Comparison of tau spread in people with Down syndrome versus autosomal-dominant Alzheimer's disease: a cross-sectional study.


Journal

The Lancet. Neurology
ISSN: 1474-4465
Titre abrégé: Lancet Neurol
Pays: England
ID NLM: 101139309

Informations de publication

Date de publication:
May 2024
Historique:
received: 16 11 2023
revised: 01 02 2024
accepted: 21 02 2024
medline: 18 4 2024
pubmed: 18 4 2024
entrez: 17 4 2024
Statut: ppublish

Résumé

In people with genetic forms of Alzheimer's disease, such as in Down syndrome and autosomal-dominant Alzheimer's disease, pathological changes specific to Alzheimer's disease (ie, accumulation of amyloid and tau) occur in the brain at a young age, when comorbidities related to ageing are not present. Studies including these cohorts could, therefore, improve our understanding of the early pathogenesis of Alzheimer's disease and be useful when designing preventive interventions targeted at disease pathology or when planning clinical trials. We compared the magnitude, spatial extent, and temporal ordering of tau spread in people with Down syndrome and autosomal-dominant Alzheimer's disease. In this cross-sectional observational study, we included participants (aged ≥25 years) from two cohort studies. First, we collected data from the Dominantly Inherited Alzheimer's Network studies (DIAN-OBS and DIAN-TU), which include carriers of autosomal-dominant Alzheimer's disease genetic mutations and non-carrier familial controls recruited in Australia, Europe, and the USA between 2008 and 2022. Second, we collected data from the Alzheimer Biomarkers Consortium-Down Syndrome study, which includes people with Down syndrome and sibling controls recruited from the UK and USA between 2015 and 2021. Controls from the two studies were combined into a single group of familial controls. All participants had completed structural MRI and tau PET ( We included 137 people with Down syndrome (mean age 38·5 years [SD 8·2], 74 [54%] male, and 63 [46%] female), 49 individuals with autosomal-dominant Alzheimer's disease (mean age 43·9 years [11·2], 22 [45%] male, and 27 [55%] female), and 85 familial controls, pooled from across both studies (mean age 41·5 years [12·1], 28 [33%] male, and 57 [67%] female), who satisfied the PET quality-control procedure for tau-PET imaging processing. 134 (98%) people with Down syndrome, 44 (90%) with autosomal-dominant Alzheimer's disease, and 77 (91%) controls also completed an amyloid PET scan within 3 years of tau PET imaging. Spatially, tau PET burden was observed most frequently in subcortical and medial temporal regions in people with Down syndrome, and within the medial temporal lobe in people with autosomal-dominant Alzheimer's disease. Across the brain, people with Down syndrome had greater concentrations of tau for a given level of amyloid compared with people with autosomal-dominant Alzheimer's disease. Temporally, increases in tau were more strongly associated with increases in amyloid for people with Down syndrome compared with autosomal-dominant Alzheimer's disease. Although the general progression of amyloid followed by tau is similar for people Down syndrome and people with autosomal-dominant Alzheimer's disease, we found subtle differences in the spatial distribution, timing, and magnitude of the tau burden between these two cohorts. These differences might have important implications; differences in the temporal pattern of tau accumulation might influence the timing of drug administration in clinical trials, whereas differences in the spatial pattern and magnitude of tau burden might affect disease progression. None.

