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Multicenter Study
. 2024 Apr 4;15(1):2908.
doi: 10.1038/s41467-024-47286-5.

Plasma brain-derived tau is an amyloid-associated neurodegeneration biomarker in Alzheimer's disease

Fernando Gonzalez-Ortiz #  1   2 , Bjørn-Eivind Kirsebom #  3   4   5 , José Contador  6   7   8 , Jordan E Tanley  9 , Per Selnes  10 , Berglind Gísladóttir  10 , Lene Pålhaugen  10 , Mathilde Suhr Hemminghyth  11   12   13 , Jonas Jarholm  10 , Ragnhild Skogseth  14   15 , Geir Bråthen  16   17 , Gøril Grøndtvedt  16   17 , Atle Bjørnerud  18   19   20 , Sandra Tecelao  10 , Knut Waterloo  3   4 , Dag Aarsland  21   22 , Aida Fernández-Lebrero  6   7   8   23   24 , Greta García-Escobar  7   24 , Irene Navalpotro-Gómez  6   7   8   24 , Michael Turton  25 , Agnes Hesthamar  26 , Przemyslaw R Kac  26 , Johanna Nilsson  26 , Jose Luchsinger  9 , Kathleen M Hayden  9 , Peter Harrison  25 , Albert Puig-Pijoan  6   7   24   27 , Henrik Zetterberg  26   28   29   30   31   32 , Timothy M Hughes  9 , Marc Suárez-Calvet  6   7   8   33 , Thomas K Karikari  26   34 , Tormod Fladby  5   10 , Kaj Blennow  26   28
Affiliations
Multicenter Study

Plasma brain-derived tau is an amyloid-associated neurodegeneration biomarker in Alzheimer's disease

Fernando Gonzalez-Ortiz et al. Nat Commun. .

Abstract

Staging amyloid-beta (Aβ) pathophysiology according to the intensity of neurodegeneration could identify individuals at risk for cognitive decline in Alzheimer's disease (AD). In blood, phosphorylated tau (p-tau) associates with Aβ pathophysiology but an AD-type neurodegeneration biomarker has been lacking. In this multicenter study (n = 1076), we show that brain-derived tau (BD-tau) in blood increases according to concomitant Aβ ("A") and neurodegeneration ("N") abnormalities (determined using cerebrospinal fluid biomarkers); We used blood-based A/N biomarkers to profile the participants in this study; individuals with blood-based p-tau+/BD-tau+ profiles had the fastest cognitive decline and atrophy rates, irrespective of the baseline cognitive status. Furthermore, BD-tau showed no or much weaker correlations with age, renal function, other comorbidities/risk factors and self-identified race/ethnicity, compared with other blood biomarkers. Here we show that blood-based BD-tau is a biomarker for identifying Aβ-positive individuals at risk of short-term cognitive decline and atrophy, with implications for clinical trials and implementation of anti-Aβ therapies.

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Conflict of interest statement

M.T. and P.H. are employees of Bioventix Plc. H.Z. has served at scientific advisory boards and/or as a consultant for Abbvie, Alector, Annexon, Artery Therapeutics, AZTherapies, CogRx, Denali, Eisai, Nervgen, Pinteon Therapeutics, Red Abbey Labs, Passage Bio, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, and has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen, and Roche. K.B. has served as a consultant and at advisory boards for Acumen, ALZPath, BioArctic, Biogen, Eisai, Lilly, Moleac Pte. Ltd, Novartis, Ono Pharma, Prothena, Roche Diagnostics, and Siemens Healthineers; has served at data monitoring committees for Julius Clinical and Novartis; has given lectures, produced educational materials and participated in educational programs for AC Immune, Biogen, BioArctic, Celdara Medical, Eisai and Roche Diagnostics. H.Z. and K.B. are co-founders of Brain Biomarker Solutions in Gothenburg AB, a GU Ventures-based platform company at the University of Gothenburg. M.S.C. has served as a consultant and at advisory boards for Roche Diagnostics International Ltd and Grifols S.L., has given lectures in symposia sponsored by Roche Diagnostics, S.L.U. and Roche Farma, S.A., and was granted with a project funded by Roche Diagnostics International Ltd; payments were made to the institution (BBRC). A.P.P. has served on advisory boards for Schwabe Farma Iberica. T.K.K. has received honoraria from the University of Wisconsin Madison and the University of Pennsylvania and has an awarded patent (#WO2020193500A1), all unrelated to this work. B.E.K. has served as a consultant for Biogen and advisory board for Eisai. T.F. has served as a consultant and at the advisory boards for Biogen, Novo Nordisk, Eli Lilly, and Roche. The other authors declare no competing interest.

