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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For BioFINDER data, anonymized data will be shared by request from a qualified academic investigator for the sole purpose of replicating procedures and results presented in the article and as long as data transfer is in agreement with EU legislation on the general data protection regulation and decisions by the Ethical Review Board of Sweden and Region Skåne, which should be regulated in a material transfer agreement. ADNI data are stored (publicly available) in the loni database (https://ida.loni.usc.edu/).
No custom code or mathematical algorithm that was central to the conclusions was used in this study.
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Work at the authors’ research center was supported by the Swedish Research Council (2016-00906 (O.H.) and 2018-02052 (S.P.)), the Knut and Alice Wallenberg Foundation (2017-0383 (O.H.)), the Marianne and Marcus Wallenberg Foundation (2015.0125 (O.H.)), the Strategic Research Area MultiPark (Multidisciplinary Research in Parkinson’s disease) at Lund University, the Swedish Alzheimer Foundation (AF-745911 (O.H.) and AF-940046 (S.P.)), the Swedish Brain Foundation (FO2019-0326 (O.H.) and FO2020-0271 (S.P.)), the Parkinson Foundation of Sweden (1280/20 (O.H.)), the Skåne University Hospital Foundation (2020-O000028 (S.P.)), Regionalt Forskningsstöd (2020-0314 (O.H.) and 2020-0383 (S.P.)) and the Swedish federal government under the ALF agreement (2018-Projekt0279 (O.H.) and 2018-Projekt0226 (S.P.)). H.Z. is a Wallenberg Scholar supported by grants from the Swedish Research Council (2018-02532), the European Research Council (681712), Swedish State Support for Clinical Research (ALFGBG-720931), the Alzheimer Drug Discovery Foundation, USA (201809-2016862), AD Strategic Fund and the Alzheimer’s Association (ADSF-21-831376-C, ADSF-21-831381-C and ADSF-21-831377-C), the European Union’s Horizon 2020 Research and Innovation Programme under Marie Skłodowska-Curie grant agreement no. 860197 (MIRIADE) and the UK Dementia Research Institute at University College London. K.B. is supported by the Swedish Research Council (2017-00915), the Alzheimer Drug Discovery Foundation, USA (RDAPB-201809-2016615), the Swedish Alzheimer Foundation (AF-742881), Hjärnfonden, Sweden (FO2017-0243), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF agreement (ALFGBG-715986) and the European Union Joint Program for Neurodegenerative Disorders (JPND2019-466-236). The precursor of 18F-flutemetamol was sponsored by GE Healthcare. The precursor of 18F-RO948 was provided by Roche. ADNI data collection and sharing was funded by the Alzheimer’s Disease Neuroimaging Initiative (National Institutes of Health grant U01 AG024904) and Department of Defense award no. W81XWH-12-2-0012. ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering and through generous contributions from the following: AbbVie; Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica; Biogen; Bristol-Myers Squibb Company; CereSpir; Cogstate; Eisai; Elan Pharmaceuticals; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche and its affiliated company, Genentech; Fujirebio; GE Healthcare; IXICO; Janssen Alzheimer Immunotherapy Research & Development; Johnson & Johnson Pharmaceutical Research & Development; Lumosity; Lundbeck; Merck & Co.; Meso Scale Diagnostics; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals; Pfizer; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. ADNI investigators contributed to the design and implementation of the ADNI database and/or provided data but did not participate in the analysis or writing of this report. A complete listing of ADNI investigators can be found at http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California.
S.P. has served on the scientific advisory boards for Hoffman-La Roche and Geras Solutions. H.Z. has served on the scientific advisory boards for Denali, Roche Diagnostics, Wave, Samumed, Siemens Healthineers, Pinteon Therapeutics and CogRx, has given lectures in symposia sponsored by Fujirebio, Alzecure and Biogen and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. K.B. has served as a consultant, on advisory boards or on the data monitoring committees for Abcam, Axon, Biogen, JOMDD/Shimadzu, Julius Clinical, Eli Lilly, MagQu, Novartis, Roche Diagnostics and Siemens Healthineers and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. J.L.D. is an employee of Eli Lilly and Company. O.H. has acquired research support (for the institution) from AVID Radiopharmaceuticals, Biogen, Eli Lilly, Eisai, GE Healthcare, Pfizer and Roche. In the past 2 years, O.H. has also received consultancy/speaker fees from AC Immune, Alzpath, Biogen, Cerveau and Roche. S.J., P.T., N.C., E.S. and N.M.-C. report no disclosures.