Sections du résumé

BACKGROUND BACKGROUND
In people with genetic forms of Alzheimer's disease, such as in Down syndrome and autosomal-dominant Alzheimer's disease, pathological changes specific to Alzheimer's disease (ie, accumulation of amyloid and tau) occur in the brain at a young age, when comorbidities related to ageing are not present. Studies including these cohorts could, therefore, improve our understanding of the early pathogenesis of Alzheimer's disease and be useful when designing preventive interventions targeted at disease pathology or when planning clinical trials. We compared the magnitude, spatial extent, and temporal ordering of tau spread in people with Down syndrome and autosomal-dominant Alzheimer's disease.
METHODS METHODS
In this cross-sectional observational study, we included participants (aged ≥25 years) from two cohort studies. First, we collected data from the Dominantly Inherited Alzheimer's Network studies (DIAN-OBS and DIAN-TU), which include carriers of autosomal-dominant Alzheimer's disease genetic mutations and non-carrier familial controls recruited in Australia, Europe, and the USA between 2008 and 2022. Second, we collected data from the Alzheimer Biomarkers Consortium-Down Syndrome study, which includes people with Down syndrome and sibling controls recruited from the UK and USA between 2015 and 2021. Controls from the two studies were combined into a single group of familial controls. All participants had completed structural MRI and tau PET (
FINDINGS RESULTS
We included 137 people with Down syndrome (mean age 38·5 years [SD 8·2], 74 [54%] male, and 63 [46%] female), 49 individuals with autosomal-dominant Alzheimer's disease (mean age 43·9 years [11·2], 22 [45%] male, and 27 [55%] female), and 85 familial controls, pooled from across both studies (mean age 41·5 years [12·1], 28 [33%] male, and 57 [67%] female), who satisfied the PET quality-control procedure for tau-PET imaging processing. 134 (98%) people with Down syndrome, 44 (90%) with autosomal-dominant Alzheimer's disease, and 77 (91%) controls also completed an amyloid PET scan within 3 years of tau PET imaging. Spatially, tau PET burden was observed most frequently in subcortical and medial temporal regions in people with Down syndrome, and within the medial temporal lobe in people with autosomal-dominant Alzheimer's disease. Across the brain, people with Down syndrome had greater concentrations of tau for a given level of amyloid compared with people with autosomal-dominant Alzheimer's disease. Temporally, increases in tau were more strongly associated with increases in amyloid for people with Down syndrome compared with autosomal-dominant Alzheimer's disease.
INTERPRETATION CONCLUSIONS
Although the general progression of amyloid followed by tau is similar for people Down syndrome and people with autosomal-dominant Alzheimer's disease, we found subtle differences in the spatial distribution, timing, and magnitude of the tau burden between these two cohorts. These differences might have important implications; differences in the temporal pattern of tau accumulation might influence the timing of drug administration in clinical trials, whereas differences in the spatial pattern and magnitude of tau burden might affect disease progression.
FUNDING BACKGROUND
None.

Identifiants

pubmed: 38631766
pii: S1474-4422(24)00084-X
doi: 10.1016/S1474-4422(24)00084-X
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

