α-Synuclein seed amplification assay detects Lewy body co-pathology in autosomal dominant Alzheimer's disease late in the disease course and dependent on Lewy pathology burden

Johannes Levin^{1

2

3}, Simone Baiardi⁴, Corinne Quadalti⁵, Marcello Rossi⁵, Angela Mammana⁵, Jonathan Vöglein^{1

2}, Alexander Bernhardt^{1

2}, Richard J Perrin^{6

7}, Mathias Jucker^{8

9}, Oliver Preische^{8

9}, Anna Hofmann^{8

9}, Günter U Höglinger^{1

2

3}, Nigel J Cairns¹⁰, Erin E Franklin^{6

7}, Patricio Chrem¹¹, Carlos Cruchaga¹², Sarah B Berman¹³, Jasmeer P Chhatwal¹⁴, Alisha Daniels⁷, Gregory S Day¹⁵, Natalie S Ryan^{16

17}, Alison M Goate¹⁸, Brian A Gordon⁷, Edward D Huey¹⁹, Laura Ibanez¹², Celeste M Karch¹², Jae-Hong Lee²⁰, Jorge Llibre-Guerra⁷, Francisco Lopera²¹, Colin L Masters²², John C Morris⁷, James M Noble²³, Alan E Renton²⁴, Jee Hoon Roh²⁵, Matthew P Frosch²⁶, C Dirk Keene²⁷, Catriona McLean²⁸, Raquel Sanchez-Valle²⁹, Peter R Schofield^{30

31}, Charlene Supnet-Bell⁷, Chengjie Xiong³², Armin Giese³³, Oskar Hansson^{34

35}, Randall J Bateman⁷, Eric McDade⁷; Dominantly Inherited Alzheimer Network; Piero Parchi^{4

5}

Affiliations

¹ Department of Neurology, LMU University Hospital, LMU Munich, Munich, Germany.
² German Center for Neurodegenerative Diseases, Munich, Germany.
³ Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
⁴ Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
⁵ IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy.
⁶ Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, Missouri, USA.
⁷ Department of Neurology, Washington University School of Medicine, Saint Louis, Missouri, USA.
⁸ German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
⁹ Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
¹⁰ Living Systems Institute, Faculty of Health and Life Sciences, University of Exeter, Exeter, UK.
¹¹ FLENI, Montañeses 2325 (C1428AQK), Buenos Aires, Argentina.
¹² Department of Psychiatry, Washington University School of Medicine, Saint Louis, Missouri, USA.
¹³ University of Pittsburgh Neurology, Pittsburgh, Pennsylvania, USA.
¹⁴ Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
¹⁵ Department of Neurology, Mayo Clinic in Florida, Jacksonville, Florida, USA.
¹⁶ Dementia Research Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.
¹⁷ UK Dementia Research Institute at UCL, London, UK.
¹⁸ Department of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹⁹ Butler Hospital, Brown Center for Alzheimer's Disease Research, Alpert Medical School of Brown University, Providence, Rhode Island, USA.
²⁰ Department of Neurology, Asan Medical Center, Seoul, South Korea.
²¹ Grupo de Neurosciencias de Antioquia, Sede de Investigación Universitaria SIU, Medellín, Colombia.
²² Florey Institute and The University of Melbourne, Melbourne, Victoria, Australia.
²³ Department of Neurology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, and GH Sergievsky Center, Columbia University, New York, New York, USA.
²⁴ Department of Genetics and Genomic Sciences and Nash Family Dept of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
²⁵ Departments of Neurology and Physiology, Korea University College of Medicine, Seoul, South Korea.
²⁶ MassGeneral Institute for Neurodegenerative Diseases, Neuropathology Service, Massachusetts General Hospital, Boston, Massachusetts, USA.
²⁷ Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA.
²⁸ Department of Anatomical Pathology, AlfredHealth, Melbourne, Victoria, Australia.
²⁹ Alzheimer's Disease and Other Cognitive Disorders Unit, Service of Neurology, Hospital Clinic de Barcelona, FRCB-IDIBAPS, Barcelona, Spain.
³⁰ Neuroscience Research Australia, Sydney, New South Wales, Australia.
³¹ School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia.
³² Division of Biostatistics, Washington University School of Medicine, Saint Louis, Missouri, USA.
³³ Modag GmbH, Wendelsheim, Germany.
³⁴ Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Faculty of Medicine, Lund University, Lund, Sweden.
³⁵ Memory Clinic, Skåne University Hospital, Lund, Sweden.

PMID: 38666355
PMCID: PMC11180868
DOI: 10.1002/alz.13818

α-Synuclein seed amplification assay detects Lewy body co-pathology in autosomal dominant Alzheimer's disease late in the disease course and dependent on Lewy pathology burden

Johannes Levin et al. Alzheimers Dement. 2024 Jun.

