The DOI matches its Crossref record; 117 of the 119 references it cites were found in a registry or an index; 4 of the 67 sources its claims cite were checked for support.
Clinical diagnosis of Alzheimer’s disease: Recommendations of the International Working Group
Open accessAbstract
In 2018, the National Institute of Aging and the Alzheimer Association proposed a purely biological definition of Alzheimer’s disease (AD) relying on biomarkers. While the intended use of the framework was for research purposes, it has engendered debate and challenges regarding its application in everyday clinical practice. For instance, cognitively unimpaired individuals may have biomarker evidence of both amyloid and tau pathology, but may never develop clinical manifestations in their lifetime. Furthermore, a positive AD pattern may be observed in other brain diseases where AD pathology is present as co‐pathology. In this presentation, the international Working Group (IWG) presents what we consider to be the current limitations of biomarkers in the diagnosis of AD, and on the basis of this evidence we propose recommendations for how biomarkers should and should not be used for diagnosis of AD in a clinical setting. We recommend that AD diagnosis be restricted to the occurrence of positive biomarkers together with specific AD phenotypes, whereas biomarker positive cognitively unimpaired individuals should be considered only at‐risk for progression to AD.
Overview
AI snapshot
Written from the paper’s full text.
TL;DR
The International Working Group argues that a purely biological ATN definition of Alzheimer’s disease is not ready for clinical diagnosis and recommends restricting Alzheimer’s disease diagnosis to people with both a specific Alzheimer’s disease clinical phenotype and positive amyloid and tau biomarkers. Biomarker-positive cognitively unimpaired individuals should be considered at-risk for progression, not clinically diagnosed with Alzheimer’s disease.
Key findings
- The IWG recommends a clinical–biological diagnosis: a specific Alzheimer’s disease phenotype plus amyloid-positive and tau-positive biomarker evidence; biomarker-positive cognitively unimpaired people should be classified as at-risk, not as having Alzheimer’s disease.
- A purely biological definition has low predictive accuracy: cognitively unimpaired biomarker-positive individuals often do not progress, and best current estimates of lifetime dementia risk range from 5% to 42%.
- Alzheimer’s pathology is commonly mixed: pure Alzheimer’s disease pathology is found in 3–30% of neuropathological series of people with dementia of the Alzheimer type, and 50–60% of Alzheimer’s-type dementia is estimated to be attributable to copathologies such as α-synucleinopathy, vascular pathology, non-Alzheimer’s tauopathies, and TDP-43 pathology.
- Practical biomarker limitations include artificial thresholds, limited generalisability, and accessibility; Cochrane reviews could not recommend routine CSF or amyloid PET use in clinical practice, plasma biomarkers are not currently recommended, and biomarker investigation in cognitively unimpaired individuals is not recommended.
Methods
- Design: a Personal View and consensus recommendations from the International Working Group, not a primary empirical study.
- Data or sample: no new primary sample is reported; the paper synthesises prior diagnostic frameworks, biomarker literature, neuropathology evidence, Cochrane reviews, and cohort findings.
- Analysis: narrative evidence synthesis leading to expert recommendations, including proposed diagnostic criteria, biomarker measures, and a risk-stratification proposal for cognitively unimpaired biomarker-positive individuals.
Limitations
- The paper states that a purely biological definition risks confusion between Alzheimer’s disease lesions and Alzheimer’s disease, has low predictive accuracy, is complicated by copathologies, and faces uncertain pathogenesis, threshold, generalisability, accessibility, and ethical problems.
- The paper states that current individualised prediction models do not work sufficiently well in cognitively unimpaired people compared with people in the prodromal stage, and that disclosing individual patient-level risk would be premature and is to be avoided.
- Evident from the text: as a Personal View, the recommendations are expert consensus rather than a systematic review or meta-analysis; the proposed risk stratification is a starting point for research and requires validation studies on large cohorts with long follow-up, as the paper itself notes.
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Claims the paper makes
32 Not checked yet · 13 Own interpretation · 1 Supported · 1 Partly supported · 1 No basis given · accuracy not yet measured
Every source the paper cites for this claim was checked and supports it.
In the paper
“In cognitively unimpaired individuals, self-reported complaints and complaints reported by an informant should be clearly distinguished, because informant complaints indicate that these individuals are at increased risk of progression110 and merit a closer follow-up with regular clinical and neuropsychological evaluations.”
§ Clinical diagnosis of Alzheimer’s disease: recommendations of the International Working Group > IWG recommendations for clinical diagnosis of Alzheimer’s disease
What the sources say
- Supportedcites [110] Caselli, 2014, Subjective cognitive decline: self and informant comparisons, Alzheimers Dement source
The Methods (section 2.6) state that all participants were cognitively normal at entry. The Results (section 3) report that 9.4% of those with informant-endorsed decline developed MCI, compared with 2.2% of those without it (odds ratio 4.58, p<.05). The Discussion cautions that the number of converters was small. (LLM, conf=0.94)
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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- Supported
In the paper
“For instance, cognitively unimpaired individuals can have biomarker evidence of both amyloid β and tau pathology but will often not develop clinical manifestations in their lifetime.”
- Also stated in: § Difficulty in classifying cognitively unimpaired biomarker-positive individuals · hedged
“Cognitively unimpaired individuals with biomarker positivity will not invariably experience subsequent cognitive decline; the best current estimates of lifetime dementia risk range from 5% to 42%.33”
§ Clinical diagnosis of Alzheimer’s disease: recommendations of the International Working Group > Abstract
What the sources say
- Not checked yetcites [33] Brookmeyer, 2018, Estimation of lifetime risks of Alzheimer's disease dementia using biomarkers for preclinical disease, Alzheimers Dement source
plain- Asserted: passes — The authors put it forward as true.
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- Also stated in: § Difficulty in classifying cognitively unimpaired biomarker-positive individuals · hedged
In the paper
“current individualised prediction models do not work sufficiently well in cognitively unimpaired people compared with people who are in the prodromal stage of Alzheimer’s disease.62”
§ Clinical diagnosis of Alzheimer’s disease: recommendations of the International Working Group > Limitations of a purely biological definition of Alzheimer’s disease > Difficulty in classifying cognitively unimpaired biomarker-positive individuals
What the sources say
- Not checked yetcites [62] van Maurik, 2019, Personalized risk for clinical progression in cognitively normal subjects-the ABIDE project, Alzheimers Res Ther source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“In 2018, the US National Institute on Aging and the Alzheimer’s Association proposed a purely biological definition of Alzheimer’s disease that relies on biomarkers.”
- Also stated in: § Introduction · plain
“In 2018, the US National Institute on Aging (NIA) and the Alzheimer’s Association (AA) proposed the amyloid β, tau, neurodegeneration (ATN) research framework for the definition and diagnosis of Alzheimer’s disease (for a glossary of terms, see panel 1).1”
§ Clinical diagnosis of Alzheimer’s disease: recommendations of the International Working Group > Abstract
What the sources say
- Not checked yetcites [1] Jack, 2018, NIA–AA research framework: toward a biological definition of Alzheimer's disease, Alzheimers Dement source
plain- Asserted: passes — The authors put it forward as true.
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- Also stated in: § Introduction · plain
In the paper
“However, the follow-up of cognitively unimpaired biomarker-positive individuals suggests that the majority of these individuals do not progress over time (panel 2).”
§ Clinical diagnosis of Alzheimer’s disease: recommendations of the International Working Group > Limitations of a purely biological definition of Alzheimer’s disease > Uncertainty about the pathogenesis model of Alzheimer’s disease
What the sources say
- Not checked yetcites panel 2
hedged- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The relationship between the coexistence of tau and amyloid β pathology on the one hand, and the development of cognitive decline and neurodegeneration on the other hand, remain uncertain at an individual level.”
