & Barthel, H. (2015) · Clinical and translational imaging · doi:10.1007/s40336-015-0102-6 · Cited by 167 · see citing works
“, individuals diagnosed with AD dementia who do not show b-amyloid plaques upon autopsy) in 10–30 % of cases [4].”
BackgroundEquivalence of plasma p‐tau217 with cerebrospinal fluid in the diagnosis of Alzheimer's disease
Therriault, J., Servaes, S., Tissot, C., Rahmouni, N., Ashton, N. J., Benedet, A. L., Karikari, T. K., Macedo, A. C., Lussier, F. Z., Stevenson, J., et al. (2023) · Alzheimer s & Dementia · doi:10.1002/alz.13026 · Cited by 172 · see citing works
“Highly specialized centers misdiagnose AD in approximately 15%–30% of cases 1,2 and the rate of misdiagnosis in primary care settings is estimated to be even greater.”
BackgroundPalmqvist, S., Whitson, H. E., Allen, L. A., Suárez‐Calvet, M., Galasko, D., Karikari, T. K., Okrahvi, H. R., Paczynski, M., Schindler, S. E., Teunissen, C. E., et al. (2025) · Alzheimer s & Dementia · doi:10.1002/alz.70535 · Cited by 186 · see citing works
“4,5 Furthermore, these tools remain out of reach to most healthcareproviders,eveninmanyspecializedclinicalsettings.”
Braak, H., & Tredici, K. D. (2014) · Advances in anatomy, embryology and cell biology · doi:10.1007/978-3-319-12679-1_1 · Cited by 167 · see citing works
A multiomics approach to heterogeneity in Alzheimer’s disease: focused review and roadmap
Badhwar, A., McFall, G. P., Sapkota, S., Black, S. E., Chertkow, H. M., Duchesne, S., Masellis, M., Li, L., Dixon, R. A., & Bellec, P. (2019) · Brain · doi:10.1093/brain/awz384 · Cited by 168 · see citing works
An accurate fully automated panel of plasma biomarkers for Alzheimer's disease
Palmqvist, S., Stomrud, E., Cullen, N. C., Janelidze, S., Manuilova, E., Jethwa, A., Bittner, T., Eichenlaub, U., Suridjan, I., Kollmorgen, G., et al. (2022) · Alzheimer s & Dementia · doi:10.1002/alz.12751 · Cited by 161 · see citing works
“16 Having tests that accurately estimate the presence of abnormal A β accumulation (“A β positivity”) is therefore crucial for identifying suitable persons to enroll in drug trials, for ensuring an accurate AD diagnosis, 17–19 and before starting anti-A β treatment.”
BackgroundClinical and multimodal biomarker correlates of ADNI neuropathological findings
Toledo, J. B., Cairns, N. J., Da, X., Chen, K., Carter, D. R., Fleisher, A., Householder, E., Ayutyanont, N., Roontiva, A., Bauer, R. J., III, et al. (2013) · Acta Neuropathologica Communications · doi:10.1186/2051-5960-1-65 · Cited by 165 · see citing works
“clinical dementia syndromes have degrees of clinicopathological correlation, therefore if clinical diagnosis is used to estimate the accuracy of biomarkers and their cutoffs, inaccurate results may occur [13-15].”
BackgroundDifferential diagnosis of Alzheimer’s disease using spectrochemical analysis of blood
Paraskevaidi, M., Morais, C. L. M., Lima, K. M. G., Snowden, J. S., Saxon, J. A., Richardson, A. M. T., Jones, M. S., Mann, D. M. A., Allsop, D., Martin‐Hirsch, P. L., et al. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1701517114 · Cited by 163 · see citing works
Blood-Brain Glucose Transfer in Alzheimer’s disease: Effect of GLP-1 Analog Treatment
Gejl, M., Brock, B., Egefjord, L., Vang, K., Rungby, J., & Gjedde, A. (2017) · Scientific Reports · doi:10.1038/s41598-017-17718-y · Cited by 163 · see citing works
Spellman, D. S., Wildsmith, K. R., Honigberg, L. A., Tuefferd, M., Baker, D., Raghavan, N., Nairn, A. C., Croteau, P., Schirm, M., Allard, R., et al. (2015) · PROTEOMICS – Clinical Applications · doi:10.1002/prca.201400178 · Cited by 161 · see citing works
“Despite these established guidelines, and experienced clinicians at specialized AD Centers, the accuracy of clinical AD diagnostic methods is still quite low (comprehensively reviewed by Beach et al. [6]).”
