'Presymptomatic AD' or 'Asymptomatic at Risk'? Dx Criteria Disagree
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As diagnostic criteria for Alzheimer’s disease are being refined, the U.S. and Europe have taken different paths. Broadly speaking, leading clinicians in the U.S. use Alzheimer’s Association criteria, while those in Europe hew to recommendations from the International Working Group. Both sides agree AD should be defined as a biological disease based on its pathology. Both have been slowly working toward this goal for nearly 20 years, issuing periodic iterations of updated criteria that incorporate new biological evidence every time.
- Association criteria label unimpaired people with AD biomarkers as having presymptomatic AD.
- IWG criteria calls them asymptomatic at-risk.
- Both groups agree that clinicians should not test for biomarkers in asymptomatic people.
Where they still differ is in how to label cognitively unimpaired people who have biomarker evidence of AD. The Association’s criteria consider these people to have preclinical AD, full stop. The IWG approach calls them “asymptomatic at-risk.” Both groups have some members from the “other” continent, as well.
At the Clinical Trials on Alzheimer’s Disease conference, held last month in Madrid, Howard Feldman of the University of California, San Diego, laid out IWG’s reasoning. Because many older people with amyloid plaques in their brains will not develop symptoms of AD, diagnosing them as such could cause them unnecessary distress and use up scarce medical resources, Feldman said. Labeling such people as at-risk instead would enable clinicians to discuss preventative measures with them, without pathologizing their condition. “We’re providing an alternative viewpoint to that of the Alzheimer’s Association working group,” he noted.
Some scientists in Madrid pushed back on this approach, arguing that people with Alzheimer’s pathology already have the biological disease. They noted that because current Association criteria do not recommend biomarker testing in people without symptoms, defining biomarker positivity as Alzheimer’s disease does not affect clinical practice, but is important conceptually.
Both viewpoints were featured in the November 1 JAMA Neurology, in articles penned by Bruno Dubois of University Salpêtrière Hospital in Paris and colleagues, and Ron Petersen of the Mayo Clinic in Rochester, Minnesota, and colleagues, respectively. Petersen told Alzforum he sees the difference between the positions as largely semantic at this point, since the groups agree on patient care.
Patients in Waiting? Worldwide, only a quarter of people with amyloid plaques are estimated to be cognitively impaired (medium and dark blue). [Courtesy of Howard Feldman.]
Spearheaded by Dubois and Feldman, the IWG was the first to put AD diagnosis on a biological footing, by recommending bolstering the clinical evaluation with supportive biomarkers (Jul 2007 news). The U.S. National Institute on Aging, with the Alzheimer’s Association, issued its own first stab soon after (Apr 2011 news). It took a further step in 2018, defining the disease solely by biomarkers, though only for research purposes (Apr 2018 news; Nov 2018 conference news). This led IWG to emphasize that AD clinical diagnosis should be restricted to people with symptoms (Dubois et al., 2021).
The latest rewrite of the Association criteria agrees with this approach in practice, but not in principle. It again defines AD as positivity on amyloid and tau biomarkers (Aug 2023 conference news; Nov 2023 conference news). The IWG includes more clinicians who see patients regularly than does the Association’s working group, which includes more clinician-researchers focused on biomarker development.
In Madrid, Feldman argued that biomarkers are imperfect predictors of disease progression. He pointed to a study from Rik Ossenkoppele of Lund University, Sweden, that found that people positive for amyloid, but not tau, had little risk of progressing over the next three years, while those who were A+T+ had a 50 percent risk (Ossenkoppele et al., 2022). The likelihood that an A+T+ person will become cognitively impaired over three years varies widely between studies, ranging from 33 to 88 percent, according to a meta-analysis (Strikwerda-Brown et al., 2022). “Biomarkers are probabilistic, not deterministic,” Feldman concluded. “There must be a clinical context for biomarker interpretation.”
Feldman acknowledged that for certain groups with a very high risk, it would be appropriate to diagnose AD in asymptomatic patients. These include people with an autosomal-dominant gene or Down’s syndrome. They would be labeled as having presymptomatic AD, rather than being asymptomatic at-risk, Feldman said.
Reisa Sperling of Brigham and Women’s Hospital, Boston, questioned why someone with a mutation but no biomarker evidence could be labeled as presymptomatic, while another person with biomarker evidence of AD would only be considered at risk. “Disease is in the brain, and you can’t simultaneously have the disease and be at risk for the disease,” she said.
Feldman said that as biomarker predictions become more accurate, the IWG’s definition of presymptomatic disease could expand to include certain biomarker signs. “It’s possible that neocortical tau will reach that deterministic threshold, but we’re not there yet,” Feldman said.
Why is the distinction between presymptomatic disease versus asymptomatic risk important? Feldman said that of the 400 million people worldwide estimated to have abnormal AD biomarkers, only a quarter are cognitively impaired (image above). “Diagnosing based on biomarkers could create many ‘patients in waiting’ who will never develop dementia,” he said.
Gil Rabinovici at the University of California, San Francisco, raised another concern, noting that amyloid immunotherapy is more effective at earlier disease stages. Once people are symptomatic, they have extensive pathology. “There’s the potential that by the time we diagnose the disease, the pathology will be so widespread that any intervention will be less effective,” he said in Madrid. Feldman agreed that if the secondary prevention trials now underway show treatment benefits in asymptomatic people, then the diagnostic calculus will shift. “We expect that will be a game changer,” he said. In other words, this difference between criteria may become moot once preventative treatments are available.
In the meantime, some clinicians favor the IWG approach, even among biomarker and preventive therapy enthusiasts. “Upon much consideration, we came down on [the IWG criteria] being better for our patients at this point,” Jonathan Schott of Queen Square Institute of Neurology, London, told Alzforum.—Madolyn Bowman Rogers
References
News Citations
- AD Diagnosis: Time for Biomarkers to Weigh In?
- Revised Diagnostic Criteria for Alzheimer’s Are Published
- New Definition of Alzheimer’s Hinges on Biology, Not Symptoms
- How Does The NIA-AA Framework Measure Up Against Real Data?
- Revised Again: Alzheimer's Diagnostic Criteria Get Another Makeover
- New Alzheimer’s Diagnostic Criteria Remain ‘Research Only’
Paper Citations
- Dubois B, Villain N, Frisoni GB, Rabinovici GD, Sabbagh M, Cappa S, Bejanin A, Bombois S, Epelbaum S, Teichmann M, Habert MO, Nordberg A, Blennow K, Galasko D, Stern Y, Rowe CC, Salloway S, Schneider LS, Cummings JL, Feldman HH. Clinical diagnosis of Alzheimer's disease: recommendations of the International Working Group. Lancet Neurol. 2021 Jun;20(6):484-496. Epub 2021 Apr 29 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.
Other Citations
Further Reading
News
Primary Papers
- 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.
- Petersen RC, Mormino E, Schneider JA. Alzheimer Disease-What's in a Name?. JAMA Neurol. 2024 Dec 1;81(12):1245-1246. PubMed.
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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.
Sorbonne 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.
University 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.
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