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. 2025 Jul 1;82(7):666-675.
doi: 10.1001/jamaneurol.2025.1100.

Evaluation of the Revised Criteria for Biological and Clinical Staging of Alzheimer Disease

Alexa Pichet Binette  1   2   3 , Ruben Smith  1   4 , Gemma Salvadó  1 , Pontus Tideman  1   4 , Isabelle Glans  1   4 , Danielle van Westen  5   6 , Colin Groot  7 , Rik Ossenkoppele  1   7 , Erik Stomrud  1   4 , Piero Parchi  8   9 , Henrik Zetterberg  10   11   12   13   14   15 , Kaj Blennow  10   11   16   17 , Niklas Mattsson-Carlgren  1   18   19 , Shorena Janelidze  1 , Sebastian Palmqvist  1   4 , Oskar Hansson  1 ; Alzheimer’s Disease Neuroimaging Initiative
Collaborators, Affiliations

Evaluation of the Revised Criteria for Biological and Clinical Staging of Alzheimer Disease

Alexa Pichet Binette et al. JAMA Neurol. .

Erratum in

  • Error in Figure Key.
    [No authors listed] [No authors listed] JAMA Neurol. 2025 Aug 11:e252990. doi: 10.1001/jamaneurol.2025.2990. Online ahead of print. JAMA Neurol. 2025. PMID: 40788635 Free PMC article. No abstract available.

Abstract

Importance: While clinical disease stages remained largely unchanged in the 2024 update of the Alzheimer disease (AD) criteria, tau-positron emission tomography (PET) was introduced as a core biomarker and its spatial extent was incorporated into the revised biological stages of the disease. It is important to consider both the clinical and the biological stages and understand their discrepancies.

Objective: To compare individuals who have discrepant biological and clinical stages with those who have congruent stages in terms of copathologies, comorbidities, and demographics.

Design, setting, and participants: Participants were from the Swedish BioFINDER-2 (inclusion from 2017 through 2023) and the Alzheimer's Disease Neuroimaging Initiative (ADNI) (inclusion from 2015 through 2024). BioFINDER-2 included a prospective population-based (cognitively normal [CN] older adults) and memory clinic-based cohort (participants with subjective cognitive impairment [SCD], mild cognitive impairment [MCI], and dementia). ADNI included a volunteer-based sample. All participants who were amyloid-β positive and had undergone tau-PET were included. In BioFINDER-2, 838 participants of a total of 1979 were included, and of 927 with tau-PET in ADNI, 380 were included.

Exposures: The clinical (CN to dementia) and biological (based on PET; initial [amyloid-β-positive only] to advanced [amyloid-β-positive, elevated, and widespread tau]) stages from the revised AD criteria.

Main outcomes and measures: Cross-sectional measures of neurodegeneration (cortical thickness, TAR DNA-binding protein 43 [TDP-43] imaging signature, neurofilament light [NfL]), α-synuclein cerebrospinal fluid status, plasma glial fibrillary acidic protein, white matter lesions, infarcts, microbleeds, comorbidities, and demographics.

Results: There were 838 BioFINDER-2 participants (mean age, 73.9 [SD, 7.3] years; 431 women [51%]; 407 men [49%]) and 380 ADNI participants (average age, 72.9 [SD, 7.0] years; 194 women [51%]; 186 mean [49%]) included. In BioFINDER-2, 37.7% of the sample had congruent biological and clinical stages (reference group), 51.3% had more advanced clinical impairment compared with their clinical stage (clinical > biological) and 11.0% had the opposite (biological > clinical). The main differences were between the reference group and the clinical > biological group: the latter participants were more often positive for α-synuclein pathology, had higher NfL levels, greater TDP-43-like atrophy, and higher burden of cerebral small vessel disease lesions (all false discovery rate P < .05). The only difference between the biological > clinical and the reference group was that the former had less neurodegeneration (thicker cortex; all false discovery rate P < .001). The main results were replicated in the independent ADNI cohort, where congruent 56.1% of participants had biological and clinical stages; 36.1% were in the category clinical > biological, and 7.9% in biological > clinical.

