The Longitudinal Early-onset Alzheimer's Disease Study (LEADS): Framework and methodology

Liana G Apostolova^{1

2

3}, Paul Aisen⁴, Ani Eloyan⁵, Anne Fagan⁶, Keith N Fargo⁷, Tatiana Foroud³, Constantine Gatsonis⁵, Lea T Grinberg^{8

9}, Clifford R Jack Jr¹⁰, Joel Kramer⁹, Robert Koeppe¹¹, Walter A Kukull¹², Melissa E Murray¹³, Kelly Nudelman³, Malia Rumbaugh³, Arthur Toga¹⁴, Prashanthi Vemuri¹⁰, Amy Trullinger¹⁵, Leonardo Iaccarino⁹, Gregory S Day¹⁶, Neill R Graff-Radford¹⁶, Lawrence S Honig¹⁷, David T Jones^{10

18}, Joseph Masdeu¹⁹, Mario Mendez²⁰, Erik Musiek⁶, Chiadi U Onyike²¹, Emily Rogalski²², Steve Salloway²³, David A Wolk²⁴, Thomas S Wingo²⁵, Maria C Carrillo²⁶, Bradford C Dickerson²⁷, Gil D Rabinovici⁹; LEADS Consortium¹

Affiliations

¹ Department of Neurology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
² Department of Radiology and Imaging Sciences, Center for Neuroimaging, Indiana University School of Medicine Indianapolis, Indianapolis, Indiana, USA.
³ Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA.
⁴ Alzheimer's Therapeutic Research Institute, University of Southern California, San Diego, California, USA.
⁵ Department of Biostatistics, Center for Statistical Sciences, Brown University, Providence, Rhode Island, USA.
⁶ Department of Neurology, Washington University in St. Louis, St. Louis, Missouri, USA.
⁷ Charcot-Marie Tooth Research Foundation, Naperville, Illinois, USA.
⁸ Department of Pathology, University of California, San Francisco, California, USA.
⁹ Department of Neurology, University of California, San Francisco, California, USA.
¹⁰ Department of Radiology, Mayo Clinic, Rochester, Minnesota, USA.
¹¹ Department of Radiology, University of Michigan, Ann Arbor, Michigan, USA.
¹² Department of Epidemiology, University of Washington, Seattle, Washington, USA.
¹³ Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
¹⁴ Laboratory of Neuro Imaging, USC Stevens Neuroimaging and Informatics Institute, Keck School of Medicine of USC, Los Angeles, California, USA.
¹⁵ Indiana Clinical and Translational Sciences Institute, Indiana University School of Medicine Indianapolis, Indianapolis, Indiana, USA.
¹⁶ Department of Neurology, Mayo Clinic, Jacksonville, Florida, USA.
¹⁷ Taub Institute and Department of Neurology, Columbia University Irving Medical Center, New York, New York, USA.
¹⁸ Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA.
¹⁹ Nantz National Alzheimer Center, Houston Methodist and Weill Cornell Medicine, Houston, Texas, USA.
²⁰ Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
²¹ Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
²² Department of Psychiatry and Behavioral Sciences, Mesulam Center for Cognitive Neurology and Alzheimer's Disease, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
²³ Department of Neurology, Alpert Medical School, Brown University, Providence, Rhode Island, USA.
²⁴ Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
²⁵ Department of Neurology and Human Genetics, Emory University School of Medicine, Atlanta, Georgia, USA.
²⁶ Medical & Scientific Relations Division, Alzheimer's Association, Chicago, Illinois, USA.
²⁷ Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.

PMID: 34018654
PMCID: PMC8939858
DOI: 10.1002/alz.12350

The Longitudinal Early-onset Alzheimer's Disease Study (LEADS): Framework and methodology

Liana G Apostolova et al. Alzheimers Dement. 2021 Dec.

. 2021 Dec;17(12):2043-2055.

doi: 10.1002/alz.12350. Epub 2021 May 21.

