The IWG criteria are put forward as strongly contrasting the Alzheimer Association (AA) Revised Criteria. We feel that this contrast is made larger than it actually is. Similar to the IWG, the AA Revised criteria recommend diagnosis of AD only in the symptomatic stages, and advise against AD diagnosis in presymptomatic individuals.
As such, we feel that whilst the diagnosis of preclinical AD is put forward as a major point of divergence between the two recommendations, similarities are in fact larger. Both groups define AD biologically as a driving theoretical construct, and underscore the long preclinical phase of biological changes due to AD before symptoms become apparent. The recognition of the long preclinical phase is paramount to tackle the disease before irreversible damage has occurred.
The AA criteria are not meant as clinical guidelines on how to use the biomarkers in clinical practice. Considering the work that has to be done to move to clinical guidelines, for plasma biomarkers the AA has started a working group, including authors of both IWG and AA criteria, to perform a meta-analysis of available literature and define a draft clinical guidance on use of plasma biomarkers in symptomatic individuals.
One of the arguments behind the IWG recommendations to be careful with the use of biomarkers in cognitively unimpaired individuals is that many people with amyloid positivity at postmortem did not experience cognitive decline during their lives. However, there is limited literature to support this statement, because there are few studies that compared in vivo clinical and biomarker results with tissue autopsy results obtained after only a short time lag. In addition, postmortem studies often suffer from survival bias. Importantly, there are very few postmortem AD studies in individuals at their ages where biomarkers have their strongest relevance, i.e., individuals younger than 75. Cognitively healthy individuals in such postmortem studies where people did die relatively young, before clinical dementia has started: another bias. This is an issue we cannot easily resolve due to the long time lag between build-up of pathology and clinical symptoms in AD. This warrants new study designs, large enough to evaluate sources of bias, and relying on approved in vivo methods for detection of AD pathology, i.e., amyloid and tau PET, and CSF analysis.
Given that preclinical AD may have a disease course of at least 20 years and that the first amyloid PET tracer came to the market only 20 years ago, it is evident that it is not yet possible to reliably answer the question how many individuals remain asymptomatic in the face of AD pathology. New longitudinal studies with biomarker measurements at baseline and sufficient duration of follow-up are needed to determine how many amyloid positive individuals remain cognitively unimpaired in the long run.
The IWG highlights the crucial distinction between three categories: 1) asymptomatic at-risk individuals, who have an increased yet still low probability of developing AD; 2) presymptomatic individuals, who are at a very high risk of developing the disease; and 3) individuals with diagnosed AD, characterized by the emergence of specific symptoms (Dubois et al., 2024).
The continuum proposed by Cliff Jack and colleagues primarily applies to individuals who progress to dementia. It overlooks a crucial question: How many do not reach that stage (Jack et al., 2010)? The amyloid cascade suggests a deterministic link between amyloid aggregates and dementia, yet it has significant limitations in sporadic AD (Frisoni et al., 2022). Research increasingly indicates a low risk of progression among asymptomatic “A+T-“ individuals in longitudinal cohorts (Ossenkoppele et al., 2022; Strikwerda-Brown et al., 2022), with studies that account for mortality revealing a lifetime risk of developing AD dementia ranging from 5 percent to 31 percent (Brookmeyer and Abdalla, 2018). Our reanalysis of the National Alzheimer’s Coordinating Center (NACC) dataset found that two-thirds of cognitively unimpaired, amyloid-positive individuals globally show minimal AD neuropathological changes . As a result (Moscoso and Villain, 2024), nearly half of the amyloid-positive population meets the revised Alzheimer’s Association definition of AD while remaining asymptomatic and exhibiting a low lifetime risk of dementia.
AD is a major public health issue, a “devastating” and “fatal” disease, as we all claim. Is that still the case when considering the AD definition proposed by the Alzheimer Association Workgroup? Redefining AD as a purely biological construct risks diluting its gravity and leads to misconceptions among stakeholders, particularly the belief that a biological diagnosis implies a poor prognosis for individuals.