Heywood, W., Galimberti, D., Bliss, E., Sirka, E., Paterson, R. W., Magdalinou, N. K., Carecchio, M., Reid, E. S., Heslegrave, A., Fenoglio, C., et al. (2015) · Molecular Neurodegeneration · doi:10.1186/s13024-015-0059-y · Cited by 159 · see citing works
“) is difficult especially in the earliest stages: specialist centres typically only achieve an accurate pre-mortem diagnosis in 70–90 % of cases [2].”
BackgroundLongitudinal changes in microstructural white matter metrics in Alzheimer's disease
Mayo, C. D., Mazerolle, E. L., Ritchie, L. J., Fisk, J. D., & Gawryluk, J. R. (2016) · NeuroImage Clinical · doi:10.1016/j.nicl.2016.12.012 · Cited by 159 · see citing works
“Pathologically, AD is characterized by extracellular aggregation of amyloid-beta into senile plaques and hyper-phosphorylated tau protein accumulation in intraneuronal neurofibrillary tangles (Beach et al., 2012).”
BackgroundVogel, J. W., Corriveau‐Lecavalier, N., Franzmeier, N., Pereira, J. B., Brown, J. A., Maaß, A., Botha, H., Seeley, W. W., Bassett, D. S., Jones, D. T., et al. (2023) · Nature reviews. Neuroscience · doi:10.1038/s41583-023-00731-8 · Cited by 160 · see citing works
Sensitivity and Specificity of Diagnostic Criteria for Progressive Supranuclear Palsy
Ali, F., Martin, P. R., Botha, H., Ahlskog, J. E., Bower, J. H., Masumoto, J. Y., Maraganore, D. M., Hassan, A., Eggers, S. D. Z., Boeve, B. F., et al. (2019) · Movement Disorders · doi:10.1002/mds.27619 · Cited by 157 · see citing works
“8%.(25) Similarly, criteria for “possible bvFTD” have sensitivity of 95% and specificity of 82%, whereas “probable bvFTD” has a sensitivity of 85% and specificity of 95%.”
BackgroundAlzheimer's disease first symptoms are age dependent: Evidence from the NACC dataset
Barnes, J., Dickerson, B. C., Frost, C. D., Jiskoot, L. C., Wolk, D. A., & van der Flier, W. M. (2015) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2014.12.007 · Cited by 152 · see citing works
“Notably, a clinical diagnosis of probable AD in the NACC neuropathological cohort was shown to have a sensitivity and specificity of 71% compared with a pathological diagnosis [51].”
MethodIs Alzheimer’s Disease Risk Modifiable?
Serrano‐Pozo, A., & Growdon, J. H. (2019) · Journal of Alzheimer s Disease · doi:10.3233/jad181028 · Cited by 157 · see citing works
“In addition, in most cases the diagnosis of MCI or AD dementia at enrollment was based on clinical criteria without biomarker support, but the clinical constructs of MCI and AD dementia are pathologically heterogeneous due to the high frequency of pathological comorbidities and to clinical misdiagnosis [8,15,16].”
Rabinovici, G. D., Carrillo, M. C., Forman, M. S., DeSanti, S., Miller, D. S., Kozauer, N., Petersen, R. C., RANDOLPH, C. C., Knopman, D. S., Smith, E. E., et al. (2016) · Alzheimer s & Dementia Translational Research & Clinical Interventions · doi:10.1016/j.trci.2016.09.002 · Cited by 152 · see citing works
“[29] Beach TG, Monsell SE, Phillips LE, Kukull W.”
BackgroundArtificial Intelligence for Alzheimer’s Disease: Promise or Challenge?
Fabrizio, C., Termine, A., Caltagirone, C., & Sancesario, G. M. (2021) · Diagnostics · doi:10.3390/diagnostics11081473 · Cited by 156 · see citing works
“However, AD shares many common clinical features with other neurodegenerative dementia, including Lewy body dementia [2], frontotemporal disorders [3], and vascular dementia, making early and differential diagnosis difficult, especially in the first stage of the disease [4,5].”