500-510

Investigateurs

Howard J Aizenstein (HJ)
Howard F Andrews (HF)
Karen Bell (K)
Rasmus M Birn (RM)
Peter Bulova (P)
Amrita Cheema (A)
Kewei Chen (K)
Isabel Clare (I)
Lorraine Clark (L)
Ann D Cohen (AD)
John N Constantino (JN)
Eric W Doran (EW)
Eleanor Feingold (E)
Tatiana M Foroud (TM)
Sigan L Hartley (SL)
Christy Hom (C)
Lawrence Honig (L)
Milos D Ikonomovic (MD)
Sterling C Johnson (SC)
Courtney Jordan (C)
M Ilyas Kamboh (MI)
David Keator (D)
William E Klunk (WE)
Julia K Kofler (JK)
William C Kreisl (WC)
Sharon J Krinsky-McHale (SJ)
Patrick Lao (P)
Charles Laymon (C)
Ira T Lott (IT)
Victoria Lupson (V)
Chester A Mathis (CA)
Davneet S Minhas (DS)
Neelesh Nadkarni (N)
Deborah Pang (D)
Melissa Petersen (M)
Julie C Price (JC)
Margaret Pulsifer (M)
Eric Reiman (E)
Batool Rizvi (B)
Marwan N Sabbagh (MN)
Nicole Schupf (N)
Dana L Tudorascu (DL)
Rameshwari Tumuluru (R)
Benjamin Tycko (B)
Badri Varadarajan (B)
Desiree A White (DA)
Michael A Yassa (MA)
Shahid Zaman (S)
Fan Zhang (F)
Randall Bateman (R)
Alisha J Daniels (AJ)
Laura Courtney (L)
Eric McDade (E)
Jorge J Llibre-Guerra (JJ)
Charlene Supnet-Bell (C)
Chengie Xiong (C)
Xiong Xu (X)
Ruijin Lu (R)
Guoqiao Wang (G)
Yan Li (Y)
Emily Gremminger (E)
Richard J Perrin (RJ)
Erin Franklin (E)
Laura Ibanez (L)
Gina Jerome (G)
Elizabeth Herries (E)
Jennifer Stauber (J)
Bryce Baker (B)
Matthew Minton (M)
Carlos Cruchaga (C)
Alison M Goate (AM)
Alan E Renton (AE)
Danielle M Picarello (DM)
Tammie Benzinger (T)
Brian A Gordon (BA)
Russall Hornbeck (R)
Jason Hassenstab (J)
Jennifer Smith (J)
Sarah Stout (S)
Andrew J Aschenbrenner (AJ)
Celeste M Karch (CM)
Jacob Marsh (J)
John C Morris (JC)
David M Holtzman (DM)
Nicolas Barthelemy (N)
Jinbin Xu (J)
James M Noble (JM)
Sarah B Berman (SB)
Snezana Ikonomovic (S)
Neelesh K Nadkarni (NK)
Gregory Day (G)
Neill R Graff-Radford (NR)
Martin Farlow (M)
Jasmeer P Chhatwal (JP)
Takeshi Ikeuchi (T)
Kensaku Kasuga (K)
Yoshiki Niimi (Y)
Edward D Huey (ED)
Stephen Salloway (S)
Peter R Schofield (PR)
William S Brooks (WS)
Jacob A Bechara (JA)
Ralph Martins (R)
Nick C Fox (NC)
David M Cash (DM)
Natalie S Ryan (NS)
Mathias Jucker (M)
Christoph Laske (C)
Anna Hofmann (A)
Elke Kuder-Buletta (E)
Susanne Graber-Sultan (S)
Ulrike Obermueller (U)
Johannes Levin (J)
Yvonne Roedenbeck (Y)
Jonathan Vöglein (J)
Jae-Hong Lee (JH)
Jee Hoon Roh (JH)
Raquel Sanchez-Valle (R)
Pedro Rosa-Neto (P)
Ricardo F Allegri (RF)
Patricio Chrem Mendez (P)
Ezequiel Surace (E)
Silvia Vazquez (S)
Francisco Lopera (F)
Yudy Milena Leon (YM)
Laura Ramirez (L)
David Aguillon (D)
Allan I Levey (AI)
Erik C B Johnson (ECB)
Nicholas T Seyfried (NT)
John Ringman (J)
Hiroshi Mori (H)

