. 2023 Nov;19 Suppl 9(Suppl 9):S115-S125.

doi: 10.1002/alz.13399. Epub 2023 Jul 25.

Cerebrospinal fluid biomarkers in the Longitudinal Early-onset Alzheimer's Disease Study

Jeffrey L Dage^{1

2}, Ani Eloyan³, Maryanne Thangarajah³, Dustin B Hammers¹, Anne M Fagan⁴, Julia D Gray⁴, Suzanne E Schindler⁴, Casey Snoddy², Kelly N H Nudelman², Kelley M Faber², Tatiana Foroud², Paul Aisen⁵, Percy Griffin⁶, Lea T Grinberg^{7

8}, Leonardo Iaccarino⁷, Kala Kirby¹, Joel Kramer⁷, Robert Koeppe⁹, Walter A Kukull¹⁰, Renaud La Joie⁷, Nidhi S Mundada⁷, Melissa E Murray¹¹, Malia Rumbaugh², David N Soleimani-Meigooni⁷, Arthur W Toga¹², Alexandra Touroutoglou¹³, Prashanthi Vemuri¹⁴, Alireza Atri¹⁵, Laurel A Beckett¹⁶, Gregory S Day¹⁷, Neill R Graff-Radford¹⁷, Ranjan Duara¹⁸, Lawrence S Honig¹⁹, David T Jones^{14

20}, Joseph C Masdeu²¹, Mario F Mendez²², Erik Musiek⁴, Chiadi U Onyike²³, Meghan Riddle²⁴, Emily Rogalski²⁵, Stephen Salloway²⁴, Sharon J Sha²⁶, Raymond S Turner²⁷, Thomas S Wingo²⁸, David A Wolk²⁹, Kyle B Womack⁴, Maria C Carrillo⁶, Bradford C Dickerson¹³, Gil D Rabinovici⁷, Liana G Apostolova^{1

5

30}; LEADS Consortium

Affiliations

¹ Department of Neurology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
² Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA.
³ Department of Biostatistics, Center for Statistical Sciences, Brown University, Providence, Rhode Island, USA.
⁴ Department of Neurology, Washington University in St. Louis, St. Louis, Missouri, USA.
⁵ Alzheimer's Therapeutic Research Institute, University of Southern California, San Diego, California, USA.
⁶ Medical & Scientific Relations Division, Alzheimer's Association, Chicago, Illinois, USA.
⁷ Department of Neurology, University of California - San Francisco, San Francisco, California, USA.
⁸ Department of Pathology, University of California - San Francisco, San Francisco, California, USA.
⁹ Department of Radiology, University of Michigan, Ann Arbor, Michigan, USA.
¹⁰ Department of Epidemiology, University of Washington, Seattle, Washington, USA.
¹¹ Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
¹² Laboratory of Neuro Imaging, USC Stevens Neuroimaging and Informatics Institute, Keck School of Medicine of USC, Los Angeles, California, USA.
¹³ Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
¹⁴ Department of Radiology, Mayo Clinic, Rochester, Minnesota, USA.
¹⁵ Banner Sun Health Research Institute, Sun City, Arizona, USA.
¹⁶ Department of Public Health Sciences, University of California-Davis, Davis, California, USA.
¹⁷ Department of Neurology, Mayo Clinic, Jacksonville, Florida, USA.
¹⁸ Wien Center for Alzheimer's Disease and Memory Disorders, Mount Sinai Medical Center, Miami, Florida, USA.
¹⁹ Taub Institute and Department of Neurology, Columbia University Irving Medical Center, New York, New York, USA.
²⁰ Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA.
²¹ Nantz National Alzheimer Center, Houston Methodist and Weill Cornell Medicine, Houston, Texas, USA.
²² Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
²³ Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
²⁴ Department of Neurology, Alpert Medical School, Brown University, Providence, Rhode Island, USA.
²⁵ Department of Psychiatry and Behavioral Sciences, Mesulam Center for Cognitive Neurology and Alzheimer's Disease, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
²⁶ Department of Neurology & Neurological Sciences, Stanford University, Palo Alto, California, USA.
²⁷ Department of Neurology, Georgetown University, Washington, D.C., USA.
²⁸ Department of Neurology and Human Genetics, Emory University School of Medicine, Atlanta, Georgia, USA.
²⁹ Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
³⁰ Department of Radiology and Imaging Sciences, Center for Neuroimaging, Indiana University School of Medicine Indianapolis, Indianapolis, Indiana, USA.