§ Clinical diagnosis of Alzheimer’s disease: recommendations of the International Working Group > Limitations of a purely biological definition of Alzheimer’s disease > Uncertainty about the pathogenesis model of Alzheimer’s disease
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Several studies (panel 2) indicate that the presence of both tau and amyloid β positivity is insufficient to definitively predict the occurrence of symptoms (mild cognitive impairment or dementia) in individuals without clinical impairment.”
§ Clinical diagnosis of Alzheimer’s disease: recommendations of the International Working Group > Limitations of a purely biological definition of Alzheimer’s disease > Low predictive accuracy
What the sources say
- Not checked yetcites panel 2
hedged- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
In the paper
“Pure Alzheimer’s disease pathology is the exception rather than the rule (found in 3–30% of neuropathological series of people with dementia of the Alzheimer type, depending on age40) at post-mortem examination.”
§ Clinical diagnosis of Alzheimer’s disease: recommendations of the International Working Group > Limitations of a purely biological definition of Alzheimer’s disease > Presence of other pathologies
What the sources say
- Not checked yetcites [40] Robinson, 2018, Neurodegenerative disease concomitant proteinopathies are prevalent, age-related and APOE4-associated, Brain source
plain- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“50–60% of Alzheimer’s-type dementia (dementia defined clinically as Alzheimer’s disease) is estimated to be attributable to these copathologies.40,42–45”
§ Clinical diagnosis of Alzheimer’s disease: recommendations of the International Working Group > Limitations of a purely biological definition of Alzheimer’s disease > Presence of other pathologies
What the sources say
- Not checked yetcites [40] Robinson, 2018, Neurodegenerative disease concomitant proteinopathies are prevalent, age-related and APOE4-associated, Brain source
- Not checked yetcites [42] Yokota, 2018, Neuropathological comorbidity associated with argyrophilic grain disease, Neuropathology source
- Not checked yetcites [43] Ossenkoppele, 2020, Assessment of demographic, genetic, and imaging variables associated with brain resilience and cognitive resilience to pathological tau in patients with Alzheimer disease, JAMA Neurol source
- Not checked yetcites [44] Karanth, 2020, Prevalence and clinical phenotype of quadruple misfolded proteins in older adults, JAMA Neurol source
- Not checked yetcites [45] Nelson, 2019, Limbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report, Brain source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Furthermore, a positive Alzheimer’s disease pattern of biomarkers can be observed in other brain diseases in which Alzheimer’s disease pathology is present as a comorbidity.”
- Also stated in: § Presence of other pathologies · hedged
“Another challenge with using a biomarker-only diagnosis of Alzheimer’s disease is that the in-vivo presence of biomarkers of Alzheimer’s disease lesions could certify Alzheimer’s disease as the primary diagnosis, because such lesions are commonly found in people who have other neurodegenerative diseases, most often dementia with Lewy bodies.40”
§ Clinical diagnosis of Alzheimer’s disease: recommendations of the International Working Group > Abstract
What the sources say
- Not checked yetcites [40] Robinson, 2018, Neurodegenerative disease concomitant proteinopathies are prevalent, age-related and APOE4-associated, Brain source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Also stated in: § Presence of other pathologies · hedged
- It may state two separate claims as one. 19
- Probably not a substantial claim. 7
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“The positivity of both amyloid and tau biomarkers is required because an amnestic phenotype with only amyloid positivity is not specific to Alzheimer’s disease and is seen in other neurodegenerative diseases with amyloid copathology (including LATE and dementia with Lewy bodies1,40,41,100) or in patients with cerebral amyloid angiopathy and amnestic vascular cognitive impairment101 (appendix p 2).”
§ Clinical diagnosis of Alzheimer’s disease: recommendations of the International Working Group > IWG recommendations for clinical diagnosis of Alzheimer’s disease
What the sources say
- Partly supportedcites [1] Jack, 2018, NIA–AA research framework: toward a biological definition of Alzheimer's disease, Alzheimers Dement sourceExperimental — accuracy not yet measured
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
- Partly supportedcites [40] Robinson, 2018, Neurodegenerative disease concomitant proteinopathies are prevalent, age-related and APOE4-associated, Brain sourceExperimental — accuracy not yet measured
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
- Partly supportedcites [41] McKeith, 2017, Diagnosis and management of dementia with Lewy bodies: fourth consensus report of the DLB Consortium, Neurology sourceExperimental — accuracy not yet measured
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Partly supported
None of the sources cited for this claim have been checked yet.
In the paper
“Most of all, this binary threshold does not reflect the reality of amyloid β and tau pathology, which is continuous and present at a minimal extent in almost all people older than 70 years,17 with important discrepancies between pathology burden and clinical symptoms at intermediate extents (panel 2).”
§ Clinical diagnosis of Alzheimer’s disease: recommendations of the International Working Group > Limitations of a purely biological definition of Alzheimer’s disease > Biomarker thresholds
What the sources say
- Not checked yetcites [17] Braak, 2011, Stages of the pathologic process in Alzheimer disease: age categories from 1 to 100 years, J Neuropathol Exp Neurol source
- Not checked yetcites panel 2
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The clear-cut separation between negative and positive patients in relation to a given biomarker is somewhat artificial and differs between sites and studies.”
§ Clinical diagnosis of Alzheimer’s disease: recommendations of the International Working Group > Limitations of a purely biological definition of Alzheimer’s disease > Biomarker thresholds
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In summary, amyloid β and tau biomarkers are not sufficient to confidently predict progression to prodromal Alzheimer’s disease or Alzheimer’s disease dementia, or to define a person’s position on the Alzheimer’s disease continuum, without clinical input.”
§ Clinical diagnosis of Alzheimer’s disease: recommendations of the International Working Group > Limitations of a purely biological definition of Alzheimer’s disease > Uncertainty about the pathogenesis model of Alzheimer’s disease
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Cognitively unimpaired individuals with biomarker positivity will not invariably experience subsequent cognitive decline; the best current estimates of lifetime dementia risk range from 5% to 42%.33”
§ Clinical diagnosis of Alzheimer’s disease: recommendations of the International Working Group > Limitations of a purely biological definition of Alzheimer’s disease > Difficulty in classifying cognitively unimpaired biomarker-positive individuals
What the sources say
- Not checked yetcites [33] Brookmeyer, 2018, Estimation of lifetime risks of Alzheimer's disease dementia using biomarkers for preclinical disease, Alzheimers Dement source
hedged- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
In the paper
“For physicians, Alzheimer’s disease equates with Alzheimer’s disease neuropathological changes, whereas for patients, Alzheimer’s disease equates with dementia, dependency, and death.”
§ Clinical diagnosis of Alzheimer’s disease: recommendations of the International Working Group > Limitations of a purely biological definition of Alzheimer’s disease > Ethical concerns
What the sources say
- Not checked yetcites [12] Frisoni, 2019, Re-aligning scientific and lay narratives of Alzheimer's disease, Lancet Neurol source
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“CSF investigation is prioritised because it provides simultaneous information on the two types of biomarkers (amyloid β and tau) and is less expensive than amyloid PET, tau PET, or both.”
§ Clinical diagnosis of Alzheimer’s disease: recommendations of the International Working Group > IWG recommendations for clinical diagnosis of Alzheimer’s disease
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. It may state two separate claims as one.
