Biomarker clustering in autosomal dominant Alzheimer's disease

for the Dominantly Inherited Alzheimer Network (DIAN)

doi:10.1002/alz.12661

Biomarker clustering in autosomal dominant Alzheimer's disease

for the Dominantly Inherited Alzheimer Network (DIAN)

Radiology

Research output: Contribution to journal › Article › peer-review

Abstract

INTRODUCTION: As the number of biomarkers used to study Alzheimer's disease (AD) continues to increase, it is important to understand the utility of any given biomarker, as well as what additional information a biomarker provides when compared to others. METHODS: We used hierarchical clustering to group 19 cross-sectional biomarkers in autosomal dominant AD. Feature selection identified biomarkers that were the strongest predictors of mutation status and estimated years from symptom onset (EYO). Biomarkers identified included clinical assessments, neuroimaging, cerebrospinal fluid amyloid, and tau, and emerging biomarkers of neuronal integrity and inflammation. RESULTS: Three primary clusters were identified: neurodegeneration, amyloid/tau, and emerging biomarkers. Feature selection identified amyloid and tau measures as the primary predictors of mutation status and EYO. Emerging biomarkers of neuronal integrity and inflammation were relatively weak predictors. DISCUSSION: These results provide novel insight into our understanding of the relationships among biomarkers and the staging of biomarkers based on disease progression.

Original language	English (US)
Pages (from-to)	274-284
Number of pages	11
Journal	Alzheimer's and Dementia
Volume	19
Issue number	1
DOIs	https://doi.org/10.1002/alz.12661
State	Published - Jan 2023

Keywords

Autosomal dominant Alzheimer's disease
biomarkers
machine learning

ASJC Scopus subject areas

Epidemiology
Health Policy
Developmental Neuroscience
Clinical Neurology
Geriatrics and Gerontology
Cellular and Molecular Neuroscience
Psychiatry and Mental health

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10.1002/alz.12661

Cite this

@article{6828a13e7eb7411dbbfce7ca3c284487,

title = "Biomarker clustering in autosomal dominant Alzheimer's disease",

abstract = "INTRODUCTION: As the number of biomarkers used to study Alzheimer's disease (AD) continues to increase, it is important to understand the utility of any given biomarker, as well as what additional information a biomarker provides when compared to others. METHODS: We used hierarchical clustering to group 19 cross-sectional biomarkers in autosomal dominant AD. Feature selection identified biomarkers that were the strongest predictors of mutation status and estimated years from symptom onset (EYO). Biomarkers identified included clinical assessments, neuroimaging, cerebrospinal fluid amyloid, and tau, and emerging biomarkers of neuronal integrity and inflammation. RESULTS: Three primary clusters were identified: neurodegeneration, amyloid/tau, and emerging biomarkers. Feature selection identified amyloid and tau measures as the primary predictors of mutation status and EYO. Emerging biomarkers of neuronal integrity and inflammation were relatively weak predictors. DISCUSSION: These results provide novel insight into our understanding of the relationships among biomarkers and the staging of biomarkers based on disease progression.",

keywords = "Autosomal dominant Alzheimer's disease, biomarkers, machine learning",

author = "{for the Dominantly Inherited Alzheimer Network (DIAN)} and Luckett, {Patrick H.} and Charlie Chen and Gordon, {Brian A.} and Julie Wisch and Berman, {Sarah B.} and Chhatwal, {Jasmeer P.} and Carlos Cruchaga and Fagan, {Anne M.} and Farlow, {Martin R.} and Fox, {Nick C.} and Mathias Jucker and Johannes Levin and Masters, {Colin L.} and Hiroshi Mori and Noble, {James M.} and Stephen Salloway and Schofield, {Peter R.} and Brickman, {Adam M.} and Brooks, {William S.} and Cash, {David M.} and Fulham, {Michael J.} and Bernardino Ghetti and Jack, {Clifford R.} and Jonathan V{\"o}glein and Klunk, {William E.} and Robert Koeppe and Yi Su and Michael Weiner and Qing Wang and Daniel Marcus and Deborah Koudelis and Nelly Joseph-Mathurin and Lisa Cash and Russ Hornbeck and Chengjie Xiong and Perrin, {Richard J.} and Karch, {Celeste M.} and Jason Hassenstab and Eric McDade and Morris, {John C.} and Benzinger, {Tammie L.S.} and Bateman, {Randall J.} and Ances, {Beau M.}",