Informations de copyright

Copyright © 2024 Elsevier Ltd. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests TLSB has received funding from the National Institutes of Health and Siemens; has a licensing agreement from Sora Neuroscience but receives no financial compensation; has received honoraria for lectures, presentations, speakers bureaus, or educational events from Biogen and Eisai Genetech; has served on a scientific advisory board for Biogen; holds a leadership role in other board, society, committee, or advocacy groups for the American Society for Neuroradiology (unpaid) and Quantitative Imaging Biomarkers Alliance (unpaid); and has participated in radiopharmaceuticals and technology transfers with Avid Radiopharmaceuticals, Cerveau, and LMI. EMD received support from the National Institute on Aging, an anonymous organisation, the GHR Foundation, the DIAN-TU Pharma Consortium, Eli Lilly, and F Hoffmann La-Roche; has received speaking fees from Eisai and Eli Lilly; and is on the data safety and monitoring board and advisory boards of Eli Lilly, Alector, and Alzamend. WS has received research funding from the National Institute on Aging and the Eunice Kennedy Shriver National Institute of Child Health and Human Development. JPC serves as the chair of the American Neurological Association Dementia and Aging Special Interest Group and is on the medical advisory board of Humana Healthcare. CC has received consulting fees from GSK and Alector. AMF reports personal fees from Roche Diagnostics, Araclon/Grifols, and Diadem Research and grants from Biogen, outside the submitted work. BLH has received research funding from Roche and Autism Speaks; receives royalties from Oxford University Press for book publications; and is the chair of the data safety and monitoring board for the US Department of Defense-funded study Comparative Effectiveness of EIBI and MABA (NCT04078061). BTC receives research funding from the National Institutes of Health. EH receives research funding from the National Institutes of Health and the BrightFocus Foundation. FL is supported by grants from the National Institute on Aging. HDR has received funding from the National Institutes of Health and is on the scientific advisory committee for the Hereditary Disease Foundation. J-HL has received research funding from the National Institutes of Health and the National Institute on Aging. RJP receives research funding from the National Institutes of Health and the National Institute on Aging. RJB is Director of DIAN-TU and Principal Investigator of DIAN-TU001; receives research support from the National Institute on Aging of the National Institutes of Health, DIAN-TU trial pharmaceutical partners (Eli Lilly, F Hoffmann-La Roche, Janssen, Eisai, Biogen, and Avid Radiopharmaceuticals), the Alzheimer's Association, the GHR Foundation, an anonymous organisation, the DIAN-TU Pharma Consortium (active members Biogen, Eisai, Eli Lilly, Janssen, and F Hoffmann-La Roche/Genentech; previous members AbbVie, Amgen, AstraZeneca, Forum, Mithridion, Novartis, Pfizer, Sanofi, and United Neuroscience), the NfL Consortium (F Hoffmann-La Roche, Biogen, AbbVie, and Bristol Myers Squibb), and the Tau SILK Consortium (Eli Lilly, Biogen, and AbbVie); has been an invited speaker and consultant for AC Immune, F Hoffmann-La Roche, the Korean Dementia Association, the American Neurological Association, and Janssen; has been a consultant for Amgen, F Hoffmann-La Roche, and Eisai; and has submitted the US non-provisional patent application named Methods for Measuring the Metabolism of CNS Derived Biomolecules In Vivo (13/005,233 [RJB and DH]) and a provisional patent application named Plasma Based Methods for Detecting CNS Amyloid Deposition (PCT/UC2018/030518 [VO and RJB]). BMA receives research funding from the National Institutes of Health and has a patent (Markers of Neurotoxicity in CAR T Patients). MSR has received consulting fees from AC Immune, Embic, and Keystone Bio and has received research support from the National Institutes of Health, Avid, Baxter, Eisai, Elan, Genentech, Janssen, Lilly, Merck, and Roche. JHR has received funding from the Korea Dementia Research Project through the Korea Dementia Research Center, funded by the Ministry of Health & Welfare and the Ministry of Science and ICT, South Korea (HU21C0066). All other authors declare no competing interests.

Auteurs

Julie K Wisch (JK)

Department of Neurology, Washington University in St Louis, St Louis, MO, USA. Electronic address: julie.wisch@wustl.edu.

Nicole S McKay (NS)

Department of Radiology, Washington University in St Louis, St Louis, MO, USA.

Anna H Boerwinkle (AH)

McGovern Medical School, University of Texas in Houston, Houston, TX, USA.

James Kennedy (J)

Department of Neurology, Washington University in St Louis, St Louis, MO, USA.

Shaney Flores (S)

Department of Radiology, Washington University in St Louis, St Louis, MO, USA.

Benjamin L Handen (BL)

Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.

Bradley T Christian (BT)

Department of Medical Physics and Psychiatry, University of Wisconsin-Madison, Madison, WI, USA.

Elizabeth Head (E)

Department of Pathology, Gillespie Neuroscience Research Facility, University of California, Irvine, CA, USA.

Mark Mapstone (M)

Department of Neurology, University of California Irvine School of Medicine, Irvine, CA, USA.

Michael S Rafii (MS)

Alzheimer's Therapeutic Research Institute, Keck School of Medicine of USC, Los Angeles, CA, USA.

Sid E O'Bryant (SE)

Institute for Translational Research Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX, USA.

Julie C Price (JC)

Department of Radiology, Harvard Medical School, Massachusetts General Hospital, Charlestown, MA, USA.

Charles M Laymon (CM)

Department of Radiology, University of Pittsburgh, Pittsburgh, PA, USA.

Sharon J Krinsky-McHale (SJ)

Department of Psychology, New York State Institute for Basic Research in Developmental Disabilities, New York, NY, USA.

Florence Lai (F)

Department of Neurology, Harvard Medical School, Massachusetts General Hospital, Charlestown, MA, USA.

H Diana Rosas (HD)

Department of Radiology, Harvard Medical School, Massachusetts General Hospital, Charlestown, MA, USA; Department of Neurology, Harvard Medical School, Massachusetts General Hospital, Charlestown, MA, USA.

