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. 2024 Nov;4(11):1529-1537.
doi: 10.1038/s43587-024-00731-y. Epub 2024 Nov 12.

Diagnosis of Alzheimer's disease using plasma biomarkers adjusted to clinical probability

Joseph Therriault  1   2 , Shorena Janelidze  3 , Andréa Lessa Benedet  4 , Nicholas J Ashton  4   5   6   7 , Javier Arranz Martínez  8   9 , Armand Gonzalez-Escalante  10   11   12 , Bruna Bellaver  13 , Daniel Alcolea  8   9 , Agathe Vrillon  14   15 , Helmet Karim  13   16 , Michelle M Mielke  17   18 , Chang Hyung Hong  16 , Hyun Woong Roh  16 , José Contador  8   9   19 , Albert Puig Pijoan  9   19   20   21 , Alicia Algeciras-Schimnich  22 , Prashanthi Vemuri  23 , Jonathan Graff-Radford  18 , Val J Lowe  23 , Thomas K Karikari  4   13 , Erin Jonaitis  24   25 , Wagner Brum  4   26 , Cécile Tissot  27   28 , Stijn Servaes  27   29 , Nesrine Rahmouni  27   29 , Arthur C Macedo  27   29 , Jenna Stevenson  27   29 , Jaime Fernandez-Arias  27   29 , Yi-Ting Wang  27   29 , Marcel S Woo  27   30 , Manuel A Friese  30 , Wan Lu Jia  27   29 , Julien Dumurgier  14   15 , Claire Hourregue  14   15 , Emmanuel Cognat  14   15 , Pamela Lukasewicz Ferreira  13 , Paolo Vitali  29 , Sterling Johnson  22   25 , Tharick A Pascoal  13 , Serge Gauthier  27   29 , Alberto Lleó  8   9 , Claire Paquet  14   15 , Ronald C Petersen  17   18 , David Salmon  31 , Niklas Mattsson-Carlgren  3   32   33 , Sebastian Palmqvist  3   34 , Erik Stomrud  3   34 , Douglas Galasko  31 , Sang Joon Son  16 , Henrik Zetterberg  4   5   24   35   36   37   38 , Juan Fortea  8   9   21   39   40 , Marc Suárez-Calvet  9   10   11   40 , Clifford R Jack Jr  23 , Kaj Blennow  4   5 , Oskar Hansson #  3   38 , Pedro Rosa-Neto #  41   42
Affiliations

Diagnosis of Alzheimer's disease using plasma biomarkers adjusted to clinical probability

Joseph Therriault et al. Nat Aging. 2024 Nov.

Abstract

Recently approved anti-amyloid immunotherapies for Alzheimer's disease (AD) require evidence of amyloid-β pathology from positron emission tomography (PET) or cerebrospinal fluid (CSF) before initiating treatment. Blood-based biomarkers promise to reduce the need for PET or CSF testing; however, their interpretation at the individual level and the circumstances requiring confirmatory testing are poorly understood. Individual-level interpretation of diagnostic test results requires knowledge of disease prevalence in relation to clinical presentation (clinical pretest probability). Here, in a study of 6,896 individuals evaluated from 11 cohort studies from six countries, we determined the positive and negative predictive value of five plasma biomarkers for amyloid-β pathology in cognitively impaired individuals in relation to clinical pretest probability. We observed that p-tau217 could rule in amyloid-β pathology in individuals with probable AD dementia (positive predictive value above 95%). In mild cognitive impairment, p-tau217 interpretation depended on patient age. Negative p-tau217 results could rule out amyloid-β pathology in individuals with non-AD dementia syndromes (negative predictive value between 90% and 99%). Our findings provide a framework for the individual-level interpretation of plasma biomarkers, suggesting that p-tau217 combined with clinical phenotyping can identify patients where amyloid-β pathology can be ruled in or out without the need for PET or CSF confirmatory testing.

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Conflict of interest statement

Competing interests J.T. has served as a consultant for the Neurotorium educational platform, outside of the scope of the submitted work. H.Z. has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics and Wave; has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen and Roche; and is a co-founder of Brain Biomarker Solutions in Gothenburg AB, which is a part of the GU Ventures Incubator Program (outside submitted work). O.H. has acquired research support (for the institution) from ADx, AVID Radiopharmaceuticals, Biogen, Eli Lilly, Eisai, Fujirebio, GE Healthcare, Pfizer and Roche. In the past 2 years, he has received consultancy/speaker fees from AC Immune, Amylyx, Alzpath, BioArctic, Biogen, Cerveau, Eisai, Eli Lilly, Fujirebio, Merck, Novartis, Novo Nordisk, Roche, Sanofi and Siemens. R.C.P. has consulted for Roche, Genentech, Eli Lilly, Eisai and Nestle, all outside the scope of the current work. 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 at advisory boards for Schwabe Farma Iberica. D.A. participated in advisory boards from Fujirebio-Europe, Roche Diagnostics, Grifols S.A. and Lilly, and received speaker honoraria from Fujirebio-Europe, Roche Diagnostics, Nutricia, Krka Farmacéutica S.L., Zambon S.A.U. and Esteve Pharmaceuticals S.A. D.A. declares a filed patent application (WO2019175379 A1 Markers of synaptopathy in neurodegenerative disease). S. Johnson has served at scientific advisory boards or as a consultant for ALZpath, Prothena, Roche Diagnostics, and Enigma. M.M.M. has served as a consultant and at advisory boards for Biogen, Eisai, Lilly, Merck, Roche, and Siemens Healthineers. P.R.-N. has served at scientific advisory boards and/or as a consultant for Roche, Novo Nordisk, Eisai, and Cerveau radiopharmaceuticals. A.A.-S. has participated in advisory boards for Roche Diagnostics, Fujirebio Diagnostics and Siemens Healthineers. The remaining authors declare no competing interests.

Figures

Fig. 1
Fig. 1. PPVs and NPVs of plasma AD biomarkers in individuals with MCI.
Age-associated PPV (left) and NPV (right) of five plasma biomarkers for amyloid PET positivity in MCI. The solid lines represent the point estimate, and error bars represent 95% CIs. Source data
Fig. 2
Fig. 2. PPVs and NPVs of plasma biomarkers of AD in individuals with probable AD dementia.
Age-associated PPV (left) and NPV (right) of five plasma biomarkers for amyloid PET positivity in probable AD dementia. The solid lines represent the point estimate, and error bars represent 95% CIs. Source data
See this image and copyright information in PMC

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