In the paper
“However, this increased sensitivity in the detection of cognitive decline comes at the expense of a reduced specificity, and numerous other causes than neurodegeneration or Alzheimer’s disease can be responsible for the observed changes, such as metabolic disorders, psychiatric disorders, or sleep apnoea.72”
§ Clinical diagnosis of Alzheimer’s disease: recommendations of the International Working Group > Limitations of a purely biological definition of Alzheimer’s disease > Biomarker thresholds
What the sources say
- Not checked yetcites [72] Chipi, 2019, Biomarker-based signature of alzheimer's disease in pre-MCI individuals, Brain Sci source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Biomarker thresholds also depend on their intended use (eg, to identify the first signs of amyloid β pathology, or to predict the occurrence of clinical symptoms) and no consensus on the context of use (eg, in asymptomatic vs symptomatic individuals; in people who complain about subjective cognitive decline vs non-complainers) is currently available.1”
§ Clinical diagnosis of Alzheimer’s disease: recommendations of the International Working Group > Limitations of a purely biological definition of Alzheimer’s disease > Biomarker thresholds
What the sources say
- Not checked yetcites [1] Jack, 2018, NIA–AA research framework: toward a biological definition of Alzheimer's disease, Alzheimers Dement source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“In both situations, pathophysiological Alzheimer’s disease biomarkers can be positive.111”
§ Clinical diagnosis of Alzheimer’s disease: recommendations of the International Working Group > IWG recommendations for clinical diagnosis of Alzheimer’s disease
What the sources say
- Not checked yetcites [111] Niemantsverdriet, 2018, Added diagnostic value of cerebrospinal fluid biomarkers for differential dementia diagnosis in an autopsy-confirmed cohort, J Alzheimers Dis source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“As shown in panel 2, the effect of biomarker positivity on clinical progression remains weak to moderate and was established using selected volunteers from research cohorts.”
§ Clinical diagnosis of Alzheimer’s disease: recommendations of the International Working Group > Limitations of a purely biological definition of Alzheimer’s disease > Generalisability and accessibility in clinical practice
What the sources say
- Not checked yetcites panel 2
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“This deep difference in use and understanding of the term can adversely affect the therapeutic alliance.12”
§ Clinical diagnosis of Alzheimer’s disease: recommendations of the International Working Group > Limitations of a purely biological definition of Alzheimer’s disease > Ethical concerns
What the sources say
- Not checked yetcites [12] Frisoni, 2019, Re-aligning scientific and lay narratives of Alzheimer's disease, Lancet Neurol source
plainconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
None of the sources cited for this claim have been checked yet.
In the paper
“The current in-vivo detection of tau positivity using 18F-flortaucipir PET seems to correspond only to widespread tau pathology in the brain (ie, Braak stages ≥IV),69 whereas CSF phosphorylated tau elevation can reflect earlier stages of tauopathy.70”
§ Clinical diagnosis of Alzheimer’s disease: recommendations of the International Working Group > Limitations of a purely biological definition of Alzheimer’s disease > Biomarker thresholds
What the sources say
- Not checked yetcites [69] Fleisher, 2020, Positron emission tomography imaging with [18F]flortaucipir and postmortem assessment of Alzheimer disease neuropathologic changes, JAMA Neurol source
- Not checked yetcites [70] Mattsson-Carlgren, 2020, Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive tau PET in Alzheimer's disease, Sci Adv source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“If a person decides to receive the results and the results are positive, they should be counselled that they are at risk for subsequent clinical progression to prodromal Alzheimer’s disease or Alzheimer’s disease dementia, but are not clinically diagnosed as having Alzheimer’s disease.”
§ Clinical diagnosis of Alzheimer’s disease: recommendations of the International Working Group > IWG recommendations for clinical diagnosis of Alzheimer’s disease
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
In the paper
“As underscored by the Cochrane reviews, the prognostic value of a diagnosis based on biomarkers remains limited, first because there is a high variability of decline rate among individuals with biomarker-positive Alzheimer’s disease,79 and second because non-Alzheimer’s disease neurodegenerative diseases contribute to cognitive decline.”
§ Clinical diagnosis of Alzheimer’s disease: recommendations of the International Working Group > Limitations of a purely biological definition of Alzheimer’s disease > Generalisability and accessibility in clinical practice
What the sources say
- Not checked yetcites [79] Jang, 2019, Prediction of fast decline in amyloid positive mild cognitive impairment patients using multimodal biomarkers, Neuroimage Clin source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In symptomatic patients, the identification of the specific clinical phenotype (interfering or not with independence in everyday activities) is a major step in diagnosis, because it expresses the brain dysfunction that the biomarkers are signalling.”
§ Clinical diagnosis of Alzheimer’s disease: recommendations of the International Working Group > Limitations of a purely biological definition of Alzheimer’s disease > Difficulty in classifying cognitively unimpaired biomarker-positive individuals
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
None of the sources cited for this claim have been checked yet.
In the paper
“Subjective cognitive decline might be a risk factor of clinical progression,24 but the ability of subjective cognitive decline to predict progression to objective cognitive decline (ie, mild cognitive decline, or dementia, or both) remains low (OR 1·5–3·081).”
§ Clinical diagnosis of Alzheimer’s disease: recommendations of the International Working Group > Limitations of a purely biological definition of Alzheimer’s disease > Generalisability and accessibility in clinical practice
What the sources say
- Not checked yetcites [24] Ebenau, 2020, ATN classification and clinical progression in subjective cognitive decline: the SCIENCe project, Neurology source
- Not checked yetcites [81] Slot, 2019, Subjective cognitive decline and rates of incident Alzheimer's disease and non-Alzheimer's disease dementia, Alzheimers Dement source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“However, an isolated amnestic syndrome of the hippocampal type with only tau biomarker positivity can occur in primary age-related tauopathy37,38 or in atypical presentations of mixed 3 repeat or 4 repeat tau frontotemporal lobar degeneration100,102 (appendix p 2).”
§ Clinical diagnosis of Alzheimer’s disease: recommendations of the International Working Group > IWG recommendations for clinical diagnosis of Alzheimer’s disease
What the sources say
- Not checked yetcites [37] Toledo, 2015, Alzheimer's disease cerebrospinal fluid biomarker in cognitively normal subjects, Brain source
- Not checked yetcites [38] Bell, 2019, Neuropathologic, genetic, and longitudinal cognitive profiles in primary age-related tauopathy (PART) and Alzheimer's disease, Alzheimers Dement source
- Not checked yetcites [100] Villain, 2019, Alzheimer's disease including focal presentations, Semin Neurol source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Subjective memory complaints and subjective cognitive decline, if isolated and not supported by objective cognitive impairment, are not specific enough to be considered part of the Alzheimer’s disease phenotype.109”
§ Clinical diagnosis of Alzheimer’s disease: recommendations of the International Working Group > IWG recommendations for clinical diagnosis of Alzheimer’s disease
What the sources say
- Not checked yetcites [109] Jessen, 2020, Prediction of dementia of Alzheimer type by different types of subjective cognitive decline, Alzheimers Dement source
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“individuals included in such longitudinal cohorts are usually recruited by advertisement and do not represent the variety of individuals to whom the biomarker investigations would be applied in clinical practice.”
§ Clinical diagnosis of Alzheimer’s disease: recommendations of the International Working Group > Limitations of a purely biological definition of Alzheimer’s disease > Generalisability and accessibility in clinical practice
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In clinical practice, such an extension to earlier thresholds in amyloid or tau biomarkers might lengthen the duration of the asymptomatic stages and decrease the lifetime probability of clinical progression.”
