Combining plasma phospho-tau and accessible measures to evaluate progression to Alzheimer's dementia in mild cognitive impairment patients

Alexa Pichet Binette, Sebastian Palmqvist, Divya Bali, Gill Farrar, Christopher J Buckley, David A Wolk, Henrik Zetterberg, Kaj Blennow, Shorena Janelidze, Oskar Hansson, Alexa Pichet Binette, Sebastian Palmqvist, Divya Bali, Gill Farrar, Christopher J Buckley, David A Wolk, Henrik Zetterberg, Kaj Blennow, Shorena Janelidze, Oskar Hansson

Abstract

Background: Up to now, there are no clinically available minimally invasive biomarkers to accurately identify mild cognitive impairment (MCI) patients who are at greater risk to progress to Alzheimer's disease (AD) dementia. The recent advent of blood-based markers opens the door for more accessible biomarkers. We aimed to identify which combinations of AD related plasma biomarkers and other easily accessible assessments best predict progression to AD dementia in patients with mild cognitive impairment (MCI).

Methods: We included patients with amnestic MCI (n = 110) followed prospectively over 3 years to assess clinical status. Baseline plasma biomarkers (amyloid-β 42/40, phosphorylated tau217 [p-tau217], neurofilament light and glial fibrillary acidic protein), hippocampal volume, APOE genotype, and cognitive tests were available. Logistic regressions with conversion to amyloid-positive AD dementia within 3 years as outcome was used to evaluate the performance of different biomarkers measured at baseline, used alone or in combination. The first analyses included only the plasma biomarkers to determine the ones most related to AD dementia conversion. Second, hippocampal volume, APOE genotype and a brief cognitive composite score (mPACC) were combined with the best plasma biomarker.

Results: Of all plasma biomarker combinations, p-tau217 alone had the best performance for discriminating progression to AD dementia vs all other combinations (AUC 0.84, 95% CI 0.75-0.93). Next, combining p-tau217 with hippocampal volume, cognition, and APOE genotype provided the best discrimination between MCI progressors vs. non-progressors (AUC 0.89, 0.82-0.95). Across the few best models combining different markers, p-tau217 and cognition were consistently the main contributors. The most parsimonious model including p-tau217 and cognition had a similar model fit, but a slightly lower AUC (0.87, 0.79-0.95, p = 0.07).

Conclusion: We identified that combining plasma p-tau217 and a brief cognitive composite score was strongly related to greater risk of progression to AD dementia in MCI patients, suggesting that these measures could be key components of future prognostic algorithms for early AD.

Trial registration: NCT01028053 , registered December 9, 2009.

Keywords: Alzheimer’s disease; Dementia; Mild cognitive impairment; Plasma biomarkers; p-tau.

Conflict of interest statement

Henrik Zetterberg has served at scientific advisory boards and/or as a consultant for Abbvie, Alector, Eisai, Denali, Roche, Wave, Samumed, Siemens Healthineers, Pinteon Therapeutics, Nervgen, AZTherapies, CogRx, and Red Abbey Labs, has given lectures in symposia sponsored by Cellectricon, 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. Oskar Hansson has acquired research support (for the institution) from AVID Radiopharmaceuticals, Biogen, Eli Lilly, Eisai, GE Healthcare, Pfizer, and Roche. In the past 2 years, he has received consultancy/speaker fees from AC Immune, Alzpath, Biogen, Cerveau and Roche. Sebastian Palmqvist has served on scientific advisory boards and/or given lectures in symposia sponsored by F. Hoffmann-La Roche, Biogen, and Geras Solutions. Kaj Blennow has served as a consultant, at advisory boards, or at data monitoring committees for Abcam, Axon, Biogen, JOMDD/Shimadzu. Julius Clinical, Lilly, MagQu, Novartis, Prothena, 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. Gill Farrar and Christopher Buckley are full time employees of GE Healthcare who sponsored the Wolk et al (2018) study from which these plasma samples were derived. Dr. Wolk has received research support (for the institution) for Eli Lilly, Biogen, and Merck. He has also received consulting fees from GE Healthcare and Neuronix and Honoria for DSMB participation from Functional Neuromodulation.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Comparisons of plasma biomarkers between MCI who progressed to AD dementia and those who did not. Levels of plasma p-tau217 (A), NfL (B), Aβ42/Aβ40 ratio (C), and GFAP (D) between MCI patients who did not progress to AD dementia (non-progressors) vs. those who progressed to AD dementia (progressors) within 3 years. Boxes represent the first and third quartile of each distribution, and whiskers extend up to 1.5-times the interquartile range. Corresponding p-value and Cohen’s d effect size are reported on the top of each panel. Aβ, beta-amyloid; GFAP, glial fibrillary acidic protein; NfL, neurofilament light; MCI, mild cognitive impairment; p-tau217, phosphorylated tau 217
Fig. 2
Fig. 2
Receiver operating characteristic curves from different combinations of markers related to conversion to AD dementia. Receiver operating characteristic curves from logistic regression models discriminating MCI patients who progressed to AD dementia within 3 years (n = 23) vs. those who did not (n = 77) in the subsample with plasma p-tau217 and all other AD markers of interest (global cognition from mPACC, hippocampal volume and APOE4 status). All details of the different models are reported in Table 3. APOE, apolipoprotein E genotype (carrying at least one ε4 allele); AUC, area under the curve; hipp, hippocampal volume (adjusted for total intracranial volume); mPACC, modified Preclinical Alzheimer’s Cognitive Composite; p-tau217, phosphorylated tau 217

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