Sigan L Hartley (SL)

Waisman Center, University of Wisconsin-Madison, Madison, WI, USA.

Shahid Zaman (S)

Cambridge Intellectual and Developmental Disabilities Research Group, University of Cambridge, Cambridge, UK.

Ira T Lott (IT)

Department of Pediatrics, University of California Irvine School of Medicine, Irvine, CA, USA.

Dana Tudorascu (D)

Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.

Matthew Zammit (M)

Department of Medical Physics and Psychiatry, University of Wisconsin-Madison, Madison, WI, USA.

Adam M Brickman (AM)

Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA.

Joseph H Lee (JH)

Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA; Department of Epidemiology, Columbia University Irving Medical Center, New York, NY, USA.

Thomas D Bird (TD)

Department of Neurology, University of Washington, Seattle, WA, USA.

Annie Cohen (A)

Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.

Patricio Chrem (P)

Centro de Memoria y Envejecimiento, Buenos Aires, Argentina.

Alisha Daniels (A)

Department of Neurology, Washington University in St Louis, St Louis, MO, USA.

Jasmeer P Chhatwal (JP)

Department of Neurology, Harvard Medical School, Massachusetts General Hospital, Charlestown, MA, USA.

Carlos Cruchaga (C)

Department of Psychiatry, Washington University in St Louis, St Louis, MO, USA; Hope Center for Neurological Disorders, Washington University in St Louis, St Louis, MO, USA.

Laura Ibanez (L)

Department of Psychiatry, Washington University in St Louis, St Louis, MO, USA.

Mathias Jucker (M)

Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.

Celeste M Karch (CM)

Department of Neurology, Washington University in St Louis, St Louis, MO, USA; Department of Psychiatry, Washington University in St Louis, St Louis, MO, USA; German Center for Neurodegenerative Diseases, Tübingen, Germany.

Gregory S Day (GS)

Department of Neurology, Mayo Clinic Florida, Jacksonville, FL, USA.

Jae-Hong Lee (JH)

Department of Neurology, University of Ulsan College of Medicine, Asian Medical Center, Seoul, South Korea.

Johannes Levin (J)

Department of Neurology, LMU University Hospital, LMU Munich, Munich, Germany; German Center for Neurodegenerative Diseases, site Munich, Munich, Germany; Munich Cluster for Systems Neurology, Munich, Germany.

Jorge Llibre-Guerra (J)

Hope Center for Neurological Disorders, Washington University in St Louis, St Louis, MO, USA.

Yan Li (Y)

Department of Neurology, Washington University in St Louis, St Louis, MO, USA; Department of Biostatistics, Washington University in St Louis, St Louis, MO, USA.

Francisco Lopera (F)

Grupo de Neurociencias de Antioquia, Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia.

Jee Hoon Roh (JH)

Departments of Physiology and Neurology, Korea University College of Medicine, Seoul, South Korea.

John M Ringman (JM)

Alzheimer's Therapeutic Research Institute, Keck School of Medicine of USC, Los Angeles, CA, USA.

Charlene Supnet-Bell (C)

Department of Neurology, Washington University in St Louis, St Louis, MO, USA.

Christopher H van Dyck (CH)

School of Medicine, Yale University, New Haven, CT, USA.

Chengjie Xiong (C)

Department of Biostatistics, Washington University in St Louis, St Louis, MO, USA.

Guoqiao Wang (G)

Department of Neurology, Washington University in St Louis, St Louis, MO, USA; Department of Biostatistics, Washington University in St Louis, St Louis, MO, USA.

John C Morris (JC)

Department of Neurology, Washington University in St Louis, St Louis, MO, USA.

Eric McDade (E)

Department of Neurology, Washington University in St Louis, St Louis, MO, USA.

Randall J Bateman (RJ)

Department of Neurology, Washington University in St Louis, St Louis, MO, USA.

Tammie L S Benzinger (TLS)

Department of Radiology, Washington University in St Louis, St Louis, MO, USA.

Brian A Gordon (BA)

Department of Radiology, Washington University in St Louis, St Louis, MO, USA.

Beau M Ances (BM)

Department of Neurology, Washington University in St Louis, St Louis, MO, USA.

Classifications MeSH