The IWG's proposal to categorize asymptomatic low-risk conditions as a separate nosological entity could help mitigate these misunderstandings. This approach mirrors practices in other medical fields, where biological definitions coexist with distinct categories when clinical outcomes significantly differ between asymptomatic and symptomatic individuals. For example, in oncology, there are asymptomatic precancerous conditions like monoclonal gammopathy of undetermined significance (MGUS) and "smoldering" multiple myeloma. Similar distinctions exist in diabetes (impaired glucose tolerance vs. diabetes), infectious diseases (latent tuberculosis infection vs. active tuberculosis), genetic disorders (reduced penetrance Huntington vs. Huntington's disease), etc. (Villain and Planche, 2024).
Differentiating between discrete clinical-biological categories and a biological continuum has profound implications for clinical care and research. In a clinical setting, distinguishing between asymptomatic at-risk individuals and those with AD based on cognitive impairment is essential for implementing tailored clinical care pathways. Traditional memory clinics address diagnostic assessments, disease disclosure, and therapeutic management for individuals with cognitive impairment and typically poor outcomes. Conversely, emerging Brain Health Services cater to cognitively unimpaired individuals by emphasizing risk assessment, effective communication of risk, and personalized prevention strategies that address but are not limited to asymptomatic proteinopathies (Frisoni et al., 2023).
While these two care pathways are interrelated, they allow healthcare providers to tailor their approach to the specific needs of each population, focusing on critical clinical prognosis. here In a research setting, subgrouping asymptomatic individuals based on risk will effectively identify individuals of interest, significantly enhancing the development and implementation of targeted interventions within the heterogeneous preclinical AD population. Identifying at-risk individuals facilitates the establishment of diverse, multimodal research initiatives. It allows for nuanced risk assessments and the design of tailored clinical trials that emphasize intervention tolerance and practicality. It is crucial to address the unique needs of these individuals to conduct appropriate risk-benefit analyses in trial designs and evaluate outcomes effectively.
On the other hand, the poor prognosis in presymptomatic individuals underlines the necessity for a more proactive therapeutic strategy akin to that applied in symptomatic AD. This group might be integrated into existing clinical trials targeting early stage AD, as we anticipate that certain pharmacological interventions will yield greater benefits when administered during the presymptomatic phases of the disease.
We foresee the necessity for further refinement of the IWG framework concerning the presymptomatic AD category. This refinement should address the defined risk levels associated with progression and establish the minimal evidentiary standards for validating this categorization. Although preliminary evidence from small, convenience-based cohorts suggests that neocortical Tau PET imaging may meet these criteria, we expect that future collaborative efforts to aggregate data from population-based cohorts will enhance the validation of these findings. Additionally, exploring other high-risk categories, such as individuals with very high amyloid burden APOE4 homozygote carriers, warrants further investigation.
We practice medicine based on real patients and their prognosis data. While life expectancy may not reach 150 years in the near future, the evidence consistently highlights the low risk of AD symptoms in asymptomatic “A+T-“ individuals. Let’s embrace this data and reimagine our definition of the disease by exploring distinct disease categories, centered on the patients’ trajectories rather than a simple continuum. This approach is vital for advancing research and clinical strategies to treat presymptomatic phases and prevent AD.
References:
Dubois B, Villain N, Schneider L, Fox N, Campbell N, Galasko D, Kivipelto M, Jessen F, Hanseeuw B, Boada M, Barkhof F, Nordberg A, Froelich L, Waldemar G, Frederiksen KS, Padovani A, Planche V, Rowe C, Bejanin A, Ibanez A, Cappa S, Caramelli P, Nitrini R, Allegri R, Slachevsky A, de Souza LC, Bozoki A, Widera E, Blennow K, Ritchie C, Agronin M, Lopera F, Delano-Wood L, Bombois S, Levy R, Thambisetty M, Georges J, Jones DT, Lavretsky H, Schott J, Gatchel J, Swantek S, Newhouse P, Feldman HH, Frisoni GB.
Alzheimer Disease as a Clinical-Biological Construct-An International Working Group Recommendation.
JAMA Neurol. 2024 Dec 1;81(12):1304-1311.
PubMed.