§ Clinical diagnosis of Alzheimer’s disease: recommendations of the International Working Group > Limitations of a purely biological definition of Alzheimer’s disease > Biomarker thresholds
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Overall, evidence for the use of biomarkers in clinical practice remains highly disputed and suffers from a dearth of evidence-based data to recommend biomarker assessments for cognitively unimpaired individuals.”
§ Clinical diagnosis of Alzheimer’s disease: recommendations of the International Working Group > Limitations of a purely biological definition of Alzheimer’s disease > Generalisability and accessibility in clinical practice
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Although the definition of Alzheimer’s disease based exclusively on biological markers has gained substantial traction in research settings, emerging studies suggest that the biomarker definition is not ready for application in clinical settings and for diagnosis of individuals without cognitive impairment.”
§ Clinical diagnosis of Alzheimer’s disease: recommendations of the International Working Group > Conclusion
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper relies on this without support.
A specific clinical phenotype of Alzheimer’s disease can be reliably identified in clinical practice.
“It requires the presence of both a specific clinical phenotype of Alzheimer’s disease (phenotype positive) and biomarker evidence of Alzheimer’s disease pathology (amyloid-positive and tau positive).”
The paper relies on this without support.
Biomarkers are currently unavailable for the pathological changes that underlie the non-Alzheimer’s neurodegenerative diseases often found in people with dementia.
“Unfortunately, biomarkers are currently unavailable for the pathological changes that underlie the non-Alzheimer’s neurodegenerative diseases often found in people with dementia, and disentangling Alzheimer’s disease from other neurodegenerative diseases continues to depend on phenotype or postmortem examination.”
The paper relies on this without support.
In some complex cases, only post-mortem evaluation will provide definitive information about whether Alzheimer's disease is the primary pathology or a copathology.
“In some complex cases, only post-mortem evaluation will provide definitive information.”
The paper relies on this without support.
Biomarker investigations can be limited by the availability, cost, and health-care payment coverage of biomarkers across countries, centres, and clinical situations.
“Biomarker investigations can also be limited by the availability, cost, and health-care payment coverage of biomarkers across countries, centres, and clinical situations.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“Disease onset can occur at < 65 (familial early-onset) or > 65 years of age (sporadic late-onset), with the latter afflicting more than 95% of patients [87, 213]”
From Microglia and monocytes in inflammatory CNS disease: integrating phenotype and function (2022) · cites this paper as [87]
Experimental — accuracy not yet measuredIn the citing paper
“In 2021, new recommendations for the clinical diagnosis of AD were proposed by the International working group, highlighting that the diagnosis of AD should be restricted to people who have positive biomarkers together with specific AD phenotypes. Cognitively unimpaired individuals who are only positive to biomarkers should be considered at-risk for progression to AD [10].”
From Role of Oxidative Damage in Alzheimer’s Disease and Neurodegeneration: From Pathogenic Mechanisms to Biomarker Discovery (2021) · cites this paper as [10]
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Revised criteria for diagnosis and staging of Alzheimer's disease: Alzheimer's Association Workgroup
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“158,159 Differentphenotypesoftenoverlapwithin an individual, and the severity of impairment within each domain can be variable.”
Alzheimer’s Disease: Epidemiology and Clinical Progression
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“However, the International Working Group recommended against widespread biomarker testing of cognitively unimpaired individuals [21].”
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“Further, the CSF criteria also suggest using AD biomarkers in patients with SCD at increased risk of AD, but there is an ongoing debate on the clinical use of biomarkers in patients without objective cognitive impairment such as in SCD. 93 Naturally, patients with cognitive symp-tomsshouldundergorelevantclinicalassess…”
BackgroundSelf-citationOssenkoppele, R., Pichet Binette, A., Groot, C., Smith, R., Strandberg, O., Palmqvist, S., Stomrud, E., Tideman, P., Ohlsson, T., Jögi, J., et al. (2022) · Nature Medicine · doi:10.1038/s41591-022-02049-x · Cited by 496
Self-citationAlzheimer Disease as a Clinical-Biological Construct—An International Working Group Recommendation
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Self-citationBlood Biomarkers to Detect Alzheimer Disease in Primary Care and Secondary Care
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Self-citationBlood phospho-tau in Alzheimer disease: analysis, interpretation, and clinical utility
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Self-citationPrevalence Estimates of Amyloid Abnormality Across the Alzheimer Disease Clinical Spectrum
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Self-citationPlasma proteomic profiles predict future dementia in healthy adults
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“Beyond predictive accuracy, optimal dementia prediction biomarkers should be highly specific for the corresponding pathology 11,19 .”
The amyloid cascade hypothesis: an updated critical review
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“…to predict cognitive decline in cognitively unim-paired individuals, biomarker-only diagnosis of AD generally has modest predictive accuracy in cognitively unimpaired individuals [11] because these subjects may show amyloid positivity and not display clinical manifestations within their lifetime.”
BackgroundMethodInfluentialSelf-citationCSF MTBR-tau243 is a specific biomarker of tau tangle pathology in Alzheimer’s disease
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Self-citationBrain-derived tau: a novel blood-based biomarker for Alzheimer’s disease-type neurodegeneration
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Self-citationQuantification of amyloid PET for future clinical use: a state-of-the-art review
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“Updated in 2021 [7], the guidelines now further highlight amyloid’s central role in the AD diagnostic process.”
BackgroundMicroglia and monocytes in inflammatory CNS disease: integrating phenotype and function
Spiteri, A. G., Wishart, C. L., Pamphlett, R., Locatelli, G., & King, N. J. C. (2022) · Acta Neuropathologica · doi:10.1007/s00401-021-02384-2 · Cited by 216
“Disease onset can occur at < 65 (familial early-onset) or > 65 years of age (sporadic late-onset), with the latter afflicting more than 95% of patients [87, 213].”
BackgroundDesigning 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
Self-citationFrisoni, G. B., Altomare, D., Ribaldi, F., Villain, N., Brayne, C., Mukadam, N., Abramowicz, M. J., Barkhof, F., Berthier, M. L., Bieler-Aeschlimann, M., et al. (2023) · The Lancet Regional Health - Europe · doi:10.1016/j.lanepe.2022.100576 · Cited by 187
“25 All risk factors are reported in Table 2 and categorized into genetic, potentially modi fi able without measured brain pathology (in early life, midlife, and late life), and potentially modi fi able of brain pathology.”
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PM2.5 exposure in association with AD-related neuropathology and cognitive outcomes
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Self-citationCurrent Understanding of Hydrogel for Drug Release and Tissue Engineering
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“With changes in the social environment, neurological diseases such as insomnia, Alzheimer’s disease, and Parkinson’s disease pose a serious threat to human health [155].”
BackgroundThe Role of Glymphatic System in Alzheimer’s and Parkinson’s Disease Pathogenesis
Buccellato, F. R., D’Anca, M., Serpente, M., Arighi, A., & Galimberti, D. (2022) · Biomedicines · doi:10.3390/biomedicines10092261 · Cited by 190
“The clearance of Aβ and tau into the CSF is the basis of the measurement of these proteins in CSF and their use as clinical biomarkers of AD [63,64].”
