Plasma Biomarker Strategy for Selecting Patients With Alzheimer Disease for Antiamyloid Immunotherapies
Open accessAbstract
Importance: Antiamyloid immunotherapies against Alzheimer disease (AD) are emerging. Scalable, cost-effective tools will be needed to identify amyloid β (Aβ)–positive patients without an advanced stage of tau pathology who are most likely to benefit from these therapies. Blood-based biomarkers might reduce the need to use cerebrospinal fluid (CSF) or positron emission tomography (PET) for this. Objective: To evaluate plasma biomarkers for identifying Aβ positivity and stage of tau accumulation. Design, Setting, and Participants: The cohort study (BioFINDER-2) was a prospective memory-clinic and population-based study. Participants with cognitive concerns were recruited from 2017 to 2022 and divided into a training set (80% of the data) and test set (20%). Exposure: Baseline values for plasma phosphorylated tau 181 (p-tau181), p-tau217, p-tau231, N-terminal tau, glial fibrillary acidic protein, and neurofilament light chain. Main Outcomes and Measures: Performance to classify participants by Aβ status (defined by Aβ-PET or CSF Aβ42/40) and tau status (tau PET). Number of hypothetically saved PET scans in a plasma biomarker–guided workflow. Results: Of a total 912 participants, there were 499 males (54.7%) and 413 females (45.3%), and the mean (SD) age was 71.1 (8.49) years. Among the biomarkers, plasma p-tau217 was most strongly associated with Aβ positivity (test-set area under the receiver operating characteristic curve [AUC] = 0.94; 95% CI, 0.90-0.97). A 2–cut-point procedure was evaluated, where only participants with ambiguous plasma p-tau217 values (17.1% of the participants in the test set) underwent CSF or PET to assign definitive Aβ status. This procedure had an overall sensitivity of 0.94 (95% CI, 0.90-0.98) and a specificity of 0.86 (95% CI, 0.77-0.95). Next, plasma biomarkers were used to differentiate low-intermediate vs high tau-PET load among Aβ-positive participants. Plasma p-tau217 again performed best, with the test AUC = 0.92 (95% CI, 0.86-0.97), without significant improvement when adding any of the other plasma biomarkers. At a false-negative rate less than 10%, the use of plasma p-tau217 could avoid 56.9% of tau-PET scans needed to identify high tau PET among Aβ-positive participants. The results were validated in an independent cohort (n = 118). Conclusions and Relevance: This study found that algorithms using plasma p-tau217 can accurately identify most Aβ-positive individuals, including those likely to have a high tau load who would require confirmatory tau-PET imaging. Plasma p-tau217 measurements may substantially reduce the number of invasive and costly confirmatory tests required to identify individuals who would likely benefit from antiamyloid therapies.
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It is crucial to reduce the need for PET scans due to their inaccessibility and costliness while preserving the ability to estimate AD pathology load and distribution.
“it is crucial to find ways to reduce the need for PET scans due to their relative inaccessibility and costliness, while still preserving the ability to estimate the load and distribution of AD pathology as accurately and comprehensively. 12 , 13”
From Machine learning prediction of tau‐PET in Alzheimer's disease using plasma, MRI, and clinical data (2025) · cites this paper as [13]
The Discussion (page not provided) describes using plasma p-tau217 to reduce the need for PET while identifying amyloid positivity and high tau load, with potential cost savings. It also notes that p-tau217 only marginally predicts continuous tau-PET measurements. The paper does not show that this approach preserves an accurate, comprehensive estimate of the distribution of AD pathology. (LLM, conf=0.86)
Experimental — accuracy not yet measuredPlasma p-tau217 often shows a superior association with temporal lobe tau load compared to other plasma biomarkers, including other p-tau species.
“Nonetheless, plasma p‐tau217 often shows a superior association with temporal lobe tau load compared to other plasma biomarkers (including other p‐tau species), 13 , 25 , 36”
From Machine learning prediction of tau‐PET in Alzheimer's disease using plasma, MRI, and clinical data (2025) · cites this paper as [13]
The Discussion (page unavailable) says plasma p-tau217 was superior to several plasma biomarkers for detecting high tau load at the symptomatic stage; the Methods list other measured p-tau species. But the tau-PET measure covered all brain lobes, albeit with greater weight on parts of the temporal lobe, so the paper does not establish a superior association specifically with temporal-lobe tau load. (LLM, conf=0.86)
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Self-citationMachine learning prediction of tau‐PET in Alzheimer's disease using plasma, MRI, and clinical data
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- Authors
- Mattsson-Carlgren, N., Collij, L. E., Stomrud, E., Pichet Binette, A., Ossenkoppele, R., Smith, R., Karlsson, L., Lantero-Rodriguez, J., Snellman, A., Strandberg, O., Palmqvist, S., Ashton, N. J., Blennow, K., Janelidze, S., & Hansson, O.
- Affiliations
- Clinical Memory Research Unit, Clinical Sciences Malmö, Lund University, Lund, Sweden
- Lund University (SE)
- Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden
- University of Turku (FI)
- King's College London (GB)
- Sahlgrenska University Hospital (SE)
- ORCID
- Venue
- JAMA Neurology
- Publisher
- American Medical Association (AMA)
- Published
- 2024-01-01
- Volume
- 81
- Issue
- 1
- Pages
- 69
- ISSN
- 2168-6149 (ISSN-L)
- PMC
- PMC10696515
- OpenAlex
- W4389295024
- Cited by
- 148
- References
- 36
- Citations by year
- 2026: 39 · 2025: 53 · 2024: 55 · 2023: 1
- FWCI
- 30.00
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JAMA Neurology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Funders
- Alzheimer's Association (SG-23-1038904 QC, ZEN-21-848495, SG-23-1061717)
- Knut och Alice Wallenbergs Stiftelse
- Vetenskapsrådet (2017-00915, 2022-00775, 2018-02052, 2021-02219)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Cerebrospinal fluid and hydrocephalus
- Keywords
- Alzheimer's disease, plasma biomarkers, amyloid-beta, tau pathology, phosphorylated tau217, tau PET, neurofilament light chain, glial fibrillary acidic protein, patient selection, cost-effectiveness, cognitive concerns, memory clinics, cerebrospinal fluid biomarkers
- MeSH terms
- Aged, Alzheimer Disease, Female, Humans, Immunotherapy, Male, Cohort Studies, Biomarkers, Amyloid beta-Peptides, tau Proteins, Patient Selection, Positron-Emission Tomography, Cognitive Dysfunction
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