Jack CR, Knopman DS, Jagust WJ, Shaw LM, Aisen PS, Weiner MW, Petersen RC, Trojanowski JQ.
Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade.
Lancet Neurol. 2010 Jan;9(1):119-28.
PubMed.
Frisoni GB, Altomare D, Thal DR, Ribaldi F, van der Kant R, Ossenkoppele R, Blennow K, Cummings J, van Duijn C, Nilsson PM, Dietrich PY, Scheltens P, Dubois B.
The probabilistic model of Alzheimer disease: the amyloid hypothesis revised.
Nat Rev Neurosci. 2022 Jan;23(1):53-66. Epub 2021 Nov 23
PubMed.
Ossenkoppele R, Pichet Binette A, Groot C, Smith R, Strandberg O, Palmqvist S, Stomrud E, Tideman P, Ohlsson T, Jögi J, Johnson K, Sperling R, Dore V, Masters CL, Rowe C, Visser D, van Berckel BN, van der Flier WM, Baker S, Jagust WJ, Wiste HJ, Petersen RC, Jack CR Jr, Hansson O.
Amyloid and tau PET-positive cognitively unimpaired individuals are at high risk for future cognitive decline.
Nat Med. 2022 Nov;28(11):2381-2387. Epub 2022 Nov 10
PubMed.
Strikwerda-Brown C, Hobbs DA, Gonneaud J, St-Onge F, Binette AP, Ozlen H, Provost K, Soucy JP, Buckley RF, Benzinger TL, Morris JC, Villemagne VL, Doré V, Sperling RA, Johnson KA, Rowe CC, Gordon BA, Poirier J, Breitner JC, Villeneuve S, PREVENT-AD, HABS, and AIBL Research Groups.
Association of Elevated Amyloid and Tau Positron Emission Tomography Signal With Near-Term Development of Alzheimer Disease Symptoms in Older Adults Without Cognitive Impairment.
JAMA Neurol. 2022 Oct 1;79(10):975-985.
PubMed.
Brookmeyer R, Abdalla N.
Estimation of lifetime risks of Alzheimer's disease dementia using biomarkers for preclinical disease.
Alzheimers Dement. 2018 Aug;14(8):981-988. Epub 2018 May 22
PubMed.
Moscoso A, Villain N.
2024 AA criteria for Alzheimer's disease diagnosis: Mainly anchored at Aβ not tau.
Alzheimers Dement. 2024 Dec;20(12):9079-9081. Epub 2024 Oct 29
PubMed.
Villain N, Planche V.
Disentangling clinical and biological trajectories of neurodegenerative diseases.
Nat Rev Neurol. 2024 Dec;20(12):693-694.
PubMed.
Frisoni GB, Altomare D, Ribaldi F, Villain N, Brayne C, Mukadam N, Abramowicz M, Barkhof F, Berthier M, Bieler-Aeschlimann M, Blennow K, Brioschi Guevara A, Carrera E, Chételat G, Csajka C, Demonet JF, Dodich A, Garibotto V, Georges J, Hurst S, Jessen F, Kivipelto M, Llewellyn DJ, McWhirter L, Milne R, Minguillón C, Miniussi C, Molinuevo JL, Nilsson PM, Noyce A, Ranson JM, Grau-Rivera O, Schott JM, Solomon A, Stephen R, van der Flier W, van Duijn C, Vellas B, Visser LN, Cummings JL, Scheltens P, Ritchie C, Dubois B.
Dementia prevention in memory clinics: recommendations from the European task force for brain health services.
Lancet Reg Health Eur. 2023 Mar;26:100576. Epub 2023 Jan 31
PubMed.
Of note, 20 out of the 24 possible binomial biological-clinical stages proposed by the AA are contained in the IWG definition of AD, while the other four are considered at risk of AD by the IWG, see my illustration https://imgur.com/a/HtPlndk. Aside from this divergence, both documents underscore the importance of identifying the risk of clinical progression carried by each biological stage / biomarker profile. As commented above by colleagues, that is the crucial missing piece to better inform this and future debates.