BackgroundAn 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 166
Self-citationMolecular Mechanisms of Neuroinflammation in Aging and Alzheimer’s Disease Progression
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Clinical effects of Lewy body pathology in cognitively impaired individuals
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PET Imaging of Neuroinflammation in Alzheimer’s Disease
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Recent update on the heterogeneity of the Alzheimer’s disease spectrum
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“Clinical diagnosis of AD, according to the recommendations of the International Working Group, is to be restricted to people with positive biomarkers and specific AD phenotypes (Dubois et al. 2021), but despite the advent of more specific neuroimaging and reliable biomarkers, the final diagnosis of AD rests with postm…”
MethodThe Humanistic and Economic Burden of Alzheimer's Disease
Monfared, A. A. T., Byrnes, M. J., White, L. A., & Zhang, Q. (2022) · Neurology and Therapy · doi:10.1007/s40120-022-00335-x · Cited by 159
“framework and a 2021 international working group on the diagnosis of AD have recommended clinical-biological diagnostic criteria that incorporate biomarker evidence of AD pathology (amyloid- and tau-positive status) in addition to clinical phenotypic evidence to support a diagnosis of MCI due to AD or AD dementia [103…”
BackgroundAlzheimer’s disease profiled by fluid and imaging markers: tau PET best predicts cognitive decline
Bucci, M., Chiotis, K., Nordberg, A., & Initiative, F. T. A. D. N. (2021) · Molecular Psychiatry · doi:10.1038/s41380-021-01263-2 · Cited by 140
Self-citationRabinovici, 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 163
Self-citationChallenges in the practical implementation of blood biomarkers for Alzheimer’s disease
Schöll, M., Verberk, I. M. W., del Campo, M., Delaby, C., Therriault, J., Chong, J. R., Palmqvist, S., & Alcolea, D. A. (2024) · The Lancet Healthy Longevity · doi:10.1016/j.lanhl.2024.07.013 · Cited by 150
MRI Deep Learning-Based Solution for Alzheimer’s Disease Prediction
Saratxaga, C. L., Moya, I., Picón, A., Acosta, M., Moreno-Fernández-de-Leceta, A., Garrote, E., & Bereciartua, A. (2021) · Journal of Personalized Medicine · doi:10.3390/jpm11090902 · Cited by 145
“In recent years, the diagnosis process of the disease is evolving and initiatives based on various identified biomarkers have been proposed, with recommendations of the International Working Group on how they should be used in the clinical practice [10].”
Strikwerda‐Brown, C., Hobbs, D. A., Gonneaud, J., St‐Onge, F., Binette, A. P., Ozlen, H., Provost, K., Soucy, J., Buckley, R. F., Benzinger, T. L. S., et al. (2022) · JAMA Neurology · doi:10.1001/jamaneurol.2022.2379 · Cited by 134
Self-citationResearch Criteria for the Behavioral Variant of Alzheimer Disease
Ossenkoppele, R., Singleton, E. H., Groot, C., Dijkstra, A. A., Eikelboom, W. S., Seeley, W. W., Miller, B. L., Laforce, R. J., Scheltens, P., Papma, J. M., et al. (2021) · JAMA Neurology · doi:10.1001/jamaneurol.2021.4417 · Cited by 134
“3) Amyloid- and tau-PET 25 With tAD and 131 with CU Lateral and medial parietal and prefrontal atrophy in bvAD; no differences between bvAD vs tAD Fluorodeoxyglucose-PET or hypoperfusion single-photon emission computed tomography Snowden et al,22 2007 12 With bvAD 49 (8) 75.”
MethodSelf-citationPless, A., Ware, D., Saggu, S., Rehman, H., Morgan, J., & Wang, Q. (2023) · Frontiers in Neuroscience · doi:10.3389/fnins.2023.1263771 · Cited by 131
“Even with advanced diagnostic techniques such as CSF analysis and PET/SPECT imaging, AD remains a largely clinical diagnosis to date (Dubois et al., 2021).”
MethodPeripheral GFAP and NfL as early biomarkers for dementia: longitudinal insights from the UK Biobank
Wang, X., Shi, Z., Qiu, Y., Sun, D., & Zhou, H. (2024) · BMC Medicine · doi:10.1186/s12916-024-03418-8 · Cited by 126
“However, hidden changes in neuroinflammation and irreversible neuronal damage may occur decades before the onset of symptoms in patients with AD and dementia [5, 6], resulting in delayed diagnostic patterns that contribute to poor clinical prognosis [7, 8].”
BackgroundProtective role of IGF-1 and GLP-1 signaling activation in neurological dysfunctions
Bhalla, S., Mehan, S., Khan, A., & Rehman, M. U. (2022) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2022.104896 · Cited by 108
Perspectives and challenges in patient stratification in Alzheimer’s disease
Abdelnour, C., Agosta, F., Bozzali, M., Fougère, B., Iwata, A., Nilforooshan, R., Takada, L. T., Viñuela, F., & Traber, M. (2022) · Alzheimer's Research & Therapy · doi:10.1186/s13195-022-01055-y · Cited by 108
“Additionally, those with biomarker evidence of AD pathology but normal cognition may not progress to AD dementia [16] and may not be candidates for a DMT.”
BackgroundMethodInfluentialCan we learn lessons from the FDA's approval of aducanumab?
Liu, K. Y., & Howard, R. (2021) · Nature Reviews Neurology · doi:10.1038/s41582-021-00557-x · Cited by 104
The Amyloid Cascade Hypothesis in Alzheimer’s Disease: Should We Change Our Thinking?
Kurkinen, M. T., Fułek, M., Fułek, K., Beszłej, J. A., Kurpas, D., & Leszek, J. (2023) · Biomolecules · doi:10.3390/biom13030453 · Cited by 105
Clinical application of CSF biomarkers for Alzheimer's disease: From rationale to ratios
Bouwman, F. H., Frisoni, G. B., Johnson, S. C., Chen, X., Engelborghs, S., Ikeuchi, T., Paquet, C., Ritchie, C. W., Bozeat, S., Quevenco, F., et al. (2022) · Alzheimer s & Dementia Diagnosis Assessment & Disease Monitoring · doi:10.1002/dad2.12314 · Cited by 95
“Evidence shows that (1) CSF ratios are superior to amyloid beta (Aβ)1-42 alone; (2) concordance of CSF ratios to amyloid positron emission tomography (PET) is better thanAβ1-42 alone; and (3) phosphorylated tau (p-tau)/Aβ1-42 ratio”
BackgroundSelf-citationClinical criteria for limbic‐predominant age‐related TDP‐43 encephalopathy
Wolk, D. A., Nelson, P. T., Apostolova, L. G., Arfanakis, K., Boyle, P. A., Carlsson, C. M., Corriveau‐Lecavalier, N., Dacks, P. A., Dickerson, B. C., Domoto‐Reilly, K., et al. (2025) · Alzheimer s & Dementia · doi:10.1002/alz.14202 · Cited by 103
“Notably, this temporo-limbic memory profile is also associated with the typical amnestic syndrome ofAD, 15 reflectiveoftheoverlappingtopographicpatternofpathology in ADNC and LATE-NC.”
