Longitudinal Associations of Blood Phosphorylated Tau181 and Neurofilament Light Chain With Neurodegeneration in Alzheimer Disease
Alzheimer's Disease Neuroimaging Initiative. ; [Importance] Plasma phosphorylated tau at threonine 181 (p-tau181) has been proposed as an easily accessible biomarker for the detection of Alzheimer disease (AD) pathology, but its ability to monitor disease progression in AD remains unclear. ; [Objective] To study the potential of longitudinal plasma p-tau181 measures for assessing neurodegeneration progression and cognitive decline in AD in comparison to plasma neurofilament light chain (NfL), a disease-nonspecific marker of neuronal injury. ; [Design, Setting, and Participants] This longitudinal cohort study included data from the Alzheimer's Disease Neuroimaging Initiative from February 1, 2007, to June 6, 2016. Follow-up blood sampling was performed for up to 8 years. Plasma p-tau181 measurements were performed in 2020. This was a multicentric observational study of 1113 participants, including cognitively unimpaired participants as well as patients with cognitive impairment (mild cognitive impairment and AD dementia). Participants were eligible for inclusion if they had available plasma p-tau181 and NfL measurements and at least 1 fluorine-18–labeled fluorodeoxyglucose (FDG) positron emission tomography (PET) or structural magnetic resonance imaging scan performed at the same study visit. Exclusion criteria included any significant neurologic disorder other than suspected AD; presence of infection, infarction, or multiple lacunes as detected by magnetic resonance imaging; and any significant systemic condition that could lead to difficulty complying with the protocol. ; [Exposures] Plasma p-tau181 and NfL measured with single-molecule array technology. ; [Main Outcomes and Measures] Longitudinal imaging markers of neurodegeneration (FDG PET and structural magnetic resonance imaging) and cognitive test scores (Preclinical Alzheimer Cognitive Composite and Alzheimer Disease Assessment Scale–Cognitive Subscale with 13 tasks). Data were analyzed from June 20 to August 15, 2020. ; [Results] Of the 1113 participants (mean [SD] age, 74.0 [7.6] years; 600 men [53.9%]; 992 non-Hispanic White participants [89.1%]), a total of 378 individuals (34.0%) were cognitively unimpaired (CU) and 735 participants (66.0%) were cognitively impaired (CImp). Of the CImp group, 537 (73.1%) had mild cognitive impairment, and 198 (26.9%) had AD dementia. Longitudinal changes of plasma p-tau181 were associated with cognitive decline (CU: r = –0.24, P < .001; CImp: r = 0.34, P < .001) and a prospective decrease in glucose metabolism (CU: r = –0.05, P = .48; CImp: r = –0.27, P < .001) and gray matter volume (CU: r = –0.19, P < .001; CImp: r = –0.31, P < .001) in highly AD-characteristic brain regions. These associations were restricted to amyloid-β–positive individuals. Both plasma p-tau181 and NfL were independently associated with cognition and neurodegeneration in brain regions typically affected in AD. However, NfL was also associated with neurodegeneration in brain regions exceeding this AD-typical spatial pattern in amyloid-β–negative participants. Mediation analyses found that approximately 25% to 45% of plasma p-tau181 outcomes on cognition measures were mediated by the neuroimaging-derived markers of neurodegeneration, suggesting links between plasma p-tau181 and cognition independent of these measures. ; [Conclusions and Relevance] Study findings suggest that plasma p-tau181 was an accessible and scalable marker for predicting and monitoring neurodegeneration and cognitive decline and was, unlike plasma NfL, AD specific. The study findings suggest implications for the use of plasma biomarkers as measures to monitor AD progression in clinical practice and treatment trials. ; This work was supported by the "Miguel Servet" program grant CP19/00031 of the Spanish Instituto de Salud Carlos III (Dr Grothe); research fellowship A202f0812F from the Brightfocus Foundation, grant AF-930627 from the Swedish Alzheimer Foundation, grant FO2020-0240 from the Swedish Brain Foundation, grant 2020-00124 from the Agneta Prytz-Folkes & Gösta Folkes Foundation, and support from the Swedish Dementia Foundation, the Aina (Ann) Wallströms and Mary-Ann Sjöbloms Foundation, the Anna Lisa and Brother Björnsson's Foundation, Gamla Tjänarinnor, and the Gun and Bertil Stohnes Foundation (Dr Karikari); the Paulo Foundation and the Orion Research Foundation (Dr Snellman); grant 752310 from the European Union's Horizon 2020 Research and Innovation Program under the Marie Skłodowska-Curie action grant agreement, grant PI19/00155 from the Instituto de Salud Carlos III, and grant IJC2018-037478-I from the Spanish Ministry of Science, Innovation and Universities (Juan de la Cierva Programme) (Dr Suárez-Calvet); grant 2018-02532 from the Swedish Research Council, 681712 from the European Research Council, ALFGBG-720931 from the Swedish State Support for Clinical Research, 201809-2016862 from the Alzheimer Drug Discovery Foundation USA, and the UK Dementia Research Institute at University College London (Dr Zetterberg); grant 2017-00915 from the Swedish Research Council, RDAPB-201809-2016615 from the Alzheimer Drug Discovery Foundation USA, AF-742881 from the Swedish Alzheimer Foundation, FO2017-0243 from Hjärnfonden, Sweden, the Swedish state under the agreement between the Swedish government and the County Councils, ALFGBG-715986 from the ALF-agreement, and JPND2019-466-236 from the European Union Joint Program for Neurodegenerative Disorders (Dr Blennow); KAW 2014.0363 from the Knut and Alice Wallenberg Foundation (Wallenberg Centre for Molecular and Translational Medicine, 2017-02869 from the Swedish Research Council, ALFGBG-813971 from the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement, and AF-740191 from the Swedish Alzheimer Foundation (Dr. Schöll). Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (grant AG024904) and Department of Defense ADNI (grant W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc; Cogstate; Eisai Inc; Elan Pharmaceuticals, Inc; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc; Fujirebio; GE Healthcare; IXICO Ltd; Janssen Alzheimer Immunotherapy Research & Development, LLC; Johnson & Johnson Pharmaceutical Research & Development LLC; Lumosity; Lundbeck; Merck & Co, Inc; Meso Scale Diagnostics, LLC; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Therapeutic Research Institute at the University of Southern California. ; Peer reviewed