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. 2024 Sep 1;81(9):947-957.
doi: 10.1001/jamaneurol.2024.2619.

Plasma Phosphorylated Tau 217 and Aβ42/40 to Predict Early Brain Aβ Accumulation in People Without Cognitive Impairment

Shorena Janelidze  1 , Nicolas R Barthélemy  2   3 , Gemma Salvadó  1 , Suzanne E Schindler  2   3   4 , Sebastian Palmqvist  1   5 , Niklas Mattsson-Carlgren  1   6   7 , Joel B Braunstein  8 , Vitaliy Ovod  2   3 , James G Bollinger  2   3 , Yingxin He  2   3 , Yan Li  2   3 , Cyrus A Raji  9 , John C Morris  2 , David M Holtzman  10 , Nicholas J Ashton  11   12   13   14 , Kaj Blennow  11   15   16 , Erik Stomrud  1   5 , Randall J Bateman  2   3 , Oskar Hansson  1   5
Affiliations

Plasma Phosphorylated Tau 217 and Aβ42/40 to Predict Early Brain Aβ Accumulation in People Without Cognitive Impairment

Shorena Janelidze et al. JAMA Neurol. .

Abstract

Importance: Phase 3 trials of successful antiamyloid therapies in Alzheimer disease (AD) have demonstrated improved clinical efficacy in people with less severe disease. Plasma biomarkers will be essential for efficient screening of participants in future primary prevention clinical trials testing antiamyloid therapies in cognitively unimpaired (CU) individuals with initially low brain β-amyloid (Aβ) levels who are at high risk of accumulating Aβ.

Objective: To investigate if combining plasma biomarkers could be useful in predicting subsequent development of Aβ pathology in CU individuals with subthreshold brain Aβ levels (defined as Aβ levels <40 Centiloids) at baseline.

Design, setting, and participants: This was a longitudinal study including Swedish BioFINDER-2 (enrollment 2017-2022) and replication in 2 independent cohorts, the Knight Alzheimer Disease Research Center (Knight ADRC; enrollment 1988 and 2019) and Swedish BioFINDER-1 (enrollment 2009-2015). Included for analysis was a convenience sample of CU individuals with baseline plasma phosphorylated tau 217 (p-tau217) and Aβ42/40 assessments and Aβ assessments with positron emission tomography (Aβ-PET) or cerebrospinal fluid (CSF) Aβ42/40. Data were analyzed between April 2023 and May 2024.

Exposures: Baseline plasma levels of Aβ42/40, p-tau217, the ratio of p-tau217 to nonphosphorylated tau (%p-tau217), p-tau231, and glial fibrillary acidic protein (GFAP).

Main outcomes and measures: Cross-sectional and longitudinal PET and CSF measures of brain Aβ pathology.

Results: This study included 495 (BioFINDER-2), 283 (Knight ADRC), and 205 (BioFINDER-1) CU participants. In BioFINDER-2, the mean (SD) age was 65.7 (14.4) with 261 females (52.7%). When detecting abnormal CSF Aβ-status, a combination of plasma %p-tau217 and Aβ42/40 showed better performance (area under the curve = 0.949; 95% CI, 0.929-0.970; P <.02) than individual biomarkers. In CU participants with subthreshold baseline Aβ-PET, baseline plasma %p-tau217 and Aβ42/40 levels were significantly associated with baseline Aβ-PET (n = 384) and increases in Aβ-PET over time (n = 224). Associations of plasma %p-tau217 and Aβ42/40 and their interaction with baseline Aβ-PET (%p-tau217: β = 2.77; 95% CI, 1.84-3.70; Aβ42/40: β = -1.64; 95% CI, -2.53 to -0.75; %p-tau217 × Aβ42/40: β = -2.14; 95% CI, -2.79 to -1.49; P < .001) and longitudinal Aβ-PET (%p-tau217: β = 0.67; 95% CI, 0.48-0.87; Aβ42/40: β = -0.33; 95% CI, -0.51 to -0.15; %p-tau217 × Aβ42/40: β = -0.31; 95% CI, -0.44 to -0.18; P < .001) were also significant in the models combining the 2 baseline biomarkers as predictors. Similarly, baseline plasma p-tau217 and Aβ42/40 were independently associated with longitudinal Aβ-PET in Knight ADRC (%p-tau217: β = 0.71; 95% CI, 0.26-1.16; P = .002; Aβ42/40: β = -0.74; 95% CI, -1.26 to -0.22; P = .006) and longitudinal CSF Aβ42/40 in BioFINDER-1 (p-tau217: β = -0.0003; 95% CI, -0.0004 to -0.0001; P = .01; Aβ42/40: β = 0.0004; 95% CI, 0.0002-0.0006; P < .001) in CU participants with subthreshold Aβ levels at baseline. Plasma p-tau231 and GFAP did not provide any clear independent value.

