Four distinct trajectories of tau deposition identified in Alzheimer’s disease

doi:10.1038/s41591-021-01309-6

Four distinct trajectories of tau deposition identified in Alzheimer’s disease

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Abstract

Alzheimer’s disease (AD) is characterized by the spread of tau pathology throughout the cerebral cortex. This spreading pattern was thought to be fairly consistent across individuals, although recent work has demonstrated substantial variability in the population with AD. Using tau-positron emission tomography scans from 1,612 individuals, we identified 4 distinct spatiotemporal trajectories of tau pathology, ranging in prevalence from 18 to 33%. We replicated previously described limbic-predominant and medial temporal lobe-sparing patterns, while also discovering posterior and lateral temporal patterns resembling atypical clinical variants of AD. These ‘subtypes’ were stable during longitudinal follow-up and were replicated in a separate sample using a different radiotracer. The subtypes presented with distinct demographic and cognitive profiles and differing longitudinal outcomes. Additionally, network diffusion models implied that pathology originates and spreads through distinct corticolimbic networks in the different subtypes. Together, our results suggest that variation in tau pathology is common and systematic, perhaps warranting a re-examination of the notion of ‘typical AD’ and a revisiting of tau pathological staging.

Original language	English
Pages (from-to)	871-881
Number of pages	11
Journal	Nature Medicine
Volume	27
Issue number	5
DOIs	https://doi.org/10.1038/s41591-021-01309-6
State	Published - May 2021

Bibliographical note

Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.

Funding

The authors thank M. Chakravarty, B. Misic, P. Bellec, P. Rosa-Neto, A. Dagher, E. Hamel and W. Seeley for feedback during the composition of this manuscript. J.W.V. acknowledges support from the government of Canada through a tri-council Vanier Canada Graduate Doctoral fellowship from the McGill Centre for Integrative Neuroscience and the Healthy Brains, Healthy Lives initiative, and from the National Institutes of Health (NIH) (no. T32MH019112). A.L.Y. is supported by a Medical Research Council Skills Development Fellowship (MR/T027800/1). N.P.O. is a UK Research and Innovation Future Leaders Fellow (no. MR/S03546X/1). N.P.O. and D.C.A. acknowledge support from the UK National Institute for Health Research University College London Hospitals Biomedical Research Centre, and D.C.A. acknowledges support from the Engineering and Physical Sciences Research Council grant no. EP/ M020533/1. M.J.G. is supported by the Miguel Servet program (no. CP19/00031) and a research grant (no. PI20/00613) of the Instituto de Salud Carlos III-Fondo Europeo de Desarrollo Regional. R.L.J. acknowledges support from the NIH (no. K99AG065501). This project received funding from the European Union’s Horizon 2020 research and innovation programme under grant no. 666992. The BioFINDER studies are supported by the Swedish Research Council (no. 2016-00906), the Knut and Alice Wallenberg Foundation (no. 2017-0383), the Marianne and Marcus Wallenberg Foundation (no. 2015.0125), the Strategic Research Area MultiPark (Multidisciplinary Research in Parkinson’s disease) at Lund University, the Swedish Alzheimer’s Foundation (no. AF-939932), the Swedish Brain Foundation (no. FO2019-0326), the Swedish Parkinson Foundation (no. 1280/20), the Skåne University Hospital Foundation (no. 2020-O000028), Regionalt Forskningsstöd (no. 2020-0314) and the Swedish Federal Government under the ALF agreement (no. 2018-Projekt0279). The Tau PET study in Gangnam Severance Hospital was supported by a grant from the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education (nos. NRF2018R1D1A1B07049386 and NRF2020R1F1A1076154) and a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute funded by the Ministry of Health and Welfare, Republic of Korea (grant no. HI18C1159). We also thank B. L. Miller, H. J. Rosen, M. Gorno Tempini and W. Jagust for supporting the UCSF tau-PET studies, which were funded through the following sources: National Institute on Aging (NIA) no. R01 AG045611 (G.D.R.), no. P50 AG23501 (B.L.M., H.J.R., G.D.R.), no. P01 AG019724 (B.L.M., H.J.R., G.D.R.). The precursor of 18F-flortaucipir was provided by AVID Radiopharmaceuticals. The precursor of 18F-flutemetamol was sponsored by GE Healthcare. The precursor of 18F-RO948 was provided by Roche. Data collection and sharing for this project were funded by ADNI (NIH grant no. U01 AG024904) and Department of Defense ADNI (award no. W81XWH-12-2-0012). ADNI is funded by the NIA, 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; Biogen; Bristol Myers Squibb; CereSpir; Cogstate; Eisai; Elan Pharmaceuticals; Eli Lilly and Company; EUROIMMUN; F. Hoffmann-La Roche and its affiliated company Genentech; Fujirebio; GE Healthcare; IXICO; Janssen Alzheimer Immunotherapy Research Development; Johnson & Johnson Pharmaceutical Research Development; Lumosity; Lundbeck; Merck; Meso Scale Diagnostics; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer; 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. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. Finally, we thank all participants of this study and the families and caregivers of the patients included for their support in volunteering data for this study. Data used in the preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (http://adni.loni.usc.edu/). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report.