Self-citationPlanche, V., Bouteloup, V., Pellegrin, I., Mangin, J., Dubois, B., Ousset, P., Pasquier, F., Blanc, F., Paquet, C., Hanon, O., et al. (2022) · Neurology · doi:10.1212/wnl.0000000000201479 · Cited by 98
Self-citationConsiderations in the clinical use of amyloid PET and CSF biomarkers for Alzheimer's disease
Leuzy, A., Bollack, A., Pellegrino, D., Teunissen, C. E., Joie, R. L., Rabinovici, G. D., Franzmeier, N., Johnson, K. A., Barkhof, F., Shaw, L. M. J., et al. (2025) · Alzheimer s & Dementia · doi:10.1002/alz.14528 · Cited by 109
Self-citationVillain, N., Planche, V., & Levy, R. (2022) · Revue Neurologique · doi:10.1016/j.neurol.2022.06.012 · Cited by 87
Self-citationAdvances in Alzheimer's disease research over the past two decades
Jack, C. R. (2022) · The Lancet Neurology · doi:10.1016/s1474-4422(22)00298-8 · Cited by 83
Wee, J., Sukudom, S., Bhat, S., Marklund, M., Peiris, N. J., Hoyos, C. M., Patel, S., Naismith, S. L., Dwivedi, G., & Misra, A. (2023) · Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring · doi:10.1002/dad2.12395 · Cited by 82
Iaccarino, L., Burnham, S. C., Dell’Agnello, G., Dowsett, S. A., & Epelbaum, S. (2023) · The Journal of Prevention of Alzheimer s Disease · doi:10.14283/jpad.2023.43 · Cited by 87
“Individual biomarker assays should be used according to the assay label; *Arrow indicates direction of change in measure in individuals with AD vs healthy individuals †Visual read of PET scan approved for clinical use but PET tracer quantitation now being used in research setting; Bottom - Development timeline include…”
BackgroundMethodSelf-citationRabinovici, 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) · Journal of Nuclear Medicine · doi:10.2967/jnumed.124.268756 · Cited by 87
Self-citationDelaby, C., Estellés, T., Zhu, N., Arranz, J., Barroeta, I., Carmona‐Iragui, M., Illán‐Gala, I., Santos‐Santos, M., Altuna, M., Sala, I., et al. (2022) · Alzheimer s Research & Therapy · doi:10.1186/s13195-022-00967-z · Cited by 70
Villain, N., Planche, V., Lilamand, M., Cordonnier, C., Soto‐Martin, M., Mollion, H., Bombois, S., & Delrieu, J. (2025) · The Journal of Prevention of Alzheimer s Disease · doi:10.1016/j.tjpad.2025.100094 · Cited by 87
“These findings support the classification of these three phenotypes as common AD phenotypes according to the 2021 International Working Group AD diagnostic criteria [ 33 ].”
InfluentialSelf-citationGarone, C., Giorgio, F. D., & Carli, S. (2024) · Journal of Translational Medicine · doi:10.1186/s12967-024-05041-w · Cited by 80
“…a clinical phenotype characterized by amnestic syndrome of the hippocampal type, the posterior cortical atrophy variant and the logopenic variant primary progressive aphasia and the biological hallmarks of extracellular β-amyloid plaques and intracellular hyperphosphorylated tau tangles [169, 170].”
BackgroundAlzheimer’s disease clinical trial update 2019–2021
Pleen, J., & Townley, R. A. (2021) · Journal of Neurology · doi:10.1007/s00415-021-10790-5 · Cited by 69
“Prediction of symptom progression within clinical trials at these earlier stages remains an area of ongoing research [2, 3].”
BackgroundConsiderations regarding a diagnosis of Alzheimer’s disease before dementia: a systematic review
van der Schaar, J., Visser, L. N. C., Bouwman, F. H., Ket, J. C. F., Scheltens, P., Bredenoord, A. L., & van der Flier, W. M. (2022) · Alzheimer s Research & Therapy · doi:10.1186/s13195-022-00971-3 · Cited by 74
Rosenberg, A., Öhlund-Wistbacka, U., Hall, A., Bonnard, A., Hagman, G., Rydén, M., Thunborg, C., Wiggenraad, F., Sandebring-Matton, A., Solomon, A., et al. (2022) · Neurology · doi:10.1212/wnl.0000000000201043 · Cited by 70
“The clinical applicability and relevance of different cutoffs and appropriate methods to assess biomarker status and eligibility for disease-modifying treatments in clinical practice remain open questions.(49)”
MethodPeng, X., Guo, H., Zhang, X., Yang, Z., Ruganzu, J. B., Yang, Z., Wu, X., Bi, W., Ji, S., & Yang, W. (2023) · Molecular Neurobiology · doi:10.1007/s12035-023-03217-x · Cited by 71
Boza-Serrano, A., Vrillon, A., Minta, K., Paulus, A., Camprubí-Ferrer, L., Garcia, M., Andreasson, U., Antonell, A., Wennström, M., Gouras, G., et al. (2022) · Acta Neuropathologica · doi:10.1007/s00401-022-02469-6 · Cited by 66
“Traditionally, Aβ, p-Tau and tau are the main diagnostic biomarkers for AD used in clinical practice [16].”
Self-citationClinical Spectrum of Tauopathies
Olfati, N., Shoeibi, A., & Litvan, I. (2022) · Frontiers in Neurology · doi:10.3389/fneur.2022.944806 · Cited by 66
Fillenbaum, G. G., & Mohs, R. C. (2023) · Journal of Alzheimer s Disease · doi:10.3233/jad-230026 · Cited by 78
Frequency and Clinical Outcomes Associated With Tau Positron Emission Tomography Positivity
Moscoso, A., Heeman, F., Raghavan, S., Costoya‐Sánchez, A., van Essen, M., Mainta, I., Camacho, V., Fonseca, O. D. R., Silva‐Rodríguez, J., Perissinotti, A., et al. (2025) · JAMA · doi:10.1001/jama.2025.7817 · Cited by 74
Self-citationLiang, Y., Liu, C., Cheng, M., Geng, L., Li, J., Du, W., Song, M., Chen, N., Yeleen, T. A. N., Li, S., et al. (2024) · Alzheimer s & Dementia · doi:10.1002/alz.14057 · Cited by 73
Developments in scalable strategies for detecting early markers of cognitive decline
Whelan, R., Barbey, F. M., Cominetti, M. R., Gillan, C. M., & Rosická, A. M. (2022) · Translational Psychiatry · doi:10.1038/s41398-022-02237-w · Cited by 69
“Remote, repeated cognitive assessment Cognitive assessment remains the most common method for clinical diagnosis of disease-related cognitive decline, despite the recent shift towards biological biomarkers [95, 96].”
MethodPlasma biomarkers for neurodegenerative disorders: ready for prime time?
Balogun, W. G., Zetterberg, H., Blennow, K., & Karikari, T. K. (2023) · Current Opinion in Psychiatry · doi:10.1097/yco.0000000000000851 · Cited by 62
Self-citationMonfared, A. A. T., Phan, N. T. N., Pearson, I. V., Mauskopf, J., Cho, M., Zhang, Q., & Hampel, H. J. (2023) · Neurology and Therapy · doi:10.1007/s40120-023-00504-6 · Cited by 63
“Dubois and colleagues [12] in 2021 provided recommendations on how biomarkers could be utilized for AD diagnosis in the clinical setting.”
BackgroundRecent Advances in Neuropsychological Test Interpretation for Clinical Practice
Kiselica, A. M., Karr, J. E., Mikula, C. M., Ranum, R. M., Benge, J. F., Medina, L. D., & Woods, S. P. (2023) · Neuropsychology Review · doi:10.1007/s11065-023-09596-1 · Cited by 64
“However, if we imagine she also has neurodegeneration observed on brain MRI and hypometabolism in frontal-parietal regions on FDG-PET scan, confidence in the Alzheimer’s disease diagnosis might increase (Dubois et al., 2021).”
International consensus on the use of tau PET imaging agent 18F-flortaucipir in Alzheimer’s disease
Tian, M., Civelek, A. C., Carrió, I., Watanabe, Y., Kang, K. W., Murakami, K., Garibotto, V., Prior, J. O., Barthel, H., Zhou, R., et al. (2022) · European Journal of Nuclear Medicine and Molecular Imaging · doi:10.1007/s00259-021-05673-w · Cited by 62
Amyloid and Tau Positron Emission Tomography Imaging in Alzheimer’s Disease and Other Tauopathies
Maschio, C., & Ni, R. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.838034 · Cited by 68
Pérez, R., Burgos, V., Marín, V., Camins, A., Olloquequi, J., González‐Chavarría, I., Ulrich, H., Wyneken, Ú., Luarte, A., Ortíz, L., et al. (2023) · Antioxidants · doi:10.3390/antiox12081500 · Cited by 58
“5 million people worldwide, with an annual incidence of 4 to 6 million new cases [1].”