Conclusions and relevance: Copathologies play an important role in symptom severity in individuals who harbor less tau-tangle pathology than expected for their clinical impairment. These results highlight the importance of measuring non-AD biomarkers in patients with AD with worse cognitive impairment than expected based on their biological stage, which could impact the clinical diagnosis and prognosis.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Smith reported personal fees from Triolab and Hoffman La Roche outside the submitted work. Dr Salvadó reported grants from the Alzheimer’s Association Research Fellowship, Brightfocus Foundation, Alzheimerfonden, and Greta och Johan Kocks during the conduct of the study; grants from the European Union’s Horizon 2020 Research and Innovation Program under Marie Skłodowska-Curie action and personal fees from Springer and Adium outside the submitted work. Dr Ossenkoppele reported funding/support from Avid Radiopharmaceuticals, Janssen, Roche, Quanterix, and Optina Diagnostics, has given lectures in symposia sponsored by GE Healthcare, received speaker fees from Springer, is an advisory board member for Asceneuron, and a steering committee member for Biogen and Bristol Myers Squibb. All the aforementioned have been paid to his institutions. Dr Parchi reported grants from Ministero della Salute and Ministero della Ricerca Scientifica outside the submitted work. Dr Zetterberg reported personal fees from AbbVie, Acumen, Alector, Alzinova, ALZpath, Amylyx, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, Enigma, LabCorp, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Quanterix, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave Scientific advisory boards, personal fees from Alzecure, BioArctic, Biogen, Cellectricon, Fujirebio, Lilly, Novo Nordisk, Roche, and WebMD, and personal fees from Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (cofounder and stockholder) outside the submitted work. Dr Blennow reported having served as a consultant and at advisory boards for AbbVie, AC Immune, ALZPath, AriBio, Beckman-Coulter, BioArctic, Biogen, Eisai, Lilly, Moleac Pte, Neurimmune, Novartis, Ono Pharma, Prothena, Quanterix, Roche Diagnostics, Sanofi, and Siemens Healthineers; has served on data monitoring committees for Julius Clinical and Novartis; has given lectures, produced educational materials, and participated in educational programs for AC Immune, Biogen, Celdara Medical, Eisai, and Roche Diagnostics; and is a cofounder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program, outside the submitted work. Dr Mattsson-Carlgren reported personal fees from Biogen, Owkin, and Merck outside the submitted work. Dr Palmqvist reported acquiring research support (for the institution) from Avid and ADDF. In the past 2 years, he has received consultancy/speaker fees from Bioartic, Biogen, Esai, Eli Lilly, Novo Nordisk, and Roche. Dr Hansson has part-time employment from Eli Lilly outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Tau–Positron Emission Tomography Standardized Uptake Value Ratio (SUVR) in the 3 Regions of Interest in BioFINDER-2
The amyloid-β positive group (Aβ+) corresponds to the samples used for the biological stages. The amyloid-β negative group (Aβ−) (n = 1042) is shown to help better understand the cutoffs applied in each cohort. In all panels, the dashed lines represent the cutoff used to determine positivity in each region. MTL indicates medial temporal lobe.
Figure 2.
Figure 2.. Biological vs Clinical Staging in BioFINDER-2
A, Distribution of participants based on the biological and clinical stages. The numbers and percentages reported are based on the total number of participants. The bar graph shows the overall proportion in the 3 main categories of participants for comparisons. B, Proportion of the 4 biological stages for each of the clinical stages. C, Proportion of the 4 clinical stages for each of the biological stages. In all panels, the black outline represents the cases where the biological and clinical stages are concordant. A+T2- indicates amyloid-β positive and tau-positron emission tomography negative; A+T2-HIGH+, amyloid-β positive positive and tau-positron emission tomography positive in the neocortex; A+T2-MOD+, amyloid-β positive and tau-positron emission tomography positive in the temporal meta region of interest; A+T2-MTL+, amyloid-β positive and tau-positron emission tomography positive in the medial temporal lobe; biological > clinical, had more advanced biological impairment compared with their clinical stage; clinical > biological, had more advanced clinical impairment compared with their biological stage; CN, cognitively normal; MCI, mild cognitive impairment; SCD, subjective cognitive impairment.
Figure 3.
Figure 3.. Key Differences Between the 3 Groups, Based on the Biological and Clinical Staging
Continuous (A) and dichotomous (B) variables with significant differences compared with the reference group in BioFINDER-2. In panel A, the box limits represent the first and third quartile and the line in the box is the median. All comparisons were done relative with the reference group, with all false discovery rate (FDR) P < .05 considered as significantly different in post hoc tests. The all P FDR value is reported at the top of each graph, from 2-sided t tests for continuous measures and from Fisher tests for binary variables. biological > clinical indicates had more advanced biological impairment compared with their clinical stage; clinical > biological, had more advanced clinical impairment compared with their biological stage; ICV, intracranial volume; Nfl, neurofilament light; WMH, white matter hyperintensities.
Figure 4.
Figure 4.. Biological and Clinical Staging Correspondence Split into More Granular Groups
The BioFINDER-2 sample was split into 5 groups based on the (dis)congruence of biological and clinical stages, compared with 3 groups, as shown in Figure 1. The bar graph shows the overall proportion in the 5 categories of participants for comparisons. The black outline represents the cases where the biological and clinical stages are concordant. All statistical comparisons and descriptions of the 5 groups are shown in eTable 7 in Supplement 1. A+T2- indicates amyloid-β positive and tau-positron emission tomography negative; A+T2-HIGH+, amyloid-β positive positive and tau-positron emission tomography positive in the neocortex; A+T2-MOD+, amyloid-β positive and tau-positron emission tomography positive in the temporal meta region of interest; A+T2-MTL+, amyloid-β positive and tau-positron emission tomography positive in the medial temporal lobe; biological > clinical, had more advanced biological impairment compared with their clinical stage; clinical > biological, had more advanced clinical impairment compared with their biological stage.
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