Blood Phosphorylated Tau 181 as a Biomarker for Amyloid Burden on Brain PET in Cognitively Healthy Adults

Article type: Research Article

Authors: McGrath, Emer R.^{a; b; *} | Beiser, Alexa S.^{b; c; d} | O’Donnell, Adrienne^{b; c} | Yang, Qiong^{b; c} | Ghosh, Saptaparni^{b; d} | Gonzales, Mitzi M.^{b; e} | Himali, Jayandra J.^{b; c; d; e} | Satizabal, Claudia L.^{b; e} | Johnson, Keith A.^{f; g; h} | Tracy, Russell P.^{i; j} | Seshadri, Sudha^{b; d; e}

Affiliations: [a] HRB Clinical Research Facility, National University of Ireland Galway, Galway, Ireland | [b] The Framingham Heart Study, Framingham, MA, USA | [c] Boston University School of Public Health, Boston, MA, USA | [d] Boston University School of Medicine, Boston, MA, USA | [e] Glenn Biggs Institute for Alzheimer’s & Neurodegenerative Diseases, University of Texas Health Sciences Center, San Antonio, TX, USA | [f] Department of Radiology, Massachusetts General Hospital, the Gordon Center for Medical Imaging and the Athinoula A. Martinos Center for Biomedical Imaging, Boston, MA, USA | [g] Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA | [h] Center for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA | [i] Department of Pathology and Laboratory Medicine, Larner College of Medicine, University of Vermont, Burlington, VT, USA | [j] Department of Biochemistry, Larner College of Medicine, University of Vermont, Burlington, VT, USA

Correspondence: [*] Correspondence to: Dr. Emer McGrath, HRB Clinical Research Facility, National University of Ireland Galway, University Road, Galway H91 TK33, Ireland. Tel.: +353 91 524411; E-mail: emer.mcgrath@nuigalway.ie.

Abstract: Background:Plasma phosphorylated-tau181 (p-tau181) is a promising biomarker for Alzheimer’s disease (AD) and may offer utility for predicting preclinical disease. Objective:To evaluate the prospective association between plasma p-tau181 and amyloid-β (Aβ) and tau-PET deposition in cognitively unimpaired individuals. Methods:Plasma p-tau181 levels were measured at baseline in 52 [48% women, mean 64.4 (SD 5.5) years] cognitively unimpaired Framingham Offspring cohort participants using samples stored between 2011–2014 who subsequently underwent 11C-Pittsburgh Compound-B (PiB)-PET and/or 18F-Flortaucipir (FTP)-PET scans (n = 18 with tau-PET) a mean of 6.8 (SD 0.6) years later. Our primary outcomes included Aβ-precuneus, Aβ-FLR (frontal, lateral, and retrosplenial cortices) and tau-global composite region PET deposition. Secondary outcomes included individual regional Aβ and tau PET-deposition. P-tau181 was compared with plasma neurofilament light chain (NFL) and glial fibrillary acidic protein (GFAP) in predicting PET outcomes. Results:P-tau181 was associated with increased Aβ deposition in the FLR (β±SE, 1.25±0.30, p < 0.0001), precuneus (1.35±0.29, p < 0.001), and other cortical regions. Plasma NFL (1.30±0.49, p = 0.01) and GFAP (1.46±0.39, p < 0.001) were also associated with FLR Aβ deposition. In models including all three biomarkers adjusted for age, sex, APOE E4 allele, AD polygenic risk score and cortical atrophy score, p-tau181 (0.93±0.31, p < 0.01, R2 = 0.18) and GFAP (0.93±0.41, p = 0.03, R2 = 0.11), but not NFL (0.25±0.51, p = 0.62, R2 = 0.01), were associated with FLR-Aβ deposition. Plasma p-tau181 was not associated with tau-PET burden. Conclusion:In cognitively unimpaired adults, elevated plasma p-tau181 is associated with future increased Aβ deposition across multiple brain regions. Our results highlight the potential utility of p-tau181 as a blood-biomarker to screen for brain-amyloid deposition in cognitively healthy individuals in a community-setting.

Keywords: Dementia, brain positron emission tomography, Aβ-PET, tau-PET, biomarkers

DOI: 10.3233/JAD-215639

Journal: Journal of Alzheimer's Disease, vol. 87, no. 4, pp. 1517-1526, 2022