BackgroundA practical overview of the use of amyloid-PET Centiloid values in clinical trials and research
Iaccarino, L., Burnham, S. C., Tunali, I., Wang, J., Navitsky, M. A., Arora, A., & Pontecorvo, M. J. (2025) · NeuroImage Clinical · doi:10.1016/j.nicl.2025.103765 · Cited by 68
“…(Clark et al., 2012; Curtis et al., 2015; La Joie et al., 2019; Sabri et al., 2015); ii) diagnostic value in AD workup (Ch ´ etelat et al., 2020; Dubois et al., 2021; Jack et al., 2018); and iii) impact on patient management (Altomare et al., 2023; Barthel and Sabri, 2017; Fantoni et al., 2018;…”
Fluid biomarkers in Alzheimer's disease
Simrén, J., Elmgren, A., Blennow, K., & Zetterberg, H. (2023) · Advances in Clinical Chemistry · doi:10.1016/bs.acc.2022.09.006 · Cited by 58
Self-citationJiang, M., Chi, J., Qiao, Y., Wang, J., Zhang, Z., Liu, J., Sheng, X., & Yuan, L. (2025) · Pharmacological Research · doi:10.1016/j.phrs.2025.107578 · Cited by 68
Alzheimer disease neuropathology in a patient previously treated with aducanumab
Plowey, E. D., Bussière, T., Rajagovindan, R., Sebalusky, J., Hamann, S., von Hehn, C., Castrillo‐Viguera, C., Sandrock, A. W., Haeberlein, S. B., van Dyck, C. H., et al. (2022) · Acta Neuropathologica · doi:10.1007/s00401-022-02433-4 · Cited by 60
“AD is characterized by two neuropathologic hallmarks: (1) extracellular plaques comprised of Amyloid beta (Aβ) fibrils and (2) intraneuronal aggregates of hyperphosphorylated Tau (pTau) that accumulate in neuritic plaques (NPs), neuropil threads (NTs) and neurofibrillary tangles (NFTs) [9, 15].”
BackgroundAlzheimer’s disease: a mini-review for the clinician
Madnani, R. S. (2023) · Frontiers in Neurology · doi:10.3389/fneur.2023.1178588 · Cited by 56
“It is important to note that these guidelines are those recommended by the NIA-AA; in 2021, the International Working Group released a set of recommendations for the diagnosis of Alzheimer’s that advocates an explicitly clinical-biological method, requiring biomarker evidence in the diagnosis of AD (43).”
BackgroundLi, X., Zhang, C., Yuan, F., et al. (2024) · General Psychiatry · doi:10.1136/gpsych-2024-101641 · Cited by 53
Ossenkoppele, R., Coomans, E. M., Apostolova, L. G., Baker, S. L., Barthel, H., Beach, T. G., Benzinger, T. L. S., Betthauser, T. J., Bischof, G. N., Bottlaender, M., et al. (2025) · Nature Neuroscience · doi:10.1038/s41593-025-02000-6 · Cited by 60
“Based on the recognition of tau proteinopathy as a key manifestation of AD, tau PET tracers are increasingly used in both the clinic and trials 15 and are now incorporated into the core diagnostic criteria for AD 16,17 .”
Self-citationDing, M., Ding, S., Du, D., Wang, X., Hu, X., Guan, P., Lyu, Z., & Lin, Y. (2023) · TrAC Trends in Analytical Chemistry · doi:10.1016/j.trac.2023.117087 · Cited by 56
Tao, Q.-Q., Cai, X., Xue, Y.-Y., Ge, W., Yue, L., Li, X.-Y., Lin, R.-R., Peng, G.-P., Jiang, W., Li, S., et al. (2024) · The Innovation · doi:10.1016/j.xinn.2023.100544 · Cited by 55
Blood-Based Biomarkers of Neuroinflammation in Alzheimer’s Disease: A Central Role for Periphery?
Angiulli, F., Conti, E., Zoia, C., Re, F. D., Appollonio, I. M., Ferrarese, C., & Tremolizzo, L. (2021) · Diagnostics · doi:10.3390/diagnostics11091525 · Cited by 55
“Attempts have been made in the last few years to get to an in vivo neuropathological diagnosis of the disease, independent from the clinical symptoms [15]; however, the latest recommendation is to opt of a comprehensive approach, encompassing both the clinical assessment and in vivo neuropathological evaluation [16].”
BackgroundRecent Advances in Therapeutics for the Treatment of Alzheimer’s Disease
Thawabteh, A. M., Ghanem, A. W., AbuMadi, S., Thaher, D., Jaghama, W., Karaman, D., & Karaman, R. (2024) · Molecules · doi:10.3390/molecules29215131 · Cited by 56
Alzheimer's disease diagnosis and management: Perspectives from around the world
Kerwin, D. R., Ruiz, C. A., Caramelli, P., Ogunniyi, A. O., Shi, J., Zetterberg, H., & Traber, M. (2022) · Alzheimer s & Dementia Diagnosis Assessment & Disease Monitoring · doi:10.1002/dad2.12334 · Cited by 51
“20 In addition to screening programs at memory centers to identify patients at risk of dementia in Spain, it would be helpful to better train PCPs for early detection and use of associated diagnostic tools.”
The ATN Framework—Moving Preclinical Alzheimer Disease to Clinical Relevance
van der Flier, W. M., & Scheltens, P. (2022) · JAMA Neurology · doi:10.1001/jamaneurol.2022.2967 · Cited by 50
Estrogen, menopause, and Alzheimer’s disease: understanding the link to cognitive decline in women
Mervosh, N. L., & Devi, G. (2025) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2025.1634302 · Cited by 62
Artificial intelligence for dementia drug discovery and trials optimization
Doherty, T., Yao, Z., Khleifat, A. A. L., Tantiangco, H., Tamburin, S., Albertyn, C., Thakur, L., Llewellyn, D. J., Oxtoby, N. P., Lourida, I., et al. (2023) · Alzheimer's & Dementia · doi:10.1002/alz.13428 · Cited by 48
Erickson, P., Simrén, J., Brum, W. S., Ennis, G. E., Kollmorgen, G., Suridjan, I., Langhough, R. E., Jonaitis, E. M., Hulle, C. A. V., Betthauser, T. J., et al. (2023) · JAMA Neurology · doi:10.1001/jamaneurol.2023.2338 · Cited by 48
Self-citationAlzheimer's disease: The role of proteins in formation, mechanisms, and new therapeutic approaches
Gholami, A. (2023) · Neuroscience Letters · doi:10.1016/j.neulet.2023.137532 · Cited by 52
Lecanemab in clinical practice: real-world outcomes in early Alzheimer’s disease
Bregman, N., Nathan, T., Shir, D., Omer, N., Levy, M. H., David, A. B., Aizenstien, O., Lotan, E., Alcalay, Y., Awad, A. A., et al. (2025) · Alzheimer s Research & Therapy · doi:10.1186/s13195-025-01763-1 · Cited by 52
“Eligible participants were diagnosed based on clinical criteria for MCI or mild dementia due to AD, confirmed by biomarker evidence of amyloid pathology [9, 10, 15].”
