Plasma phosphorylated tau 217 in preclinical Alzheimer's disease

Erin M Jonaitis; Shorena Janelidze; Karly A Cody; Rebecca Langhough; Lianlian Du; Nathaniel A Chin; Niklas Mattsson-Carlgren; Kirk J Hogan; Bradley T Christian; Tobey J Betthauser; Oskar Hansson; Sterling C Johnson

doi:10.1093/braincomms/fcad057

Plasma phosphorylated tau 217 in preclinical Alzheimer's disease

Brain Commun. 2023 Mar 6;5(2):fcad057. doi: 10.1093/braincomms/fcad057. eCollection 2023.

Authors

Erin M Jonaitis^{1

2

3}, Shorena Janelidze⁴, Karly A Cody², Rebecca Langhough^{1

2

3}, Lianlian Du^{2

5}, Nathaniel A Chin³, Niklas Mattsson-Carlgren^{4

6

7}, Kirk J Hogan⁸, Bradley T Christian^{9

10}, Tobey J Betthauser^{2

3}, Oskar Hansson^{4

11}, Sterling C Johnson^{12

1

2}

Affiliations

¹ Wisconsin Alzheimer's Institute, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53726, USA.
² Wisconsin Alzheimer's Disease Research Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53792, USA.
³ Department of Medicine, Division of Geriatrics and Gerontology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53792, USA.
⁴ Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Lund 205 02, Sweden.
⁵ Department of Biostatistics and Medical Informatics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53726, USA.
⁶ Department of Neurology, Skåne University Hospital, Lund 222 42, Sweden.
⁷ Wallenberg Center for Molecular Medicine, Lund University, Lund 221 84, Sweden.
⁸ Department of Anesthesiology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53792, USA.
⁹ Department of Medical Physics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705, USA.
¹⁰ Department of Psychiatry, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53719, USA.
¹¹ Memory Clinic, Skåne University Hospital, 20502, Malmö, Sweden.
¹² Geriatric Research Education and Clinical Center of the Wm. S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA.

Abstract

An accurate blood test for Alzheimer's disease that is sensitive to preclinical proteinopathy and cognitive decline has clear implications for early detection and secondary prevention. We assessed the performance of plasma phosphorylated tau 217 ( $pTa u_{217}$ ) against brain PET markers of amyloid [ $[^{11} C]$ -labelled Pittsburgh compound B (PiB)] and tau ( $[^{18} F]$ MK-6240) and its utility for predicting longitudinal cognition. Samples were analysed from a subset of participants with up to 8 years follow-up in the Wisconsin Registry for Alzheimer's Prevention (WRAP; 2001-present; plasma 2011-present), a longitudinal cohort study of adults from midlife, enriched for parental history of Alzheimer's disease. Participants were a convenience sample who volunteered for at least one PiB scan, had usable banked plasma and were cognitively unimpaired at first plasma collection. Study personnel who interacted with participants or samples were blind to amyloid status. We used mixed effects models and receiver-operator characteristic curves to assess concordance between plasma $pTa u_{217}$ and PET biomarkers of Alzheimer's disease and mixed effects models to understand the ability of plasma $pTa u_{217}$ to predict longitudinal performance on WRAP's preclinical Alzheimer's cognitive composite (PACC-3). The primary analysis included 165 people (108 women; mean age = 62.9 $\pm$ 6.06; 160 still enrolled; 2 deceased; 3 discontinued). Plasma $pTa u_{217}$ was strongly related to PET-based estimates of concurrent brain amyloid ( ${\hat{β}}_{}$ = 0.83 (0.75, 0.90), P < 0.001). Concordance was high between plasma $pTa u_{217}$ and both amyloid PET (area under the curve = 0.91, specificity = 0.80, sensitivity = 0.85, positive predictive value = 0.58, negative predictive value = 0.94) and tau PET (area under the curve = 0.95, specificity = 1, sensitivity = 0.85, positive predictive value = 1, negative predictive value = 0.98). Higher baseline $pTa u_{217}$ levels were associated with worse cognitive trajectories ( ${\hat{β}}_{p T a u \times a g e}$ = -0.07 (-0.09, -0.06), P < 0.001). In a convenience sample of unimpaired adults, plasma $pTa u_{217}$ levels correlate well with concurrent brain Alzheimer's disease pathophysiology and with prospective cognitive performance. These data indicate that this marker can detect disease before clinical signs and thus may disambiguate presymptomatic Alzheimer's disease from normal cognitive ageing.

Keywords: Alzheimer’s disease; amyloid beta; cognitively unimpaired; pTau117; plasma.

Abstract

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