Conclusions and relevance: Results of this cohort study suggest that combining plasma p-tau217and Aβ42/40 levels could be useful for predicting development of Aβ pathology in people with early stages of subthreshold Aβ accumulation. These biomarkers might thus facilitate screening of participants for future primary prevention trials.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Barthélemy reported receiving grants from The Coins For Alzheimer's Research Trust, Tracy Family SILQ Center Pilot, and Knight ADRC Developmental Projects and having the following patents: methods to detect novel tau species in cerebrospinal fluid, methods to track tau neuropathology in Alzheimer’s disease and other tauopathies, and methods for diagnosing and treating based on site-specific tau phosphorylation, all licensed to C2N Diagnostics. Dr Schindler reported receiving personal fees from Eisai outside the submitted work. Dr Palmqvist reported receiving research support (for the institution) from Ki:elements, Alzheimer’s Drug Discovery Foundation, and Avid and consultancy/speaker fees from Bioartic, Biogen, Esai, Lilly, and Roche. Dr Braunstein reported being employed by C2N Diagnostics. Dr Ovod reported having a patent for plasma-based methods for detecting central nervous system amyloid deposition licensed to C2N Diagnostics. Dr Bollinger reported having a pending patent for plasma-based methods for detecting central nervous system amyloid deposition licensed to C2N Diagnostics. Dr Raji reported receiving grants from National Institutes of Health/National Institute on Aging and the Department of Defence and personal/consulting fees from CoreTechs.ai, Pacific Neuroscience Institute, Voxelwise, Eli Lilly, and Neurevolution outside the submitted work. Dr Morris reported receiving grants from the National Institutes of Health during the conduct of the study. Dr Holtzman reported being cofounder of, receiving equity from, and serving on the scientific advisory board of C2N Diagnostics; receiving advisory board fees from Genentech and Cajal Neurosciences; and having a patent for methods for measuring the metabolism of neutrally derived biomolecules in vivo with royalties paid from C2N Diagnostics. Dr Blennow reported serving as a consultant and on advisory boards for AbbVie, AC Immune, ALZPath, AriBio, BioArctic, Biogen, Eisai, Lilly, Moleac Pte. Ltd, Neurimmune, Novartis, Ono Pharma, Prothena, Roche Diagnostics, and Siemens Healthineers; serving on data monitoring committees for Julius Clinical and Novartis; giving lectures, producing educational materials, and participating in educational programs for AC Immune, Biogen, Celdara Medical, Eisai and Roche Diagnostics; and being 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 Bateman reported receiving research funding from the National Institutes of Health, Alzheimer’s Association, BrightFocus Foundation, Rainwater Foundation, Association for Frontotemporal Degeneration FTD Biomarkers Initiative, Tau Consortium, Novartis, Centene Corporation, Association for Frontotemporal Degeneration, the Cure Alzheimer's Fund, Coins for Alzheimer’s Research Trust Fund, The Foundation for Barnes-Jewish Hospital, Good Ventures Foundation, DIAN-TU Pharma Consortium, Centene Corporation, Tau SILK Consortium (AbbVie, Biogen, Eli Lilly and Company and an anonymous organization), the NfL Consortium (AbbVie, Biogen, Bristol Meyers Squibb, Hoffman La Roche, and an anonymous organization); speaker/consultant/advisory board honoraria from Eisai, F. Hoffman-LaRoche, Janssen, Biogen; paid travel expenses from Korean Dementia Association, American Neurological Association, Fondazione Prada, Weill Cornell Medical College, Harvard