note = "Funding Information: We would like to acknowledge the participants and their families, without whom these studies would not be possible. In addition, we thank all the participating researchers and coordinators ( https://dian.wustl.edu/our‐research/observational‐study/dian‐observational‐study‐sites/ ) who support the studies. DIAN ClinicalTrials.gov identifier: NCT00869817. This research was funded by the National Institutes of Health (NIH) (grant numbers K01AG053474, K23AG046363, R01AG052550, UFAG 032438, UL1TR000448, P30NS098577, R01EB009352, P50AG05131, U01AG042791, U01AG042791‐S1 [FNIH and Accelerating Medicines Partnership], R1AG046179]; the German Center for Neurodegenerative Diseases (DZNE); the National Institute for Health Research (NIHR) Queen Square Dementia Biomedical Research Centre; and the Medical Research Council Dementias Platform United Kingdom (UK) (grant numbers MR/L023784/1, MR/009076/1), Alzheimer's Association International Research Grant Program #AARFD‐20‐681815, NSF DMS 156243, DIAN‐J by AMED, and an anonymous organization. Furthermore, we acknowledge the support of Fred Simmons and Olga Mohan, the Barnes‐Jewish Hospital Foundation, the Charles F. and Joanne Knight Alzheimer Research Initiative, the Hope Center for Neurological Disorders, the Mallinckrodt Institute of Radiology, the Paula and Rodger O. Riney fund, and the Daniel J. Brennan fund. Funding Information: The authors declare no competing interest. Anne Fagan has received research funding from the National Institute on Aging of the National Institutes of Health, Biogen, Centene, Fujirebio, and Roche Diagnostics. She is a member of the scientific advisory boards for Roche Diagnostics and Genentech and consults for Diadem, DiamiR, and Siemens Healthcare Diagnostics Inc. Carlos Cruchaga receives research support from Biogen, EISAI, Alector, and Parabon. The funders of the study had no role in the collection, analysis, or interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. Dr. Cruchaga is also a member of the advisory board of ADx Healthcare, Halia Therapeutics, and Vivid Genomics. Jasmeer P. Chhatwal served on the medical advisory board for Otsuka Pharmaceuticals. Johannes Levin reports speaker's fees from Bayer Vital, speaker's fees from Willi Gross Foundation, consulting fees from Axon Neuroscience, consulting fees from Ionis Pharmaceuticals, author fees from Thieme medical publishers and W. Kohlhammer GmbH medical publishers, compensation for work as part‐time CMO from MODAG GmbH, and non‐financial support from AbbVie outside the submitted work. John Morris is funded by NIH grants numbers P50AG005681, P01AG003991, P01AG026276, and UF1AG032438. Dr. Jack serves on an independent data monitoring board for Roche and has served as a speaker for Eisai, but he receives no personal compensation from any commercial entity. He receives research support from NIH and the Alexander Family Alzheimer Disease Research Professorship of the Mayo Clinic. Eric McDade is involved in a clinical trial on AV‐1451 sponsored by Avid and serves on a data safety monitoring committee for Eli‐Lilly and Alector and is on the Scientific Advisory Board for Alzamend; and receives research support from Eli‐Lilly and Hoffman‐La Roche. Dr. McDade is a co‐inventor of the {"}Methods of diagnosing AD with phosphorylation changes{"} technology licensed by Washington University to C2N Diagnostics. Washington