Prediction of future Alzheimer’s disease dementia using plasma phospho-tau combined with other accessible measures
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Abstract
A combination of plasma phospho-tau (P-tau) and other accessible biomarkers might provide accurate prediction about the risk of developing Alzheimer's disease (AD) dementia. We examined this in participants with subjective cognitive decline and mild cognitive impairment from the BioFINDER (n = 340) and Alzheimer's Disease Neuroimaging Initiative (ADNI) (n = 543) studies. Plasma P-tau, plasma Aβ42/Aβ40, plasma neurofilament light, APOE genotype, brief cognitive tests and an AD-specific magnetic resonance imaging measure were examined using progression to AD as outcome. Within 4 years, plasma P-tau217 predicted AD accurately (area under the curve (AUC) = 0.83) in BioFINDER. Combining plasma P-tau217, memory, executive function and APOE produced higher accuracy (AUC = 0.91, P < 0.001). In ADNI, this model had similar AUC (0.90) using plasma P-tau181 instead of P-tau217. The model was implemented online for prediction of the individual probability of progressing to AD. Within 2 and 6 years, similar models had AUCs of 0.90-0.91 in both cohorts. Using cerebrospinal fluid P-tau, Aβ42/Aβ40 and neurofilament light instead of plasma biomarkers did not improve the accuracy significantly. The clinical predictions by memory clinic physicians had significantly lower accuracy (4-year AUC = 0.71). In summary, plasma P-tau, in combination with brief cognitive tests and APOE genotyping, might greatly improve the diagnostic prediction of AD and facilitate recruitment for AD trials.
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The participants in this study were relatively young (average age 65 years) compared to ADNI and BioFinder cohorts.
“According to our inclusion criteria, the participants in this study were relatively young (average age: 65 years) comparing to ADNI and BioFinder cohorts11,40,41.”
From Integrated algorithm combining plasma biomarkers and cognitive assessments accurately predicts brain β-amyloid pathology (2023) · cites this paper as [11]
The ‘Participants in BioFINDER’ section reports a mean age of 70.7 years, supporting the comparison with the citing study’s stated average of 65. The ‘Validation cohort’ section gives ADNI participants’ age range as 55–91 years, but the passages do not establish that their average age exceeded 65. The cited paper also does not report the citing study’s average age. (LLM, conf=0.78)
Experimental — accuracy not yet measuredPrevious research attempted to develop algorithms combining multiple factors and showed better and more robust performance in predicting Aβ positivity of Alzheimer's disease.
“Previous research attempted to develop algorithms combining multiple factors and showed better and more robust performance in predicting Aβ positivity of Alzheimer’s disease.”
From Integrated algorithm combining plasma biomarkers and cognitive assessments accurately predicts brain β-amyloid pathology (2023) · cites this paper as [11]
The Discussion reports that an algorithm combining plasma P-tau, cognitive measures and APOE genotype performed robustly across two cohorts. But its predicted outcome was progression to Alzheimer’s disease dementia, not Aβ positivity; the Cross-validation section likewise describes the algorithm as estimating dementia risk within four years. Aβ-related measures appear as predictors or proxies, not as the outcome claimed. (LLM, conf=0.88)
Experimental — accuracy not yet measuredAmong existing plasma biomarkers, P-tau has shown the highest predictive accuracy for Aβ positivity.
“Among the existing plasma biomarkers, P-tau has shown the highest predictive accuracy for Aβ positivity11,12.”
From Integrated algorithm combining plasma biomarkers and cognitive assessments accurately predicts brain β-amyloid pathology (2023) · cites this paper as [11]
The Discussion (page unavailable) says plasma P-tau reflects Aβ pathology, supporting an association with Aβ status. But the paper’s reported prediction accuracies concern progression to Alzheimer’s dementia, not Aβ positivity; it does not establish that P-tau has the highest accuracy among plasma biomarkers for predicting Aβ positivity. (LLM, conf=0.84)
Experimental — accuracy not yet measuredAbnormality for plasma biomarkers was determined in a standardized manner across all cohorts using z-scores created based on the means and s.d. of cognitively unimpaired individuals without elevated amyloid-β pathology.
“Abnormality for plasma biomarkers was determined in a standardized manner across all cohorts using z-scores created based on the means and s.d. of cognitively unimpaired individuals without elevated amyloid-β pathology, as previously done in several studies8,62,63.”
From Diagnosis of Alzheimer's disease using plasma biomarkers adjusted to clinical probability (2024) · cites this paper as [62]
The Plasma biomarkers section says that Aβ-negative cognitively normal reference groups in BioFINDER and ADNI supplied the means and standard deviations for plasma P-tau cutoffs and z-scores. But abnormality was defined by a mean-plus-2-s.d. cutoff in each cohort; z-scores were used in a secondary model, and the described procedure concerns plasma P-tau rather than plasma biomarkers generally. (LLM, conf=0.88)
Experimental — accuracy not yet measuredA standardized method of determining plasma biomarker abnormality was used across centers.
“Abnormality for plasma biomarkers was determined in a standardized manner across all cohorts using z-scores created based on the means and s.d. of cognitively unimpaired individuals without elevated amyloid-β pathology, as previously done in several studies8,62,63.”
From Diagnosis of Alzheimer's disease using plasma biomarkers adjusted to clinical probability (2024) · cites this paper as [62]
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“Among the existing plasma biomarkers, P-tau has shown the highest predictive accuracy for A β positivity 11,12 .”
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- Authors
- Palmqvist, S., Tideman, P., Cullen, N., Zetterberg, H., Blennow, K., Initiative, T. A. D. N., Dage, J. L., Stomrud, E., Janelidze, S., Mattsson-Carlgren, N., & Hansson, O.
- Affiliations
- Lund University (SE)
- Sahlgrenska University Hospital (SE)
- Eli Lilly (United States) (US)
- Corresponding author
- Palmqvist, Sebastian
- Hansson, Oskar
- ORCID
- Venue
- Nature Medicine
- Published
- 2021-05-24
- Volume
- 27
- Issue
- 6
- Pages
- 1034-1042
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W3119309452
- Semantic Scholar
- b24b591a0e125929a503d5506d666ab4e3592696
- Cited by
- 524
- References
- 60
- Citations by year
- 2026: 72 · 2025: 101 · 2024: 128 · 2023: 99 · 2022: 107 · 2021: 16
- FWCI
- 63.08
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Nature Medicine (publishedVersion)
- Research Square (acceptedVersion, cc-by)
- PubMed (publishedVersion)
- Purdue University Indianapolis (Indiana University) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- IUScholarWorks (Indiana University) (submittedVersion)
- Funders
- Vetenskapsrådet (2018-02052, 2016-00906)
- Hjärnfonden (FO2020-0271)
- Alzheimerfonden (AF-940046, AF-745911)
- Knut och Alice Wallenbergs Stiftelse (2017-0383)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cancer-related cognitive impairment studies
- Keywords
- Alzheimer's disease, dementia prediction, p-tau217, p-tau181, APOE genotype, subjective cognitive decline, mild cognitive impairment, neurofilament light chain, brief cognitive tests, diagnostic accuracy, clinical trial recruitment
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Apolipoproteins E, Female, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Neuropsychological Tests, Prognosis, Risk Factors, Biomarkers, Amyloid beta-Peptides, tau Proteins, Neuroimaging, Cognitive Dysfunction
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