A remote speech-based AI system to screen for early Alzheimer's disease via smartphones
Fristed, E., Skirrow, C., Meszaros, M., Lenain, R., Meepegama, U., Cappa, S., Aarsland, D., & Weston, J. (2022) · Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring · doi:10.1002/dad2.12366 · Cited by 47
“recall test after a 30-minute delay from initial presentation; (3) Digit Symbol Coding,21 a symbol substitution test; (4) the sumof free+ total recall items from the Free and Cued Selective Reminding Test,22 amultimodal associative memory test; and (5) Category Fluency (animals, vegetables, fruits), a semantic memory…”
MethodSelf-citationAdvanced Overview of Biomarkers and Techniques for Early Diagnosis of Alzheimer’s Disease
Rani, S., Dhar, S. B., Khajuria, A., Gupta, D., Jaiswal, P. K., Singla, N., Kaur, M., Singh, G., & Barnwal, R. P. (2023) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-023-01330-y · Cited by 48
Aggregation-induced emission: An illuminator in the brain
Duo, Y., Yang, Y., Xu, T., Zhou, R., Wang, R., Luo, G., & Tang, B. Z. (2023) · Coordination Chemistry Reviews · doi:10.1016/j.ccr.2023.215070 · Cited by 44
A New Framework for Dementia Nomenclature
Petersen, R. C., Weıntraub, S., Sabbagh, M. N., Karlawish, J. H., Adler, C. H., Dilworth‐Anderson, P., Frank, L. B., Hummel, C. H., Taylor, A., & Initiative, D. N. (2023) · JAMA Neurology · doi:10.1001/jamaneurol.2023.3664 · Cited by 47
Self-citationWalsh, S., Merrick, R. L., Milne, R., Nurock, S., Richard, E., & Brayne, C. (2024) · Alzheimer s & Dementia · doi:10.1002/alz.14108 · Cited by 44
Planche, V., & Villain, N. (2021) · JAMA Neurology · doi:10.1001/jamaneurol.2021.3126 · Cited by 43
Self-citationDiscovery of High-Affinity Amyloid Ligands Using a Ligand-Based Virtual Screening Pipeline
Chisholm, T. S., Mackey, M. D., & Hunter, C. A. (2023) · Journal of the American Chemical Society · doi:10.1021/jacs.3c03749 · Cited by 45
Circular RNAs: Emblematic Players of Neurogenesis and Neurodegeneration
D’Anca, M., Buccellato, F. R., Fenoglio, C., & Galimberti, D. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23084134 · Cited by 44
Emerging nanotechnology for Alzheimer's disease: From detection to treatment
Song, N., Sun, S., Chen, K., Wang, Y., Wang, H., Meng, J., Guo, M., Zhang, X.-D., & Zhang, R. (2023) · Journal of Controlled Release · doi:10.1016/j.jconrel.2023.07.004 · Cited by 44
Metagenomic analysis characterizes stage-specific gut microbiota in Alzheimer’s disease
Jia, L., Ke, Y., Zhao, S., Liu, J., Luo, X., Cao, J., Liu, Y., Guo, Q., Chen, W., Chen, F., et al. (2025) · Molecular Psychiatry · doi:10.1038/s41380-025-02973-7 · Cited by 52
“Despite these advances, the practical application of these diagnostic tools is limited due to the high cost of positron emission tomography (PET) scanning and the invasiveness of fl uid-based technologies [14].”
Mass Spectrometry for Neurobiomarker Discovery: The Relevance of Post-Translational Modifications
Azevedo, R., Jacquemin, C., Villain, N., Fenaille, F., Lamari, F., & Bécher, F. (2022) · Cells · doi:10.3390/cells11081279 · Cited by 45
“, 18F-fluorodeoxyglucose positron emission tomography (PET), magnetic resonance imaging, and amyloid or tau PET) [4,5], and cerebrospinal fluid (CSF) biomarkers in the case of Alzheimer’s disease (AD) [6].”
BackgroundSelf-citation
Metadata
- Authors
- Dubois, B., Villain, N., Frisoni, G. B., Rabinovici, G. D., Sabbagh, M., Cappa, S., Bejanin, A., Bombois, S., Epelbaum, S., Teichmann, M., Habert, M.-O., Nordberg, A., Blennow, K., Galasko, D., Stern, Y., Rowe, C. C., Salloway, S., Schneider, L. S., Cummings, J. L., & Feldman, H. H.
- Affiliations
- Sorbonne Université (FR)
- University of Geneva (CH)
- University of California, San Francisco (US)
- Cleveland Clinic (US)
- Istituto Universitario di Studi Superiori di Pavia (IT)
- Universitat Autònoma de Barcelona (ES)
- Inserm (FR)
- Institut national de recherche en sciences et technologies du numérique (FR)
- Centre National de la Recherche Scientifique (FR)
- Karolinska University Hospital (SE)
- Sahlgrenska University Hospital (SE)
- University of California San Diego (US)
- Columbia University (US)
- The University of Melbourne (AU)
- Brown University (US)
- University of Southern California (US)
- Corresponding author
- Dubois, Bruno
- ORCID
- Dubois, Bruno
- Villain, Nicolas
- Frisoni, Giovanni B
- Rabinovici, Gil D
- Cappa, Stefano
- Bejanin, Alexandre
- Bombois, Stéphanie
- Epelbaum, Stéphane
- Teichmann, Marc
- Habert, Marie-Odile
- Nordberg, Agneta
- Blennow, Kaj
- Galasko, Douglas
- Stern, Yaakov
- Rowe, Christopher C
- Salloway, Stephen
- Schneider, Lon S
- Cummings, Jeffrey L
- Feldman, Howard H
- Venue
- The Lancet Neurology
- Publisher
- Elsevier BV
- Published
- 2021-06
- Volume
- 20
- Issue
- 6
- Pages
- 484-496
- ISSN
- 1474-4422 (ISSN-L)
- PMC
- PMC8339877
- OpenAlex
- W3159530258
- Semantic Scholar
- dc5f525087f24d7c6a95d667de138557d460fc7e
- Cited by
- 1,051
- References
- 119
- Citations by year
- 2026: 146 · 2025: 272 · 2024: 237 · 2023: 209 · 2022: 153 · 2021: 33
- FWCI
- 28.16
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (am, 171 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- The Lancet Neurology (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- HAL (submittedVersion, other-oa)
- HAL (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Oskar-Bordeaux (Universite de Bordeaux) (submittedVersion)
- Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
- Funders
- National Institutes of Health
- Merck
- Rainwater Charitable Foundation
- U.S. Department of Defense
- Novartis
- National Health and Medical Research Council
- National Institute on Aging
- Roche
- Eisai
- National Institute of General Medical Sciences
- Medtronic
- Adamas Pharmaceuticals
- Johnson and Johnson
- UCB Pharma
- Abbott Laboratories
- American College of Radiology
- Alzheimer's Drug Discovery Foundation
- ACADIA Pharmaceuticals
- Eli Lilly and Company
- Avid Radiopharmaceuticals
- Genentech
- Merz Pharmaceuticals
- Biogen
- Sorbonne Université
- Alzheimer's Association
- GE Healthcare
- National Institute of Neurological Disorders and Stroke
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Oncology › Cancer-related cognitive impairment studies
- Keywords
- Alzheimer's disease, diagnosis, biomarkers, amyloid-beta, tau pathology, NIA-AA criteria, cognitively unimpaired individuals, prodromal Alzheimer's disease, at-risk individuals, comorbidities, diagnostic recommendations
- MeSH terms
- Alzheimer Disease, Humans, Phenotype, Biomarkers, Amyloid beta-Peptides, tau Proteins, Disease Progression, Cognitive Dysfunction
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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