Peer review information Nature Medicine thanks Ronald Petersen, Stephen Salloway and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Jerome Staal was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team
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Eligible population was defined as being referred to any of the participating memory clinics and being non-demented.
Extended Data Fig. 2 Univariable logistic regression models for predicting progression to AD dementia vs other conditions within 2–6 years.
Data are shown as AUCs at each time point (error bars show the 95% CIs of the AUCs). AUCs above the dashed lines represent a predictive accuracy better than chance (AUC 0.5). APOE genotype was coded as 0, 1 or 2 ε4 alleles. Regarding the cognitive measures, memory had high accuracy from short- to long-term predictions, while executive function had lower accuracies for long-term prediction. This suggest that memory changes earlier than executive function during the development of AD. Regarding the biomarkers, cortical thickness representing AD-specific neurodegeneration were best for short- to mid-term prediction, plasma P-tau217 for mid- to long-term prediction and plasma Aβ42/Aβ40 better for long-term prediction. This is congruent with the model for the development of AD that begins with the accumulation of Aβ, then phosphorylation of tau and the deposition of tau tangles, and finally neurodegeneration.
Extended Data Fig. 3 Model selection process and performance for predicting AD dementia within 2 years in BioFINDER.
a, Model selection process. Best Model Fit shows the data-driven model selection with the lowest AIC (that is, the best model fit). The parsimonious model shows the model that had a similar model fit (ΔAIC <2) with as few significant predictors as possible. In subsequent models, the least important modalities were removed in a step-wise procedure. Model specifications including comparisons between all models are shown in Supplementary Table 2. b, ROC curves of the different models. Abbreviations: AD, Alzheimer’s disease; AIC, Akaike Information Criterion; APOE, Apolipoprotein E genotype (number of ε4 alleles); AUC, Area under the ROC curve; MRI, Cortical thickness of a temporal AD-specific region; ROC, Receiver Operating Characteristic.
Extended Data Fig. 4 Model selection process and performance for predicting AD dementia within 6 years in BioFINDER.
a, Model selection process. Best Model Fit shows the data-driven model selection with the lowest AIC (that is, the best model fit). The parsimonious model shows the model that had a similar model fit (ΔAIC <2) with as few significant predictors as possible. In subsequent models, the least important modalities were removed in a step-wise procedure. Model specifications including comparisons between all models are shown in Supplementary Table 3. b, ROC curves of the different models. Abbreviations: AD, Alzheimer’s disease; AIC, Akaike Information Criterion; APOE, Apolipoprotein E genotype (number of ε4 alleles); AUC, Area under the ROC curve; MRI, Cortical thickness of a temporal AD-specific region; ROC, Receiver Operating Characteristic.
Extended Data Fig. 5 Cross-validation and implementation of an algorithm using plasma P-tau z-scores.
Plasma P-tau z-scores based on the distribution of Aβ-negative cognitively unimpaired participants in BioFINDER and ADNI, respectively (see Methods), was used in the logistic regression models. Model coefficients were established in BioFINDER (AUC 0.90) and tested in ADNI (AUC 0.89). Cognitive z-scores have been inverted so that higher scores equal poorer results. This model is implemented at http://predictAD.app where one can enter the raw cognitive test scores that constitute the z-scores, number of APOE ε4 alleles and plasma P-tau z-score (either from P-tau217 or P-tau181).
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Palmqvist, S., Tideman, P., Cullen, N. et al. Prediction of future Alzheimer’s disease dementia using plasma phospho-tau combined with other accessible measures. Nat Med 27, 1034–1042 (2021). https://doi.org/10.1038/s41591-021-01348-z
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