University also holds 5% equity in C2N. Through these relationships, Washington University and Dr. McDade are entitled to receive royalties from the license agreement with C2N. Dr. David Holtzman, Chair of Neurology at Washington University Medical School, is a co‐founder of C2N and serves on C2N's advisory board. Randall Bateman is on the scientific advisory board of C2N Diagnostics and reports research support from AbbVie, Biogen, Eisai, Eli Lilly, Co/Avid Radiopharmaceuticals, Roche, Janssen, and United Neuroscience. Dr. Weiner receives support for NIH grants: 5U19AG024904‐14; 1R01AG053798‐01A1; R01 MH098062; U24 AG057437‐01; 1U2CA060426‐01; 1R01AG058676‐01A1; and 1RF1AG059009‐01, DOD: W81XWH‐15‐2‐0070; 0W81XWH‐12‐2‐0012; W81XWH‐14‐1‐0462; W81XWH‐13‐1‐0259, PCORI: PPRN‐1501‐26817, California Dept. of Public Health: 16–10054, U. Michigan: 18‐PAF01312, Siemens: 444951–54249, Biogen: 174552, Hillblom Foundation: 2015‐A‐011‐NET, Alzheimer's Association: BHR‐16‐459161; The State of California: 18–109929. He also receives support from Johnson & Johnson, Kevin and Connie Shanahan, GE, VUmc, Australian Catholic University (HBI‐BHR), The Stroke Foundation, and the Veterans Administration. He has served on Advisory Boards for Eli Lilly, Cerecin/Accera, Roche, Alzheon, Inc., Merck Sharp & Dohme Corp., Nestle/Nestec, PCORI/PPRN, Dolby Family Ventures, National Institute on Aging (NIA), Brain Health Registry and ADNI. He serves on the Editorial Boards for Alzheimer's & Dementia, TMRI and MRI. He has provided consulting and/or acted as a speaker/lecturer to Cerecin/Accera, Inc., BioClinica, Nestle/Nestec, Roche, Genentech, NIH, The Buck Institute for Research on Aging, FUJIFILM‐Toyama Chemical (Japan), Garfield Weston, Baird Equity Capital, University of Southern California (USC), Cytox, and Japanese Organization for Medical Device Development, Inc. (JOMDD) and T3D Therapeutics. He holds stock options with Alzheon, Inc., Alzeca, and Anven. Funding Information: We would like to acknowledge the participants and their families, without whom these studies would not be possible. In addition, we thank all the participating researchers and coordinators (https://dian.wustl.edu/our-research/observational-study/dian-observational-study-sites/) who support the studies. DIAN ClinicalTrials.gov identifier: NCT00869817. This research was funded by the National Institutes of Health (NIH) (grant numbers K01AG053474, K23AG046363, R01AG052550, UFAG 032438, UL1TR000448, P30NS098577, R01EB009352, P50AG05131, U01AG042791, U01AG042791-S1 [FNIH and Accelerating Medicines Partnership], R1AG046179]; the German Center for Neurodegenerative Diseases (DZNE); the National Institute for Health Research (NIHR) Queen Square Dementia Biomedical Research Centre; and the Medical Research Council Dementias Platform United Kingdom (UK) (grant numbers MR/L023784/1, MR/009076/1), Alzheimer's Association International Research Grant Program #AARFD-20-681815, NSF DMS 156243, DIAN-J by AMED, and an anonymous organization. Furthermore, we acknowledge the support of Fred Simmons and Olga Mohan, the Barnes-Jewish Hospital Foundation, the Charles F. and Joanne Knight Alzheimer Research Initiative, the Hope Center for Neurological Disorders, the Mallinckrodt Institute of Radiology, the Paula and Rodger O. Riney fund, and the Daniel J. Brennan fund. Publisher Copyright: {\textcopyright} 2022 the Alzheimer's Association.",