Funders	Funder number
Araclon Biotech
CereSpir, Inc.
US Department of Defense ADNI	W81XWH-12-2-0012
Canada Excellence Research Chairs, Government of Canada
Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden
Instituto de Salud Carlos III-Fondo Europeo de Desarrollo Regional
McGill Centre for Integrative Neuroscience
Korean Ministry of Health and Welfare
National Institute of Mental Health
National Institute on Aging
National Research Foundation of Korea
Regionalt Forskningsstöd	2020-0314
Swedish Alzheimer’s Foundation	AF-939932
Swedish Federal Government	2018-Projekt0279
National Institutes of Health (NIH)	T32MH019112
National Institutes of Health (NIH)
National Institute on Aging	K99AG065501, U01AG024904, R01 AG045611, P50 AG23501, P01 AG019724
National Institute on Aging
National Institute of Biomedical Imaging and Bioengineering
Alzheimer's Association
Bristol-Myers Squibb
Alzheimer's Drug Discovery Foundation
Eli Lilly and Company
Genentech Incorporated
Biogen IDEC
GE Healthcare
F. Hoffmann-La Roche AG
DoD Alzheimer's Disease Neuroimaging Initiative	U01 AG024904
DoD Alzheimer's Disease Neuroimaging Initiative
BioClinica Inc.
Parkinsonfonden	1280/20
Parkinsonfonden
Horizon 2020 Framework Programme	666992
Horizon 2020 Framework Programme
Ministère de l’Éducation, Gouvernement de l’Ontario	NRF2020R1F1A1076154, NRF2018R1D1A1B07049386
Ministère de l’Éducation, Gouvernement de l’Ontario
AbbVie Canada
Canada Excellence Research Chairs, Government of Canada
Medical Research Council	MR/T027800/1
Medical Research Council
Engineering and Physical Sciences Research Council	CP19/00031, EP/ M020533/1, PI20/00613
Engineering and Physical Sciences Research Council
Lunds Universitet
Korean Ministry of Health and Welfare	HI18C1159
Korean Ministry of Health and Welfare
National Research Foundation of Korea
Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden	FO2019-0326
Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden
Knut och Alice Wallenbergs Stiftelse	2017-0383
Knut och Alice Wallenbergs Stiftelse
Vetenskapsrådet	2016-00906
Vetenskapsrådet
Fujirebio Europe
Marcus och Amalia Wallenbergs minnesfond	2015.0125
Marcus och Amalia Wallenbergs minnesfond
UCLH Biomedical Research Centre
University of Alberta Hospital Foundation	2020-O000028
University of Alberta Hospital Foundation
tri-council Vanier Canada Graduate Doctoral

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1038/s41591-021-01309-6

Cite this

@article{502a8fc7ee1c4af59ae4cd13d4dbaea5,

title = "Four distinct trajectories of tau deposition identified in Alzheimer{\textquoteright}s disease",

abstract = "Alzheimer{\textquoteright}s disease (AD) is characterized by the spread of tau pathology throughout the cerebral cortex. This spreading pattern was thought to be fairly consistent across individuals, although recent work has demonstrated substantial variability in the population with AD. Using tau-positron emission tomography scans from 1,612 individuals, we identified 4 distinct spatiotemporal trajectories of tau pathology, ranging in prevalence from 18 to 33%. We replicated previously described limbic-predominant and medial temporal lobe-sparing patterns, while also discovering posterior and lateral temporal patterns resembling atypical clinical variants of AD. These {\textquoteleft}subtypes{\textquoteright} were stable during longitudinal follow-up and were replicated in a separate sample using a different radiotracer. The subtypes presented with distinct demographic and cognitive profiles and differing longitudinal outcomes. Additionally, network diffusion models implied that pathology originates and spreads through distinct corticolimbic networks in the different subtypes. Together, our results suggest that variation in tau pathology is common and systematic, perhaps warranting a re-examination of the notion of {\textquoteleft}typical AD{\textquoteright} and a revisiting of tau pathological staging.",

author = "Vogel, {Jacob W.} and Young, {Alexandra L.} and Oxtoby, {Neil P.} and Ruben Smith and Rik Ossenkoppele and Strandberg, {Olof T.} and {La Joie}, Renaud and Aksman, {Leon M.} and Grothe, {Michel J.} and Yasser Iturria-Medina and Michael Weiner and Paul Aisen and Ronald Petersen and Jack, {Clifford R.} and William Jagust and Trojanowki, {John Q.} and Toga, {Arthur W.} and Laurel Beckett and Green, {Robert C.} and Saykin, {Andrew J.} and John Morris and Shaw, {Leslie M.} and Enchi Liu and Tom Montine and Thomas, {Ronald G.} and Michael Donohue and Sarah Walter and Devon Gessert and Tamie Sather and Gus Jiminez and Danielle Harvey and Matthew Bernstein and Nick Fox and Paul Thompson and Norbert Schuff and Charles DeCArli and Bret Borowski and Jeff Gunter and Matt Senjem and Prashanthi Vemuri and David Jones and Kejal Kantarci and Chad Ward and Koeppe, {Robert A.} and Norm Foster and Reiman, {Eric M.} and Kewei Chen and Chet Mathis and Greg Jicha and Richard King",

note = "Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.",

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Four distinct trajectories of tau deposition identified in Alzheimer’s disease

Abstract

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