Authors

Affiliations

¹ Department of Neurology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
² Department of Radiology and Imaging Sciences, Center for Neuroimaging, Indiana University School of Medicine Indianapolis, Indianapolis, Indiana, USA.
³ Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA.
⁴ Alzheimer's Therapeutic Research Institute, University of Southern California, San Diego, California, USA.
⁵ Department of Biostatistics, Center for Statistical Sciences, Brown University, Providence, Rhode Island, USA.
⁶ Department of Neurology, Washington University in St. Louis, St. Louis, Missouri, USA.
⁷ Charcot-Marie Tooth Research Foundation, Naperville, Illinois, USA.
⁸ Department of Pathology, University of California, San Francisco, California, USA.
⁹ Department of Neurology, University of California, San Francisco, California, USA.
¹⁰ Department of Radiology, Mayo Clinic, Rochester, Minnesota, USA.
¹¹ Department of Radiology, University of Michigan, Ann Arbor, Michigan, USA.
¹² Department of Epidemiology, University of Washington, Seattle, Washington, USA.
¹³ Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
¹⁴ Laboratory of Neuro Imaging, USC Stevens Neuroimaging and Informatics Institute, Keck School of Medicine of USC, Los Angeles, California, USA.
¹⁵ Indiana Clinical and Translational Sciences Institute, Indiana University School of Medicine Indianapolis, Indianapolis, Indiana, USA.
¹⁶ Department of Neurology, Mayo Clinic, Jacksonville, Florida, USA.
¹⁷ Taub Institute and Department of Neurology, Columbia University Irving Medical Center, New York, New York, USA.
¹⁸ Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA.
¹⁹ Nantz National Alzheimer Center, Houston Methodist and Weill Cornell Medicine, Houston, Texas, USA.
²⁰ Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
²¹ Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
²² Department of Psychiatry and Behavioral Sciences, Mesulam Center for Cognitive Neurology and Alzheimer's Disease, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
²³ Department of Neurology, Alpert Medical School, Brown University, Providence, Rhode Island, USA.
²⁴ Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
²⁵ Department of Neurology and Human Genetics, Emory University School of Medicine, Atlanta, Georgia, USA.
²⁶ Medical & Scientific Relations Division, Alzheimer's Association, Chicago, Illinois, USA.
²⁷ Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.

PMID: 34018654
PMCID: PMC8939858
DOI: 10.1002/alz.12350

Abstract

Patients with early-onset Alzheimer's disease (EOAD) are commonly excluded from large-scale observational and therapeutic studies due to their young age, atypical presentation, or absence of pathogenic mutations. The goals of the Longitudinal EOAD Study (LEADS) are to (1) define the clinical, imaging, and fluid biomarker characteristics of EOAD; (2) develop sensitive cognitive and biomarker measures for future clinical and research use; and (3) establish a trial-ready network. LEADS will follow 400 amyloid beta (Aβ)-positive EOAD, 200 Aβ-negative EOnonAD that meet National Institute on Aging-Alzheimer's Association (NIA-AA) criteria for mild cognitive impairment (MCI) or AD dementia, and 100 age-matched controls. Participants will undergo clinical and cognitive assessments, magnetic resonance imaging (MRI), [¹⁸ F]Florbetaben and [¹⁸ F]Flortaucipir positron emission tomography (PET), lumbar puncture, and blood draw for DNA, RNA, plasma, serum and peripheral blood mononuclear cells, and post-mortem assessment. To develop more effective AD treatments, scientists need to understand the genetic, biological, and clinical processes involved in EOAD. LEADS will develop a public resource that will enable future planning and implementation of EOAD clinical trials.

Keywords: Alzheimer's disease; EOAD; LEADS; YOAD; early-onset; young onset.