year = "2023",

month = jan,

doi = "10.1002/alz.12661",

language = "English (US)",

volume = "19",

pages = "274--284",

journal = "Alzheimer's and Dementia",

issn = "1552-5260",

publisher = "Elsevier Inc.",

number = "1",

}

TY - JOUR

T1 - Biomarker clustering in autosomal dominant Alzheimer's disease

AU - for the Dominantly Inherited Alzheimer Network (DIAN)

AU - Luckett, Patrick H.

AU - Chen, Charlie

AU - Gordon, Brian A.

AU - Wisch, Julie

AU - Berman, Sarah B.

AU - Chhatwal, Jasmeer P.

AU - Cruchaga, Carlos

AU - Fagan, Anne M.

AU - Farlow, Martin R.

AU - Fox, Nick C.

AU - Jucker, Mathias

AU - Levin, Johannes

AU - Masters, Colin L.

AU - Mori, Hiroshi

AU - Noble, James M.

AU - Salloway, Stephen

AU - Schofield, Peter R.

AU - Brickman, Adam M.

AU - Brooks, William S.

AU - Cash, David M.

AU - Fulham, Michael J.

AU - Ghetti, Bernardino

AU - Jack, Clifford R.

AU - Vöglein, Jonathan

AU - Klunk, William E.

AU - Koeppe, Robert

AU - Su, Yi

AU - Weiner, Michael

AU - Wang, Qing

AU - Marcus, Daniel

AU - Koudelis, Deborah

AU - Joseph-Mathurin, Nelly

AU - Cash, Lisa

AU - Hornbeck, Russ

AU - Xiong, Chengjie

AU - Perrin, Richard J.

AU - Karch, Celeste M.

AU - Hassenstab, Jason

AU - McDade, Eric

AU - Morris, John C.

AU - Benzinger, Tammie L.S.

AU - Bateman, Randall J.

AU - Ances, Beau M.