University, CTAD, FBRI, Beeson Foundation, Adler, Alzheimer’s Association Roundtable, Duke Margolis Roundtable, Bright Focus Foundation, Tau Consortium Investigator’s, NAPA Advisory Council on Alzheimer’s Research; serving as principal investigator of the DIAN-TU (which is supported by the Alzheimer’s Association, GHR Foundation, an anonymous organization and the DIAN-TU Pharma Consortium [active: Biogen, Eisai, Eli Lilly and Company/Avid Radiopharmaceuticals, F. Hoffman-La Roche/Genentech, and Janssen. Previous: AbbVie, Amgen, AstraZeneca, Forum, Mithridion, Novartis, Pfizer, Sanofi, and United Neuroscience]). The DIAN-TU-001 Clinical Trial is supported by Pharmaceutical Partners Eli Lilly and Company, F. Hoffman-La Roche and Janssen, the Alzheimer’s Association, National Institutes of Health grants U01AG042791, U01AG42791-S1 (FNIH and Accelerating Medicines Partnership), R01AG046179, R56AG053267, R01AG053267, U01AG059798, R01AG068319, Avid Radiopharmaceuticals, GHR Foundation, and an anonymous organization. In-kind support has been received from CogState, Cerveau, Signant Health and Eisai Corporation; and being a cofounder of C2N Diagnostics and receiving income from C2N Diagnostics for serving on the scientific advisory board. Washington University has equity ownership interest in C2N Diagnostics. Dr Hansson reported receiving advisory board fees from Lilly, Roche, Eisai, and Novo Nordisk outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Associations Between Plasma Biomarkers and β-Amyloid Positron Emission Tomography (Aβ-PET) at Baseline in Cognitively Unimpaired (CU) Participants With Subthreshold Baseline Aβ-PET
A, Estimates and 95% CIs from linear regression models including continuous measures of the ratio of phosphorylated tau 217 (p-tau217) to non–p-tau (%p-tau217), Aβ42/40 or %p-tau217, Aβ42/40 and their interaction, as well as age and sex as predictors and Aβ-PET as outcome. Log-transformed and z-scored plasma biomarkers were used in all regression models. Aβ-PET status was defined by a threshold of 40 Centiloids (CL). B, Differences in Aβ-PET Centiloid values between participants with plasma biomarkers levels below or above the median (mdn). A indicates Aβ42/40, pT, %p-tau217. aP <.001. bP <.0001. cP <.05. dP <.01.
Figure 2.
Figure 2.. Associations Between Plasma Biomarkers and Longitudinal β-Amyloid Positron Emission Tomography (Aβ-PET) in Cognitively Unimpaired (CU) Participants With Subthreshold Baseline Aβ-PET
A, Associations between baseline plasma biomarkers and longitudinal changes in Aβ-PET were tested using linear regression models including continuous measures of the ratio of phosphorylated tau 217 (p-tau217) to non–p-tau (%p-tau217), Aβ42/40 or %p-tau217, Aβ42/40 and their interaction, as well as age and sex as predictors and subject-specific slopes of Aβ-PET as outcome. Participant-specific slopes of Aβ-PET were derived from linear mixed-effects models including longitudinal Aβ-PET as outcome and time (years since baseline) as predictor. Log-transformed and z-scored plasma biomarkers were used in all regression models. Aβ-PET status was defined by a threshold of 40 Centiloids (CL). B, Differences in Aβ-PET slopes between participants with plasma biomarkers levels below or above the median (mdn). C, Associations between plasma biomarkers and longitudinal Aβ-PET were visualized using linear mixed-effects models with Aβ-PET as outcome and interaction between plasma biomarkers (dichotomized at mdn) and time as predictor adjusting for age and sex. The ggeffects package of R software was used to generate estimated values. A indicates Aβ42/40, pT, %p-tau217. aP <.001. bP <.05. cP <.0001.
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