Comments
VU University Medical Center
Vrije Universiteit Amsterdam
VU University Medical Center
The IWG criteria are put forward as strongly contrasting the Alzheimer Association (AA) Revised Criteria. We feel that this contrast is made larger than it actually is. Similar to the IWG, the AA Revised criteria recommend diagnosis of AD only in the symptomatic stages, and advise against AD diagnosis in presymptomatic individuals.
As such, we feel that whilst the diagnosis of preclinical AD is put forward as a major point of divergence between the two recommendations, similarities are in fact larger. Both groups define AD biologically as a driving theoretical construct, and underscore the long preclinical phase of biological changes due to AD before symptoms become apparent. The recognition of the long preclinical phase is paramount to tackle the disease before irreversible damage has occurred.
The AA criteria are not meant as clinical guidelines on how to use the biomarkers in clinical practice. Considering the work that has to be done to move to clinical guidelines, for plasma biomarkers the AA has started a working group, including authors of both IWG and AA criteria, to perform a meta-analysis of available literature and define a draft clinical guidance on use of plasma biomarkers in symptomatic individuals.
One of the arguments behind the IWG recommendations to be careful with the use of biomarkers in cognitively unimpaired individuals is that many people with amyloid positivity at postmortem did not experience cognitive decline during their lives. However, there is limited literature to support this statement, because there are few studies that compared in vivo clinical and biomarker results with tissue autopsy results obtained after only a short time lag. In addition, postmortem studies often suffer from survival bias. Importantly, there are very few postmortem AD studies in individuals at their ages where biomarkers have their strongest relevance, i.e., individuals younger than 75. Cognitively healthy individuals in such postmortem studies where people did die relatively young, before clinical dementia has started: another bias. This is an issue we cannot easily resolve due to the long time lag between build-up of pathology and clinical symptoms in AD. This warrants new study designs, large enough to evaluate sources of bias, and relying on approved in vivo methods for detection of AD pathology, i.e., amyloid and tau PET, and CSF analysis.
Given that preclinical AD may have a disease course of at least 20 years and that the first amyloid PET tracer came to the market only 20 years ago, it is evident that it is not yet possible to reliably answer the question how many individuals remain asymptomatic in the face of AD pathology. New longitudinal studies with biomarker measurements at baseline and sufficient duration of follow-up are needed to determine how many amyloid positive individuals remain cognitively unimpaired in the long run.
View all comments by Inge VerberkSorbonne University - APHP - Pitié-Salpêtrière Hospital
The IWG highlights the crucial distinction between three categories: 1) asymptomatic at-risk individuals, who have an increased yet still low probability of developing AD; 2) presymptomatic individuals, who are at a very high risk of developing the disease; and 3) individuals with diagnosed AD, characterized by the emergence of specific symptoms (Dubois et al., 2024).
The continuum proposed by Cliff Jack and colleagues primarily applies to individuals who progress to dementia. It overlooks a crucial question: How many do not reach that stage (Jack et al., 2010)? The amyloid cascade suggests a deterministic link between amyloid aggregates and dementia, yet it has significant limitations in sporadic AD (Frisoni et al., 2022). Research increasingly indicates a low risk of progression among asymptomatic “A+T-“ individuals in longitudinal cohorts (Ossenkoppele et al., 2022; Strikwerda-Brown et al., 2022), with studies that account for mortality revealing a lifetime risk of developing AD dementia ranging from 5 percent to 31 percent (Brookmeyer and Abdalla, 2018). Our reanalysis of the National Alzheimer’s Coordinating Center (NACC) dataset found that two-thirds of cognitively unimpaired, amyloid-positive individuals globally show minimal AD neuropathological changes . As a result (Moscoso and Villain, 2024), nearly half of the amyloid-positive population meets the revised Alzheimer’s Association definition of AD while remaining asymptomatic and exhibiting a low lifetime risk of dementia.
AD is a major public health issue, a “devastating” and “fatal” disease, as we all claim. Is that still the case when considering the AD definition proposed by the Alzheimer Association Workgroup? Redefining AD as a purely biological construct risks diluting its gravity and leads to misconceptions among stakeholders, particularly the belief that a biological diagnosis implies a poor prognosis for individuals.