N1 - Funding Information: We would like to acknowledge the participants and their families, without whom these studies would not be possible. In addition, we thank all the participating researchers and coordinators ( https://dian.wustl.edu/our‐research/observational‐study/dian‐observational‐study‐sites/ ) who support the studies. DIAN ClinicalTrials.gov identifier: NCT00869817. This research was funded by the National Institutes of Health (NIH) (grant numbers K01AG053474, K23AG046363, R01AG052550, UFAG 032438, UL1TR000448, P30NS098577, R01EB009352, P50AG05131, U01AG042791, U01AG042791‐S1 [FNIH and Accelerating Medicines Partnership], R1AG046179]; the German Center for Neurodegenerative Diseases (DZNE); the National Institute for Health Research (NIHR) Queen Square Dementia Biomedical Research Centre; and the Medical Research Council Dementias Platform United Kingdom (UK) (grant numbers MR/L023784/1, MR/009076/1), Alzheimer's Association International Research Grant Program #AARFD‐20‐681815, NSF DMS 156243, DIAN‐J by AMED, and an anonymous organization. Furthermore, we acknowledge the support of Fred Simmons and Olga Mohan, the Barnes‐Jewish Hospital Foundation, the Charles F. and Joanne Knight Alzheimer Research Initiative, the Hope Center for Neurological Disorders, the Mallinckrodt Institute of Radiology, the Paula and Rodger O. Riney fund, and the Daniel J. Brennan fund. Funding Information: The authors declare no competing interest. Anne Fagan has received research funding from the National Institute on Aging of the National Institutes of Health, Biogen, Centene, Fujirebio, and Roche Diagnostics. She is a member of the scientific advisory boards for Roche Diagnostics and Genentech and consults for Diadem, DiamiR, and Siemens Healthcare Diagnostics Inc. Carlos Cruchaga receives research support from Biogen, EISAI, Alector, and Parabon. The funders of the study had no role in the collection, analysis, or interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. Dr. Cruchaga is also a member of the advisory board of ADx Healthcare, Halia Therapeutics, and Vivid Genomics. Jasmeer P. Chhatwal served on the medical advisory board for Otsuka Pharmaceuticals. Johannes Levin reports speaker's fees from Bayer Vital, speaker's fees from Willi Gross Foundation, consulting fees from Axon Neuroscience, consulting fees from Ionis Pharmaceuticals, author fees from Thieme medical publishers and W. Kohlhammer GmbH medical publishers, compensation for work as part‐time CMO from MODAG GmbH, and non‐financial support from AbbVie outside the submitted work. John Morris is funded by NIH grants numbers P50AG005681, P01AG003991, P01AG026276, and UF1AG032438. Dr. Jack serves on an independent data monitoring board for Roche and has served as a speaker for Eisai, but he receives no personal compensation from any commercial entity. He receives research support from NIH and the Alexander Family Alzheimer Disease Research Professorship of the Mayo Clinic. Eric McDade is involved in a clinical trial on AV‐1451 sponsored by Avid and serves on a data safety monitoring committee for Eli‐Lilly and Alector and is on the Scientific Advisory Board for Alzamend; and receives research support from Eli‐Lilly and Hoffman‐La Roche. Dr. McDade is a co‐inventor of the "Methods of diagnosing AD with phosphorylation changes" technology licensed by Washington University to C2N Diagnostics. Washington University also holds 5% equity in C2N. Through these relationships, Washington University and Dr. McDade are entitled to receive royalties from the license agreement with C2N. Dr. David Holtzman, Chair of Neurology at Washington University Medical School, is a co‐founder of C2N and serves on C2N's advisory board. Randall Bateman is on the scientific advisory board of C2N Diagnostics and reports research support from AbbVie, Biogen, Eisai, Eli Lilly, Co/Avid Radiopharmaceuticals, Roche, Janssen, and United Neuroscience. Dr. Weiner receives support for NIH grants: 5U19AG024904‐14; 1R01AG053798‐01A1; R01 MH098062; U24 AG057437‐01; 1U2CA060426‐01; 1R01AG058676‐01A1; and 1RF1AG059009‐01, DOD: W81XWH‐15‐2‐0070; 0W81XWH‐12‐2‐0012; W81XWH‐14‐1‐0462; W81XWH‐13‐1‐0259, PCORI: PPRN‐1501‐26817, California Dept. of Public Health: 16–10054, U. Michigan: 18‐PAF01312, Siemens: 444951–54249, Biogen: 174552, Hillblom Foundation: 2015‐A‐011‐NET, Alzheimer's Association: BHR‐16‐459161; The State of California: 18–109929. He also receives support from Johnson & Johnson, Kevin and Connie Shanahan, GE, VUmc, Australian Catholic University (HBI‐BHR), The Stroke Foundation, and the Veterans Administration. He has served on Advisory Boards for Eli Lilly, Cerecin/Accera, Roche, Alzheon, Inc., Merck Sharp & Dohme Corp., Nestle/Nestec, PCORI/PPRN, Dolby Family Ventures, National Institute on Aging (NIA), Brain Health Registry and ADNI. He serves on the Editorial Boards for Alzheimer's & Dementia, TMRI and MRI. He has provided consulting and/or acted as a speaker/lecturer to Cerecin/Accera, Inc., BioClinica, Nestle/Nestec, Roche, Genentech, NIH, The Buck Institute for Research on Aging, FUJIFILM‐Toyama Chemical (Japan), Garfield Weston, Baird Equity Capital, University of Southern California (USC), Cytox, and Japanese Organization for Medical Device Development, Inc. (JOMDD) and T3D Therapeutics. He holds stock options with Alzheon, Inc., Alzeca, and Anven. Funding Information: We would like to acknowledge the participants and their families, without whom these studies would not be possible. In addition, we thank all the participating researchers and coordinators (https://dian.wustl.edu/our-research/observational-study/dian-observational-study-sites/) who support the studies. DIAN ClinicalTrials.gov identifier: NCT00869817. This research was funded by the National Institutes of Health (NIH) (grant numbers K01AG053474, K23AG046363, R01AG052550, UFAG 032438, UL1TR000448, P30NS098577, R01EB009352, P50AG05131, U01AG042791, U01AG042791-S1 [FNIH and Accelerating Medicines Partnership], R1AG046179]; the German Center for Neurodegenerative Diseases (DZNE); the National Institute for Health Research (NIHR) Queen Square Dementia Biomedical Research Centre; and the Medical Research Council Dementias Platform United Kingdom (UK) (grant numbers MR/L023784/1, MR/009076/1), Alzheimer's Association International Research Grant Program #AARFD-20-681815, NSF DMS 156243, DIAN-J by AMED, and an anonymous organization. Furthermore, we acknowledge the support of Fred Simmons and Olga Mohan, the Barnes-Jewish Hospital Foundation, the Charles F. and Joanne Knight Alzheimer Research Initiative, the Hope Center for Neurological Disorders, the Mallinckrodt Institute of Radiology, the Paula and Rodger O. Riney fund, and the Daniel J. Brennan fund. Publisher Copyright: © 2022 the Alzheimer's Association.