. 2024 Jun;20(6):4351-4365.

doi: 10.1002/alz.13818. Epub 2024 Apr 26.

Authors

Affiliations

¹ Department of Neurology, LMU University Hospital, LMU Munich, Munich, Germany.
² German Center for Neurodegenerative Diseases, Munich, Germany.
³ Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
⁴ Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
⁵ IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy.
⁶ Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, Missouri, USA.
⁷ Department of Neurology, Washington University School of Medicine, Saint Louis, Missouri, USA.
⁸ German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
⁹ Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
¹⁰ Living Systems Institute, Faculty of Health and Life Sciences, University of Exeter, Exeter, UK.
¹¹ FLENI, Montañeses 2325 (C1428AQK), Buenos Aires, Argentina.
¹² Department of Psychiatry, Washington University School of Medicine, Saint Louis, Missouri, USA.
¹³ University of Pittsburgh Neurology, Pittsburgh, Pennsylvania, USA.
¹⁴ Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
¹⁵ Department of Neurology, Mayo Clinic in Florida, Jacksonville, Florida, USA.
¹⁶ Dementia Research Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.
¹⁷ UK Dementia Research Institute at UCL, London, UK.
¹⁸ Department of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹⁹ Butler Hospital, Brown Center for Alzheimer's Disease Research, Alpert Medical School of Brown University, Providence, Rhode Island, USA.
²⁰ Department of Neurology, Asan Medical Center, Seoul, South Korea.
²¹ Grupo de Neurosciencias de Antioquia, Sede de Investigación Universitaria SIU, Medellín, Colombia.
²² Florey Institute and The University of Melbourne, Melbourne, Victoria, Australia.
²³ Department of Neurology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, and GH Sergievsky Center, Columbia University, New York, New York, USA.
²⁴ Department of Genetics and Genomic Sciences and Nash Family Dept of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
²⁵ Departments of Neurology and Physiology, Korea University College of Medicine, Seoul, South Korea.
²⁶ MassGeneral Institute for Neurodegenerative Diseases, Neuropathology Service, Massachusetts General Hospital, Boston, Massachusetts, USA.
²⁷ Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA.
²⁸ Department of Anatomical Pathology, AlfredHealth, Melbourne, Victoria, Australia.
²⁹ Alzheimer's Disease and Other Cognitive Disorders Unit, Service of Neurology, Hospital Clinic de Barcelona, FRCB-IDIBAPS, Barcelona, Spain.
³⁰ Neuroscience Research Australia, Sydney, New South Wales, Australia.
³¹ School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia.
³² Division of Biostatistics, Washington University School of Medicine, Saint Louis, Missouri, USA.
³³ Modag GmbH, Wendelsheim, Germany.
³⁴ Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Faculty of Medicine, Lund University, Lund, Sweden.
³⁵ Memory Clinic, Skåne University Hospital, Lund, Sweden.

PMID: 38666355
PMCID: PMC11180868
DOI: 10.1002/alz.13818

Abstract

Introduction: Amyloid beta and tau pathology are the hallmarks of sporadic Alzheimer's disease (AD) and autosomal dominant AD (ADAD). However, Lewy body pathology (LBP) is found in ≈ 50% of AD and ADAD brains.

Methods: Using an α-synuclein seed amplification assay (SAA) in cerebrospinal fluid (CSF) from asymptomatic (n = 26) and symptomatic (n = 27) ADAD mutation carriers, including 12 with known neuropathology, we investigated the timing of occurrence and prevalence of SAA positive reactivity in ADAD in vivo.

Results: No asymptomatic participant and only 11% (3/27) of the symptomatic patients tested SAA positive. Neuropathology revealed LBP in 10/12 cases, primarily affecting the amygdala or the olfactory areas. In the latter group, only the individual with diffuse LBP reaching the neocortex showed α-synuclein seeding activity in CSF in vivo.

Discussion: Results suggest that in ADAD LBP occurs later than AD pathology and often as amygdala- or olfactory-predominant LBP, for which CSF α-synuclein SAA has low sensitivity.

Highlights: Cerebrospinal fluid (CSF) real-time quaking-induced conversion (RT-QuIC) detects misfolded α-synuclein in ≈ 10% of symptomatic autosomal dominant Alzheimer's disease (ADAD) patients. CSF RT-QuIC does not detect α-synuclein seeding activity in asymptomatic mutation carriers. Lewy body pathology (LBP) in ADAD mainly occurs as olfactory only or amygdala-predominant variants. LBP develops late in the disease course in ADAD. CSF α-synuclein RT-QuIC has low sensitivity for focal, low-burden LBP.