BackgroundThe Past and the Future of Alzheimer’s Disease Fluid Biomarkers
Blennow, K., & Zetterberg, H. (2018) · Journal of Alzheimer s Disease · doi:10.3233/jad-170773 · Cited by 148 · see citing works
“Thus, it was not surprising that an increasing number of papers showed that these purely clinicalcriteriaforADhavepoordiagnosticaccuracy, alsoinexpertacademiccenters,withsensitivityand specificityfiguresofaround70%[12].”
Translating genetic risk of Alzheimer’s disease into mechanistic insight and drug targets
Sierksma, A. S. R., Escott‐Price, V., & Strooper, B. D. (2020) · Science · doi:10.1126/science.abb8575 · Cited by 149 · see citing works
“About 30% of clinically diagnosed patients have no neuropathological or biomarker characteristics of AD (1) and 56% of cases defined as AD present with common comorbidities such as Lewy body disease, vascular pathology or hippocampal sclerosis (2).”
Dumurgier, J., Schraen‐Maschke, S., Gabelle, A., Vercruysse, O., Bombois, S., Laplanche, J., Peoc’h, K., Sablonnière, B., Kastanenka, K. V., Delaby, C., et al. (2015) · Alzheimer s Research & Therapy · doi:10.1186/s13195-015-0114-5 · Cited by 145 · see citing works
“In most studies comparing clinical diagnosis with neuropathological findings, researchers have reported specificity lower than 70% [3].”
BackgroundGender Differences in Alzheimer Disease: Brain Atrophy, Histopathology Burden, and Cognition
Filon, J. R., Intorcia, A. J., Sue, L. I., Vazquez Arreola, E., Wilson, J., Davis, K. J., Sabbagh, M. N., Belden, C. M., Caselli, R. J., Adler, C. H., et al. (2016) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/nlw047 · Cited by 143 · see citing works
“The accuracy of the clinical diagnosis of AD is low enough, with sensitivity ranging from 71% to 87% and specificity ranging from 44% to 71% (37), to increase the likelihood of false negative findings in studies lacking neuropathological diagnosis confirmation.”
BackgroundSelf-citationMild cognitive impairment with suspected nonamyloid pathology (SNAP): Prediction of progression
Caroli, A., Prestia, A., Galluzzi, S., Ferrari, C., van der Flier, W. M., Ossenkoppele, R., Van Berckel, B., Barkhof, F., Teunissen, C., Wall, A. E., et al. (2015) · Neurology · doi:10.1212/wnl.0000000000001209 · Cited by 142 · see citing works
Alzheimer's Disease: A Clinical and Basic Science Review
Korolev, I. O. (2014) · Cited by 146 · see citing works
Rabinovici, G. D., Knopman, D. S., Arbizu, J., Benzinger, T. L. S., Donohoe, K. J., Hansson, O., Herscovitch, P., Kuo, P. H., Lingler, J. H., Minoshima, S., et al. (2025) · Alzheimer s & Dementia · doi:10.1002/alz.14338 · Cited by 151 · see citing works
Hulle, C. V., Jonaitis, E. M., Betthauser, T. J., Batrla, R., Wild, N., Kollmorgen, G., Andréasson, U., Okonkwo, O. C., Bendlin, B. B., Asthana, S., et al. (2020) · Alzheimer s & Dementia · doi:10.1002/alz.12204 · Cited by 137 · see citing works
“The following immunoassays were performed on a cobas e 601 analyzer: Elecsys β-amyloid(1-42) CSF, Elecsys Phospho-Tau (181P) CSF and Elecsys Total-Tau CSF, S100 calcium binding protein B (S100B), and interleukin-6 (IL6).”
MethodHansson, O., Batrla, R., Brix, B., Carrillo, M. C., Corradini, V., Edelmayer, R. M., Esquivel, R. N., Hall, C., Lawson, J., Bastard, N. L., et al. (2021) · Alzheimer's & Dementia · doi:10.1002/alz.12316 · Cited by 136 · see citing works
New landscape of the diagnosis of Alzheimer’s disease
Frisoni, G. B., Hansson, O., Nichols, E., Garibotto, V., Schindler, S. E., van der Flier, W. M., Jessen, F., Villain, N., Arenaza-Urquijo, E. M., Crivelli, L., et al. (2025) · The Lancet · doi:10.1016/s0140-6736(25)01294-2 · Cited by 143 · see citing works
Mattsson, N., Grinberg, L. T., Boxer, A. L., Ossenkoppele, R., Jonsson, M., Seeley, W., Ehrenberg, A. J., Spina, S., Janelidze, S., Rojas-Martinex, J., et al. (2022) · Neurology · doi:10.1212/wnl.0000000000200040 · Cited by 136 · see citing works
Genome-wide association studies for Alzheimer’s disease: bigger is not always better
Escott-Price, V., & Hardy, J. (2022) · Brain Communications · doi:10.1093/braincomms/fcac125 · Cited by 119 · see citing works
“The fi rst is that the diagnostic accuracy for Alzheimer ’ s disease is poor: of the order of 80% in clinic-basedseries based both on neuropathological criteria 2 and on genetic analysis 3 and this is certain to be worse in the case of the proxy cases used in the larger and more recent GWAS.”