Figures

Fig. 1
Fig. 1. Blood-based brain-derived tau (BD-tau) mean differences across cohorts 1 to 3, compared to A-/N- cases.
This forest plot displays the mean elevation of blood-based BD-tau according to cerebrospinal fluid (CSF) determined amyloid (A) and neurodegeneration (N) status in the Alzheimer’s Disease (AD) continuum across cohorts 1 through 3. Point estimates are log-transformed and standardized (Z-log), expressed as standard deviations relative to A-/N- cases (represented by a gray vertical bar, normalized to mean 0 as the reference). Error bars denote 95% confidence intervals. All statistical tests were two-sided and unadjusted for multiple comparisons. For cohort 1 (Dementia Disease Initiation (DDI)), A-/N- were cognitively normal (CN, n = 157). For cohort 2 (University of Gothenburg), A-/N- were CN (A-/N-, n = 9). For cohort 3 (Biodegmar, Hospital del Mar, Barcelona memory clinic cohort), A-/N- (n = 111) were mixed CN with Subjective Cognitive Decline, Mild Cognitive Impairment (MCI) and dementia.
Fig. 2
Fig. 2. Associations between baseline blood-based BD-tau, t-tau and NfL with baseline and longitudinal MRI-derived Alzheimer’s disease meta region of interest (AD meta ROI).
A–C show associations of blood-based neurodegeneration markers with baseline and longitudinal AD meta ROI. All statistical tests were two-sided, and unadjusted for multiple comparisons. All plots display model predictions generated with the “ggeffects” R package. The lines display associations between the biomarker at −1SD, Mean and +1SD and the dependent variable at baseline and over time.
Fig. 3
Fig. 3. Associations between baseline blood-based BD-tau, t-tau and NfL with baseline and longitudinal cognitive performance.
A–C show associations of neurodegeneration markers in blood with Trail-Making Test B (TMT-B) performance in cohort 1 (Dementia Disease Initiation (DDI)). D–F show associations of neurodegeneration markers in blood with Mini Mental Status Examination (MMSE) scores in cohort 3 (Biodegmar, Hospital del Mar, Barcelona memory clinic cohort). All statistical tests were two-sided, and unadjusted for multiple comparisons. All plots display model predictions generated with the “ggeffects” R package. The lines display associations between the biomarker at −1SD, Mean and +1 SD and the dependent variable at baseline and over time.
Fig. 4
Fig. 4. Associations between blood-based A/N groups with baseline and longitudinal cognitive performance and MRI-derived Alzheimer’s disease meta region of interest (AD meta ROI).
A, B Show the associations between A/N groups based on p-tau181 (A) and BD-tau (N) in blood with baseline and longitudinal cognitive performance (CERAD verbal memory recall and Trail Making Test-B (TMT-B)) in cohort 1 (Dementia Disease Initiation (DDI)). As compared to A-/N-, both A+/N- and A+/N+ profiles showed worse performance at baseline for CERAD, but only A+/N+ had worse performance for TMT-B. However, only A+/N+ profiles were associated with worsening over time for both tests. C Shows A/N groups associations with baseline and longitudinal AD meta-ROI, here only A+/N+ showed lower AD meta-ROI at baseline and increased atrophy over time. D, E Show the associations between A/N groups with baseline and longitudinal cognitive performance (Clinical Dementia Rating (CDR) and Mini Mental Status Examination (MMSE)) in cohort 3 (Biodegmar, Hospital del Mar, Barcelona memory clinic cohort). Here only A+/N+ profiles were associated with poorer scores on MMSE and CDR at baseline. While both A+/N- and A+/N+ showed higher CDRs over time, no longitudinal associations were seen for MMSE in any group. All plots display model predictions generated with the “ggeffects” R package. The lines display associations between the biomarker at -1SD, Mean and +1 SD and the dependent variable at baseline and over time. For more details see Supplementary Table 5.
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