Plasma biomarkers for diagnosis of Alzheimer's disease and prediction of cognitive decline in individuals with mild cognitive impairment

Pia Kivisäkk; Becky C Carlyle; Thadryan Sweeney; Bianca A Trombetta; Kathryn LaCasse; Leena El-Mufti; Idil Tuncali; Lori B Chibnik; Sudeshna Das; Clemens R Scherzer; Keith A Johnson; Bradford C Dickerson; Teresa Gomez-Isla; Deborah Blacker; Derek H Oakley; Matthew P Frosch; Bradley T Hyman; Anahit Aghvanyan; Pradeepthi Bathala; Christopher Campbell; George Sigal; Martin Stengelin; Steven E Arnold

doi:10.3389/fneur.2023.1069411

Plasma biomarkers for diagnosis of Alzheimer's disease and prediction of cognitive decline in individuals with mild cognitive impairment

Front Neurol. 2023 Mar 2:14:1069411. doi: 10.3389/fneur.2023.1069411. eCollection 2023.

Authors

Pia Kivisäkk¹, Becky C Carlyle^{1

2}, Thadryan Sweeney¹, Bianca A Trombetta¹, Kathryn LaCasse¹, Leena El-Mufti¹, Idil Tuncali³, Lori B Chibnik^{4

5}, Sudeshna Das⁴, Clemens R Scherzer³, Keith A Johnson⁴, Bradford C Dickerson⁴, Teresa Gomez-Isla⁴, Deborah Blacker⁶, Derek H Oakley⁷, Matthew P Frosch⁷, Bradley T Hyman⁴, Anahit Aghvanyan⁸, Pradeepthi Bathala⁸, Christopher Campbell⁸, George Sigal⁸, Martin Stengelin⁸, Steven E Arnold¹

Affiliations

¹ Alzheimer's Clinical and Translational Research Unit, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States.
² Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom.
³ Precision Neurology Program and Center for Advanced Parkinson Research, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, United States.
⁴ Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States.
⁵ Department of Epidemiology, Harvard TH Chan School of Public Health, Boston, MA, United States.
⁶ Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States.
⁷ Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States.
⁸ Meso Scale Diagnostics, LLC., Rockville, MD, United States.

Abstract

Background: The last few years have seen major advances in blood biomarkers for Alzheimer's Disease (AD) with the development of ultrasensitive immunoassays, promising to transform how we diagnose, prognose, and track progression of neurodegenerative dementias.

Methods: We evaluated a panel of four novel ultrasensitive electrochemiluminescence (ECL) immunoassays against presumed CNS derived proteins of interest in AD in plasma [phosphorylated-Tau181 (pTau181), total Tau (tTau), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP)]. Two sets of banked plasma samples from the Massachusetts Alzheimer's Disease Research Center's longitudinal cohort study were examined: A longitudinal prognostic sample (n = 85) consisting of individuals with mild cognitive impairment (MCI) and 4 years of follow-up and a cross-sectional sample (n = 238) consisting of individuals with AD, other neurodegenerative diseases (OND), and normal cognition (CN).

Results: Participants with MCI who progressed to dementia due to probable AD during follow-up had higher baseline plasma concentrations of pTau181, NfL, and GFAP compared to non-progressors. The best prognostic discrimination was observed with pTau181 (AUC = 0.83, 1.7-fold increase) and GFAP (AUC = 0.83, 1.6-fold increase). Participants with autopsy- and/or biomarker verified AD had higher plasma levels of pTau181, tTau and GFAP compared to CN and OND, while NfL was elevated in AD and further increased in OND. The best diagnostic discrimination was observed with pTau181 (AD vs CN: AUC = 0.90, 2-fold increase; AD vs. OND: AUC = 0.84, 1.5-fold increase) but tTau, NfL, and GFAP also showed good discrimination between AD and CN (AUC = 0.81-0.85; 1.5-2.2 fold increase).

Conclusions: These new ultrasensitive ECL plasma assays for pTau181, tTau, NfL, and GFAP demonstrated diagnostic utility for detection of AD. Moreover, the absolute baseline plasma levels of pTau181 and GFAP reflect cognitive decline over the next 4 years, providing prognostic information that may have utility in both clinical practice and clinical trial populations.

Keywords: Alzheimer's disease; biomarker; glial fibrillary acidic protein (GFAP); mild cognitive impairment; neurofilament light (NfL); pTau181; plasma; total Tau (tTau).

Copyright © 2023 Kivisäkk, Carlyle, Sweeney, Trombetta, LaCasse, El-Mufti, Tuncali, Chibnik, Das, Scherzer, Johnson, Dickerson, Gomez-Isla, Blacker, Oakley, Frosch, Hyman, Aghvanyan, Bathala, Campbell, Sigal, Stengelin and Arnold.

Abstract

Grants and funding