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Conflict of interest statement

Dr. Apostolova served as a paid consultant for Biogen and Two Labs, serves on a DSMB for IQVIA, and receives research support from the NIH, the Alzheimer's Association, Roche, Life Molecular Imaging, and Eli Lilly. Dr. Aisen reports grants from NIA, FNIH, the Alzheimer's Association, Janssen, Lilly, and Eisai, and personal fees from Merck, Roche, Biogen, Lundbeck, ImmunoBrain Checkpoint, and Samus. Dr. Eloyan has nothing to disclose. Dr. Fagan has received research support from Biogen, Fujirebio, and Roche Diagnostics. She is a member of the scientific advisory boards for Roche Diagnostics, Genentech, and AbbVie and also consults for Araclon/Griffols, DiademRes, and Otsuka Pharmaceuticals. Dr. Fargo has nothing to disclose. Dr. Foroud has nothing to disclose. Dr. Gatsonis has nothing to disclose. Dr. Grinberg has nothing to disclose. Dr. Jack serves on an independent data monitoring board for Roche and has consulted for and served as a speaker for Eisai, but he receives no personal compensation from any commercial entity. He receives research support from the NIH and the Alexander Family Alzheimer's Disease Research Professorship of the Mayo Clinic. Dr. Kramer has nothing to disclose. Dr. Koeppe has nothing to disclose. Dr. Kukull is supported by the NIA. Dr. Murray served as a paid consultant for AVID Radiopharmaceuticals and receives research support from the NIH, the Alzheimer's Association, and the state of Florida. Dr. Nudelman has nothing to disclose. Mrs. Rumbaugh has nothing to disclose. Dr. Toga has nothing to disclose. Dr. Vemuri has nothing to disclose. Mrs. Trullinger has nothing to disclose. Dr. Iaccarino has nothing to disclose. Dr. Day is supported by the NIA; he serves as a topic editor on dementia for DynaMed Plus (EBSCO Industries, Inc), is the clinical director for the Anti‐NMDA Receptor Encephalitis Foundation and holds stocks in ANI Pharmaceuticals. Dr. Graff‐Radford receives research support from Lilly, AbbVie, and Biogen. Dr. Honig has nothing to disclose. Dr. Jones has nothing to disclose. Dr. Masdeu served on the speaker's bureau and consulted for Biogen. He received research support from the NIH, Avanir, Abbvie, Biogen, Eli Lilly, Esai, and Novartis. Dr. Mendez receives grant support from NIA and has received support from Biogen. Dr. Musiek received research funding from Eisai Pharmaceuticals Inc. Dr. Onyike has nothing to disclose. Dr. Rogalski has nothing to disclose. Dr. Salloway received consultation fees and research support from Biogen, Eisai, Lilly, Genentech, and Roche. Dr. Wolk received grants from Eli Lilly/Avid Radiopharmaceuticals, Merck, and Biogen, and consulted for Merck, Janssen, and GE Healthcare. Dr. Wingo has nothing to disclose. Dr. Carrillo has nothing to disclose. Dr. Dickerson receives research support from the NIH and the Alzheimer's Drug Discovery Foundation. He consulted for Arkuda, Axovant, Lilly, Biogen, Merck, Novartis, and Wave LifeSciences. He is editor for Neuroimage: Clinical and Cortex. He receives royalties from Oxford University Press and Cambridge University Press. Dr. Rabinovici receives research support from the NIH, Alzheimer's Association, American College of Radiology, Rainwater Charitable Foundation, Avid Radiopharmaceuticals, Eli Lilly, GE Healthcare, Life Molecular Imaging, Genentech, and Roche. He has served as a paid consultant for Axon Neurosciences, Eisai, GE Healthcare, Genentech, Roche, and Johnson & Johnson, and is an Associate Editor for JAMA Neurology.

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The Longitudinal Early-onset Alzheimer's Disease Study (LEADS): Framework and methodology

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The Longitudinal Early-onset Alzheimer's Disease Study (LEADS): Framework and methodology

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Conflict of interest statement

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