MethodRetinal imaging in Alzheimer’s disease
Cheung, C. Y.-L., Mok, V., Foster, P. J., Trucco, E., Chen, C., & Wong, T. Y. (2021) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp-2020-325347 · Cited by 134 · see citing works
Genetic analyses of early-onset Alzheimer’s disease using next generation sequencing
Giau, V. V., Bagyinszky, E., Yang, Y. S., Youn, Y. C., An, S. S. A., & Kim, S. (2019) · Scientific Reports · doi:10.1038/s41598-019-44848-2 · Cited by 133 · see citing works
Patterns of atrophy in pathologically confirmed dementias: a voxelwise analysis
Harper, L., Bouwman, F. H., Burton, E. J., Barkhof, F., Scheltens, P., O'Brien, J. T., Fox, N. C., Ridgway, G. R., & Schott, J. M. (2017) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp-2016-314978 · Cited by 130 · see citing works
Paterson, R. W., Slattery, C. F., Poole, T., Nicholas, J. M., Magdalinou, N. K., Toombs, J., Chapman, M. D., Lunn, M. P., Heslegrave, A., Foiani, M. S., et al. (2018) · Alzheimer s Research & Therapy · doi:10.1186/s13195-018-0361-3 · Cited by 130 · see citing works
“patients diagnosed with probable AD, the sensitivity and specificity for underlying AD pathology are in the order of approximately 75% and 60%, respectively [41].”
BackgroundKamal, M. S., Northcote, A., Chowdhury, L., Dey, N., Crespo, R. A. G., & Herrera‐Viedma, E. (2021) · IEEE Transactions on Instrumentation and Measurement · doi:10.1109/tim.2021.3107056 · Cited by 128 · see citing works
- Authors
- Beach, T. G., Monsell, S. E., Phillips, L. E., & Kukull, W.
- Affiliations
- Banner Sun Health Research Institute (US)
- University of Washington (US)
- Corresponding author
- Beach, Thomas G.
- Venue
- Journal of Neuropathology & Experimental Neurology
- Publisher
- Oxford University Press (OUP)
- Published
- 2012-04
- Volume
- 71
- Issue
- 4
- Pages
- 266-273
- ISSN
- 0022-3069 (ISSN-L)
- 1554-6578
- PMC
- PMC3331862
- OpenAlex
- W1974300727
- Semantic Scholar
- 59ed18597d0cb2e750fc7f3c928871aedf079d0a
- Cited by
- 1,103
- References
- 56
- Citations by year
- 2026: 71 · 2025: 94 · 2024: 94 · 2023: 92 · 2022: 91 · 2021: 84 · 2020: 117 · 2019: 90 · 2018: 74 · 2017: 69 · 2016: 66 · 2015: 71 · 2014: 34 · 2013: 46 · 2012: 9
- FWCI
- 36.35
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuropathology & Experimental Neurology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Michael J. Fox Foundation for Parkinson's Research (P30 AG19610)
- Arizona Department of Health Services (P30 AG19610, U01 AG016976)
- National Alzheimer's Coordinating Center (U01AG016976)
- Arizona Biomedical Research Commission (P30 AG19610)
- National Institute on Aging (U01AG016976, P30AG019610, U19AG010483)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Social Sciences › Psychology › Applied Psychology › Psychological Testing and Assessment
- Keywords
- Alzheimer's disease, diagnostic accuracy, neuropathologic diagnosis, sensitivity and specificity, neuritic plaques, misdiagnosis, dementia, Lewy body disease, frontotemporal lobar degeneration, argyrophilic grain disease, hippocampal sclerosis, cerebrovascular disease
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Female, Humans, Male, Middle Aged, United States, Databases, Factual, National Institute on Aging (U.S.)
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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.
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