Keywords: Dominantly Inherited Alzheimer Network; Lewy body pathology; alpha‐synuclein seed amplification assay; real‐time quaking‐induced conversion.

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Conflict of interest statement

JL reports speaker fees from Bayer Vital, Biogen, EISAI, Merck, Roche, TEVA, and Zambon; consulting fees from Axon Neuroscience, EISAI, and Biogen; author fees from Thieme medical publishers and W. Kohlhammer GmbH medical publishers; and is inventor in a patent “Oral Phenylbutyrate for Treatment of Human 4‐Repeat Tauopathies” (EP 23 156 122.6) filed by LMU Munich. In addition, he reports compensation for serving as chief medical officer for MODAG GmbH; is beneficiary of the phantom share program of MODAG GmbH; and is inventor in a patent “Pharmaceutical Composition and Methods of Use” (EP 22 159 408.8) filed by MODAG GmbH, all activities outside the submitted work. NCF reports consulting fees from Biogen, Eisai, Ionis, Lilly, Roche/Genentech, and Siemens all paid to UCL; he has also served on a Data Safety Monitoring Board for Biogen. OH has acquired research support (for the institution) from ADx, AVID Radiopharmaceuticals, Biogen, Eli Lilly, Eisai, Fujirebio, GE Healthcare, Pfizer, and Roche. In the past 2 years, he has received consultancy/speaker fees from AC Immune, Amylyx, Alzpath, BioArctic, Biogen, Cerveau, Eisai, Eli Lilly, Fujirebio, Merck, Novartis, Novo Nordisk, Roche, Sanofi, and Siemens. FL has research support from NIA, NIH, Biogen, Tau‐Consortium, Roche and is a consultant of Viewmind and Biogen. JCM is funded by NIH grants # P30 AG066444; P01AG003991; P01AG026276. Neither Dr. Morris nor his family owns stock or has equity interest (outside of mutual funds or other externally directed accounts) in any pharmaceutical or biotechnology company. AMG serves on SABs for Genentech and Muna Therapeutics and has received consultancy/speaker fees from Biogen. RSV reports consultancy or speaker fees from Ionis, AviadoBio, NovoNordisk, Pfizer, Neuraxpharm, and Roche diagnosis. GH has ongoing research collaborations with Roche, UCB, Abbvie; serves as a consultant for Abbvie, Alzprotect, Amylyx, Aprineua, Asceneuron, Bayer, Bial, Biogen, Biohaven, Epidarex, Ferrer, Kyowa Kirin, Lundbeck, Novartis, Retrotope, Roche, Sanofi, Servier, Takeda, Teva, UCB; received honoraria for scientific presentations from Abbvie, Bayer, Bial, Biogen, Bristol Myers Squibb, Kyowa Kirin, Pfizer, Roche, Teva, UCB, Zambon; holds a patent on Treatment of Synucleinopathies (US 10,918,628 B2; EP 17 787 904.6‐1109 / 3 525 788); received publication royalties from Academic Press, Kohlhammer, and Thieme. All other authors have no conflicts to report. Author disclosures are available in the supporting information.

Figures

**FIGURE 1**
Representative LB pathology features in ADAD. The upper panel shows brain maps of LB pathology distribution in the three representative profiles (i.e., olfactory only, amygdala/limbic predominant, and diffuse) observed in the ADAD individuals at neuropathologic examination. Color scale of the brain maps represents the mean semiquantitative scores in each profile. The lower panel shows LBP features in the ADAD brains. A–C, Severe to moderate/mild LB and neuritic pathology in the amygdala (A, LBP ++++, case #3; B, LBP +++, case #21; C, LBP ++, case #18). D, Isolated syn immunoreactivity in a neuron of the medullary raphe, and (E) moderate LBP in the neocortex of the superior temporal gyrus in the only brain with diffuse LBP (case #3). F, Abundant Lewy neurites and LB in the olfactory tract, and (G) scattered LBs in the olfactory cortex of case #18. Magnification is x40 for all micrographs. ADAD, autosomal dominant Alzheimer's disease; LB, Lewy bodies; LBP, Lewy body pathology.

See this image and copyright information in PMC

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α-Synuclein seed amplification assay detects Lewy body co-pathology in autosomal dominant Alzheimer's disease late in the disease course and dependent on Lewy pathology burden

Affiliations

α-Synuclein seed amplification assay detects Lewy body co-pathology in autosomal dominant Alzheimer's disease late in the disease course and dependent on Lewy pathology burden

Authors

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Abstract

Conflict of interest statement

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