The IWG's proposal to categorize asymptomatic low-risk conditions as a separate nosological entity could help mitigate these misunderstandings. This approach mirrors practices in other medical fields, where biological definitions coexist with distinct categories when clinical outcomes significantly differ between asymptomatic and symptomatic individuals. For example, in oncology, there are asymptomatic precancerous conditions like monoclonal gammopathy of undetermined significance (MGUS) and "smoldering" multiple myeloma. Similar distinctions exist in diabetes (impaired glucose tolerance vs. diabetes), infectious diseases (latent tuberculosis infection vs. active tuberculosis), genetic disorders (reduced penetrance Huntington vs. Huntington's disease), etc. (Villain and Planche, 2024).
Differentiating between discrete clinical-biological categories and a biological continuum has profound implications for clinical care and research. In a clinical setting, distinguishing between asymptomatic at-risk individuals and those with AD based on cognitive impairment is essential for implementing tailored clinical care pathways. Traditional memory clinics address diagnostic assessments, disease disclosure, and therapeutic management for individuals with cognitive impairment and typically poor outcomes. Conversely, emerging Brain Health Services cater to cognitively unimpaired individuals by emphasizing risk assessment, effective communication of risk, and personalized prevention strategies that address but are not limited to asymptomatic proteinopathies (Frisoni et al., 2023).
While these two care pathways are interrelated, they allow healthcare providers to tailor their approach to the specific needs of each population, focusing on critical clinical prognosis. here In a research setting, subgrouping asymptomatic individuals based on risk will effectively identify individuals of interest, significantly enhancing the development and implementation of targeted interventions within the heterogeneous preclinical AD population. Identifying at-risk individuals facilitates the establishment of diverse, multimodal research initiatives. It allows for nuanced risk assessments and the design of tailored clinical trials that emphasize intervention tolerance and practicality. It is crucial to address the unique needs of these individuals to conduct appropriate risk-benefit analyses in trial designs and evaluate outcomes effectively.
On the other hand, the poor prognosis in presymptomatic individuals underlines the necessity for a more proactive therapeutic strategy akin to that applied in symptomatic AD. This group might be integrated into existing clinical trials targeting early stage AD, as we anticipate that certain pharmacological interventions will yield greater benefits when administered during the presymptomatic phases of the disease.
We foresee the necessity for further refinement of the IWG framework concerning the presymptomatic AD category. This refinement should address the defined risk levels associated with progression and establish the minimal evidentiary standards for validating this categorization. Although preliminary evidence from small, convenience-based cohorts suggests that neocortical Tau PET imaging may meet these criteria, we expect that future collaborative efforts to aggregate data from population-based cohorts will enhance the validation of these findings. Additionally, exploring other high-risk categories, such as individuals with very high amyloid burden APOE4 homozygote carriers, warrants further investigation.
We practice medicine based on real patients and their prognosis data. While life expectancy may not reach 150 years in the near future, the evidence consistently highlights the low risk of AD symptoms in asymptomatic “A+T-“ individuals. Let’s embrace this data and reimagine our definition of the disease by exploring distinct disease categories, centered on the patients’ trajectories rather than a simple continuum. This approach is vital for advancing research and clinical strategies to treat presymptomatic phases and prevent AD.
References:
Dubois B, Villain N, Schneider L, Fox N, Campbell N, Galasko D, Kivipelto M, Jessen F, Hanseeuw B, Boada M, Barkhof F, Nordberg A, Froelich L, Waldemar G, Frederiksen KS, Padovani A, Planche V, Rowe C, Bejanin A, Ibanez A, Cappa S, Caramelli P, Nitrini R, Allegri R, Slachevsky A, de Souza LC, Bozoki A, Widera E, Blennow K, Ritchie C, Agronin M, Lopera F, Delano-Wood L, Bombois S, Levy R, Thambisetty M, Georges J, Jones DT, Lavretsky H, Schott J, Gatchel J, Swantek S, Newhouse P, Feldman HH, Frisoni GB. Alzheimer Disease as a Clinical-Biological Construct-An International Working Group Recommendation. JAMA Neurol. 2024 Dec 1;81(12):1304-1311. PubMed.