PMID: 37491668
PMCID: PMC10877673
DOI: 10.1002/alz.13399

Cerebrospinal fluid biomarkers in the Longitudinal Early-onset Alzheimer's Disease Study

Jeffrey L Dage et al. Alzheimers Dement. 2023 Nov.

. 2023 Nov;19 Suppl 9(Suppl 9):S115-S125.

doi: 10.1002/alz.13399. Epub 2023 Jul 25.

Authors

Affiliations

¹ Department of Neurology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
² Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA.
³ Department of Biostatistics, Center for Statistical Sciences, Brown University, Providence, Rhode Island, USA.
⁴ Department of Neurology, Washington University in St. Louis, St. Louis, Missouri, USA.
⁵ Alzheimer's Therapeutic Research Institute, University of Southern California, San Diego, California, USA.
⁶ Medical & Scientific Relations Division, Alzheimer's Association, Chicago, Illinois, USA.
⁷ Department of Neurology, University of California - San Francisco, San Francisco, California, USA.
⁸ Department of Pathology, University of California - San Francisco, San Francisco, California, USA.
⁹ Department of Radiology, University of Michigan, Ann Arbor, Michigan, USA.
¹⁰ Department of Epidemiology, University of Washington, Seattle, Washington, USA.
¹¹ Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
¹² Laboratory of Neuro Imaging, USC Stevens Neuroimaging and Informatics Institute, Keck School of Medicine of USC, Los Angeles, California, USA.
¹³ Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
¹⁴ Department of Radiology, Mayo Clinic, Rochester, Minnesota, USA.
¹⁵ Banner Sun Health Research Institute, Sun City, Arizona, USA.
¹⁶ Department of Public Health Sciences, University of California-Davis, Davis, California, USA.
¹⁷ Department of Neurology, Mayo Clinic, Jacksonville, Florida, USA.
¹⁸ Wien Center for Alzheimer's Disease and Memory Disorders, Mount Sinai Medical Center, Miami, Florida, USA.
¹⁹ Taub Institute and Department of Neurology, Columbia University Irving Medical Center, New York, New York, USA.
²⁰ Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA.
²¹ Nantz National Alzheimer Center, Houston Methodist and Weill Cornell Medicine, Houston, Texas, USA.
²² Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
²³ Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
²⁴ Department of Neurology, Alpert Medical School, Brown University, Providence, Rhode Island, USA.
²⁵ Department of Psychiatry and Behavioral Sciences, Mesulam Center for Cognitive Neurology and Alzheimer's Disease, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
²⁶ Department of Neurology & Neurological Sciences, Stanford University, Palo Alto, California, USA.
²⁷ Department of Neurology, Georgetown University, Washington, D.C., USA.
²⁸ Department of Neurology and Human Genetics, Emory University School of Medicine, Atlanta, Georgia, USA.
²⁹ Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
³⁰ Department of Radiology and Imaging Sciences, Center for Neuroimaging, Indiana University School of Medicine Indianapolis, Indianapolis, Indiana, USA.

PMID: 37491668
PMCID: PMC10877673
DOI: 10.1002/alz.13399

Abstract

Introduction: One goal of the Longitudinal Early Onset Alzheimer's Disease Study (LEADS) is to define the fluid biomarker characteristics of early-onset Alzheimer's disease (EOAD).

Methods: Cerebrospinal fluid (CSF) concentrations of Aβ1-40, Aβ1-42, total tau (tTau), pTau181, VILIP-1, SNAP-25, neurogranin (Ng), neurofilament light chain (NfL), and YKL-40 were measured by immunoassay in 165 LEADS participants. The associations of biomarker concentrations with diagnostic group and standard cognitive tests were evaluated.

Results: Biomarkers were correlated with one another. Levels of CSF Aβ42/40, pTau181, tTau, SNAP-25, and Ng in EOAD differed significantly from cognitively normal and early-onset non-AD dementia; NfL, YKL-40, and VILIP-1 did not. Across groups, all biomarkers except SNAP-25 were correlated with cognition. Within the EOAD group, Aβ42/40, NfL, Ng, and SNAP-25 were correlated with at least one cognitive measure.

Discussion: This study provides a comprehensive analysis of CSF biomarkers in sporadic EOAD that can inform EOAD clinical trial design.

Keywords: Alzheimer's disease; Aβ42/40; CSF; NfL; SNAP-25; VILIP-1; YKL-40; amyloid; astrogliosis; biomarkers; dementia; neurogranin; pTau181; tTau; tau.