PY - 2023/1

Y1 - 2023/1

N2 - INTRODUCTION: As the number of biomarkers used to study Alzheimer's disease (AD) continues to increase, it is important to understand the utility of any given biomarker, as well as what additional information a biomarker provides when compared to others. METHODS: We used hierarchical clustering to group 19 cross-sectional biomarkers in autosomal dominant AD. Feature selection identified biomarkers that were the strongest predictors of mutation status and estimated years from symptom onset (EYO). Biomarkers identified included clinical assessments, neuroimaging, cerebrospinal fluid amyloid, and tau, and emerging biomarkers of neuronal integrity and inflammation. RESULTS: Three primary clusters were identified: neurodegeneration, amyloid/tau, and emerging biomarkers. Feature selection identified amyloid and tau measures as the primary predictors of mutation status and EYO. Emerging biomarkers of neuronal integrity and inflammation were relatively weak predictors. DISCUSSION: These results provide novel insight into our understanding of the relationships among biomarkers and the staging of biomarkers based on disease progression.

AB - INTRODUCTION: As the number of biomarkers used to study Alzheimer's disease (AD) continues to increase, it is important to understand the utility of any given biomarker, as well as what additional information a biomarker provides when compared to others. METHODS: We used hierarchical clustering to group 19 cross-sectional biomarkers in autosomal dominant AD. Feature selection identified biomarkers that were the strongest predictors of mutation status and estimated years from symptom onset (EYO). Biomarkers identified included clinical assessments, neuroimaging, cerebrospinal fluid amyloid, and tau, and emerging biomarkers of neuronal integrity and inflammation. RESULTS: Three primary clusters were identified: neurodegeneration, amyloid/tau, and emerging biomarkers. Feature selection identified amyloid and tau measures as the primary predictors of mutation status and EYO. Emerging biomarkers of neuronal integrity and inflammation were relatively weak predictors. DISCUSSION: These results provide novel insight into our understanding of the relationships among biomarkers and the staging of biomarkers based on disease progression.

KW - Autosomal dominant Alzheimer's disease

KW - biomarkers

KW - machine learning

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UR - http://www.scopus.com/inward/citedby.url?scp=85127456699&partnerID=8YFLogxK

U2 - 10.1002/alz.12661

DO - 10.1002/alz.12661

M3 - Article

AN - SCOPUS:85127456699

VL - 19

SP - 274

EP - 284

JO - Alzheimer's and Dementia

JF - Alzheimer's and Dementia

SN - 1552-5260

IS - 1

ER -

Biomarker clustering in autosomal dominant Alzheimer's disease

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