Jack CR, Knopman DS, Jagust WJ, Shaw LM, Aisen PS, Weiner MW, Petersen RC, Trojanowski JQ. Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade. Lancet Neurol. 2010 Jan;9(1):119-28. PubMed.
Frisoni GB, Altomare D, Thal DR, Ribaldi F, van der Kant R, Ossenkoppele R, Blennow K, Cummings J, van Duijn C, Nilsson PM, Dietrich PY, Scheltens P, Dubois B. The probabilistic model of Alzheimer disease: the amyloid hypothesis revised. Nat Rev Neurosci. 2022 Jan;23(1):53-66. Epub 2021 Nov 23 PubMed.
Ossenkoppele R, Pichet Binette A, Groot C, Smith R, Strandberg O, Palmqvist S, Stomrud E, Tideman P, Ohlsson T, Jögi J, Johnson K, Sperling R, Dore V, Masters CL, Rowe C, Visser D, van Berckel BN, van der Flier WM, Baker S, Jagust WJ, Wiste HJ, Petersen RC, Jack CR Jr, Hansson O. Amyloid and tau PET-positive cognitively unimpaired individuals are at high risk for future cognitive decline. Nat Med. 2022 Nov;28(11):2381-2387. Epub 2022 Nov 10 PubMed.
Strikwerda-Brown C, Hobbs DA, Gonneaud J, St-Onge F, Binette AP, Ozlen H, Provost K, Soucy JP, Buckley RF, Benzinger TL, Morris JC, Villemagne VL, Doré V, Sperling RA, Johnson KA, Rowe CC, Gordon BA, Poirier J, Breitner JC, Villeneuve S, PREVENT-AD, HABS, and AIBL Research Groups. Association of Elevated Amyloid and Tau Positron Emission Tomography Signal With Near-Term Development of Alzheimer Disease Symptoms in Older Adults Without Cognitive Impairment. JAMA Neurol. 2022 Oct 1;79(10):975-985. PubMed.
Brookmeyer R, Abdalla N. Estimation of lifetime risks of Alzheimer's disease dementia using biomarkers for preclinical disease. Alzheimers Dement. 2018 Aug;14(8):981-988. Epub 2018 May 22 PubMed.
Moscoso A, Villain N. 2024 AA criteria for Alzheimer's disease diagnosis: Mainly anchored at Aβ not tau. Alzheimers Dement. 2024 Dec;20(12):9079-9081. Epub 2024 Oct 29 PubMed.
Villain N, Planche V. Disentangling clinical and biological trajectories of neurodegenerative diseases. Nat Rev Neurol. 2024 Dec;20(12):693-694. PubMed.
Frisoni GB, Altomare D, Ribaldi F, Villain N, Brayne C, Mukadam N, Abramowicz M, Barkhof F, Berthier M, Bieler-Aeschlimann M, Blennow K, Brioschi Guevara A, Carrera E, Chételat G, Csajka C, Demonet JF, Dodich A, Garibotto V, Georges J, Hurst S, Jessen F, Kivipelto M, Llewellyn DJ, McWhirter L, Milne R, Minguillón C, Miniussi C, Molinuevo JL, Nilsson PM, Noyce A, Ranson JM, Grau-Rivera O, Schott JM, Solomon A, Stephen R, van der Flier W, van Duijn C, Vellas B, Visser LN, Cummings JL, Scheltens P, Ritchie C, Dubois B. Dementia prevention in memory clinics: recommendations from the European task force for brain health services. Lancet Reg Health Eur. 2023 Mar;26:100576. Epub 2023 Jan 31 PubMed.
View all comments by Nicolas VillainUniversity of Pittsburgh
Of note, 20 out of the 24 possible binomial biological-clinical stages proposed by the AA are contained in the IWG definition of AD, while the other four are considered at risk of AD by the IWG, see my illustration https://imgur.com/a/HtPlndk. Aside from this divergence, both documents underscore the importance of identifying the risk of clinical progression carried by each biological stage / biomarker profile. As commented above by colleagues, that is the crucial missing piece to better inform this and future debates.
View all comments by Marina Scop MedeirosMake a Comment
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