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Conflict of interest statement

CONFLICT OF INTEREST STATEMENT

Dr. Dage is an inventor on patents or patent applications of Eli Lilly and Company relating to the assays, methods, reagents, and/or compositions of matter related to measurement of P-tau217. Dr. Dage has served as a consultant for Abbvie, Genotix Biotechnologies Inc., Gates Ventures, Karuna Therapeutics, AlzPath Inc., and Cognito Therapeutics, Inc., founder of Monument Biosciences, and received research support from ADx Neurosciences, Fujirebio, AlzPath Inc., Roche Diagnostics, and Eli Lilly and Company in the past 2 years. Dr. Dage serves on a scientific advisory board for Eisai. Dr. Dage has received speaker fees from Eli Lilly and Company. Dr. Fagan has received research funding from Biogen, Centene, Fujirebio, and Roche Diagnostics. Dr. Fagan is a member of the scientific advisory boards for Roche Diagnostics, Genentech, and Diadem. Dr. Fagan consults for DiamiR and Seimens Healthcare Diagnostics Inc. Dr. Mendez, and Ms. Gray, Faber and Snoddy have no conflicts of interest to report. Dr. Schindler serves on a scientific advisory board for Eisai. Dr. Day is supported by the National Institutes of Health (NIH) (K23AG064029, U01AG057195, U19AG032438), the Alzheimer’s Association, and Chan Zuckerberg Initiative. He serves as a consultant for Parabon Nanolabs, Inc., as a Topic Editor (Dementia) for DynaMed (EBSCO) and as the Clinical Director of the Anti-NMDA Receptor Encephalitis Foundation (Canada; uncompensated). He is the co-Project PI for a clinical trial in anti-NMDAR encephalitis, which receives support from Horizon Pharmaceuticals. He has developed educational materials for PeerView Media, Inc., and Continuing Education Inc. He owns stock in ANI Pharmaceuticals. Dr. Day’s institution has received support from Eli Lilly for Dr. Day’s development and participation in an educational event promoting early diagnosis of symptomatic AD. Dr. Wingo is as a cofounder of revXon. Dr. Apostolova has received personal compensation for serving as a consultant for Biogen, Two Labs, Florida Department of Health, Genentech, NIH Biobank, Eli Lilly, GE Healthcare, Eisai, and Roche Diagnostics and for serving on a data safety and monitoring board for IQVIA. Dr. Apostolova receives research support from the National Institute on Aging, the Alzheimer’s Association, Roche Diagnostics, AVID Radiopharmaceuticals, Life Molecular Imaging, and Eli Lilly. All other authors had nothing to report. Author disclosures are available in the supporting information.

Figures

**FIGURE 1**
Correlation analysis of standardized CSF biomarkers in (A) LEADS and (B) EOAD group. Individual values for CN (gray), EOAD (dark blue), and EOnonAD (light blue) are shown by filled circles. The non-parametric densities are shown by red shading (0.90) and gray shading (0.50). The opposite side of the correlation map is masked to avoid duplication of scatter plots.

**FIGURE 2**
Standardized CSF biomarker values by diagnostic group: (A) pTau181, (B) tTau, (C) NfL, (D) Ng, (E) VILIP-1, (F) YKL-40, (G) SNAP-25, and (H) Aβ42/40. Individual values for CN (gray), EOAD (dark blue), and EOnonAD (light blue) are shown by filled circles, squares, and triangles, respectively. Error bars showing the mean and standard deviation. Significance (p values) is determined by Kruskal–Wallis test for significance and Dunn’s multiple comparisons test. ∗p < 0.05; ∗∗p < 0.01, ∗∗∗p < 0.001, ∗∗∗∗p < 0.0001.

**FIGURE 3**
Forest plot of Spearman correlations and 95% confidence limits of CSF biomarkers with cognitive tests in total LEADS population (purple circle) or EOAD group (dark blue square). CDR-SB, Clinical Dementia Rating Scale Sum of Boxes; MoCA, Montreal Cognitive Assessment Total Score; ADAS-Cog, Alzheimer’s Disease Cooperative Studies—cognitive behavior subscale. Worse performance in cognitive testing is associated with lower MoCA scores and higher scores on CDR-SB or ADAS-Cog.

See this image and copyright information in PMC

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Cerebrospinal fluid biomarkers in the Longitudinal Early-onset Alzheimer's Disease Study

Affiliations

Cerebrospinal fluid biomarkers in the Longitudinal Early-onset Alzheimer's Disease Study

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

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Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical