The association between APOE ε4 carrierships and the detection of amyloid positivity using an Alzheimer's disease proteomic blood test in asymptomatic Down syndrome

Lubnaa Badriyyah Abdullah; Fan Zhang; Melissa Petersen; James Hall; Benjamin L. Handen; Mark Mapstone; Brad Christian; Elizabeth Head; Sigan Harley; Howard Andrews; Joseph H. Lee; Dana Tudorascu; Christy Hom; Shahid Zaman; Adam M. Brickman; Diana Rosas; Annie Cohen; Jordan P. Harp; Frederick Schmitt; Lauren Ptomey; Jeffrey M. Burns; Ira T. Lott; Florence Lai; Charles Laymon; Carlos Cruchaga; Sid O'Bryant; Beau M. Ances

doi:10.1002/alz.71338

The association between APOE ε4 carrierships and the detection of amyloid positivity using an Alzheimer's disease proteomic blood test in asymptomatic Down syndrome

Lubnaa Badriyyah Abdullah
, Fan Zhang
, Melissa Petersen
, James Hall
, Benjamin L. Handen
, Mark Mapstone
, Brad Christian
, Elizabeth Head
, Sigan Harley
, Howard Andrews
, Joseph H. Lee
, Dana Tudorascu
, Christy Hom
, Shahid Zaman
, Adam M. Brickman
, Diana Rosas
, Annie Cohen
, Jordan P. Harp
, Frederick Schmitt
, Lauren Ptomey

Jeffrey M. Burns, Ira T. Lott, Florence Lai, Charles Laymon, Carlos Cruchaga, Sid O'Bryant, Beau M. Ances

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

Abstract

INTRODUCTION: This study evaluates plasma-based proteomic profiles for predicting amyloid positivity in adults with Down syndrome (DS) and examines the impact of apolipoprotein E ε4 (APOE ε4) on test performance. METHODS: Cross-sectional data from 290 adults with DS were analyzed using single molecule array (SIMOA) technology to measure plasma amyloid beta (Aβ)42, Aβ40, neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), tau phosphorylated at threonine 181, and total tau. Amyloid burden was quantified using Pittsburgh Compound B and (18)F-florbetapir Aβ positron emission tomography. Support vector machine analyses were conducted with biomarkers as predictors and age, sex, and APOE ε4 carrier status as covariates. RESULTS: Age, GFAP, and NfL contributed the most to the model performance. The proteomic profile achieved an area under the curve (AUC) of 96% in models with and without APOE ε4. DISCUSSION: These findings suggest that plasma proteomic biomarkers can effectively identify amyloid positivity in adults with DS and may support clinical triage, monitoring, and selection for clinical trials, independent of APOE ε4 status.

Original language	English
Article number	e71338
Journal	Alzheimer's and Dementia
Volume	22
Issue number	4
DOIs	https://doi.org/10.1002/alz.71338
State	Published - Apr 2026

Bibliographical note

Publisher Copyright:
© 2026 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.

Funding

ABC‐DS Investigators: Beau M. Ances, MD PhD; Howard F. Andrews, PhD; Karen Bell, MD; Rasmus M. Birn, PhD; Adam M. Brickman, PhD; Peter Bulova, MD; Jeff Burns, MD; Amrita Cheema, PhD; Kewei Chen, PhD; Bradley T. Christian, PhD; Isabel Clare, PhD; Ann D. Cohen, PhD; Eric W. Doran, MS; Tatiana M. Foroud, PhD; Benjamin L. Handen, PhD; Jordan Harp, PhD; Sigan L. Hartley, PhD; Elizabeth Head, PhD; Denise Head, PhD; Christy Hom, PhD; Lawrence Honig, MD; Milos D. Ikonomovic, MD; Sterling C Johnson, PhD; M. Ilyas Kamboh, PhD; David Keator, PhD; Julia K. Kofler, MD; William Charles Kreisl, MD; Sharon J. Krinsky‐McHale, PhD; Florence Lai, MD; Patrick Lao, PhD; Charles Laymon, PhD; Joseph Hyungwoo Lee, PhD; Ira T. Lott, MD; Victoria Lupson, PhD; Mark Mapstone, PhD; Davneet Singh Minhas, PhD; Neelesh Nadkarni, MD; Sid O'Bryant, PhD; Deborah Pang, MPH; Melissa Petersen, PhD; Julie C. Price, PhD; Lauren Ptomey, PhD; Margaret Pulsifer, PhD; Michael S. Rafii, MD PhD; Herminia Diana Rosas, MD; Frederick Schmitt, PhD; Nicole Schupf, PhD; Wayne P. Silverman, PhD; Dana L. Tudorascu, PhD; Rameshwari Tumuluru, MD; Badri Varadarajan, PhD; Michael A. Yassa, PhD; Shahid Zaman, MD PhD; Fan Zhang, PhD. NIA/NICHD: UO1 AG051406, UO1 AG051412, and U19 AG068054. All other authors report no declarations of interest. The Alzheimer's Biomarkers Consortium‐Down Syndrome (ABC‐DS) is funded by the National Institute on Aging and the National Institute for Child Health and Human Development (U01 AG051406, U01 AG051412, U19 AG068054) and the Investigation of Co‐occurring conditions across the Lifespan to Understand Down syndrome (NIH INCLUDE Project). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. ABC-DS Investigators: Beau M. Ances, MD PhD; Howard F. Andrews, PhD; Karen Bell, MD; Rasmus M. Birn, PhD; Adam M. Brickman, PhD; Peter Bulova, MD; Jeff Burns, MD; Amrita Cheema, PhD; Kewei Chen, PhD; Bradley T. Christian, PhD; Isabel Clare, PhD; Ann D. Cohen, PhD; Eric W. Doran, MS; Tatiana M. Foroud, PhD; Benjamin L. Handen, PhD; Jordan Harp, PhD; Sigan L. Hartley, PhD; Elizabeth Head, PhD; Denise Head, PhD; Christy Hom, PhD; Lawrence Honig, MD; Milos D. Ikonomovic, MD; Sterling C Johnson, PhD; M. Ilyas Kamboh, PhD; David Keator, PhD; Julia K. Kofler, MD; William Charles Kreisl, MD; Sharon J. Krinsky-McHale, PhD; Florence Lai, MD; Patrick Lao, PhD; Charles Laymon, PhD; Joseph Hyungwoo Lee, PhD; Ira T. Lott, MD; Victoria Lupson, PhD; Mark Mapstone, PhD; Davneet Singh Minhas, PhD; Neelesh Nadkarni, MD; Sid O'Bryant, PhD; Deborah Pang, MPH; Melissa Petersen, PhD; Julie C. Price, PhD; Lauren Ptomey, PhD; Margaret Pulsifer, PhD; Michael S. Rafii, MD PhD; Herminia Diana Rosas, MD; Frederick Schmitt, PhD; Nicole Schupf, PhD; Wayne P. Silverman, PhD; Dana L. Tudorascu, PhD; Rameshwari Tumuluru, MD; Badri Varadarajan, PhD; Michael A. Yassa, PhD; Shahid Zaman, MD PhD; Fan Zhang, PhD. NIA/NICHD: UO1 AG051406, UO1 AG051412, and U19 AG068054. All other authors report no declarations of interest. The Alzheimer's Biomarkers Consortium-Down Syndrome (ABC-DS) is funded by the National Institute on Aging and the National Institute for Child Health and Human Development (U01 AG051406, U01 AG051412, U19 AG068054) and the Investigation of Co-occurring conditions across the Lifespan to Understand Down syndrome (NIH INCLUDE Project). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Funders	Funder number
National Institute on Aging
National Institutes of Health (NIH)
NIH National Institute of Child Health and Human Development National Center for Medical Rehabilitation Research	U01 AG051412, U01 AG051406, U19 AG068054

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Alzheimer's disease
Down syndrome
amyloid positron emission tomography
blood-based biomarker test
proteomics
support vector machine learning

ASJC Scopus subject areas

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

Access to Document

10.1002/alz.71338

Cite this

Abdullah, L. B., Zhang, F., Petersen, M., Hall, J., Handen, B. L., Mapstone, M., Christian, B., Head, E., Harley, S., Andrews, H., Lee, J. H., Tudorascu, D., Hom, C., Zaman, S., Brickman, A. M., Rosas, D., Cohen, A., Harp, J. P., Schmitt, F., ... Ances, B. M. (2026). The association between APOE ε4 carrierships and the detection of amyloid positivity using an Alzheimer's disease proteomic blood test in asymptomatic Down syndrome. Alzheimer's and Dementia, 22(4), Article e71338. https://doi.org/10.1002/alz.71338

@article{e242e240726545d78387d50f5501b261,

title = "The association between APOE ε4 carrierships and the detection of amyloid positivity using an Alzheimer's disease proteomic blood test in asymptomatic Down syndrome",

abstract = "INTRODUCTION: This study evaluates plasma-based proteomic profiles for predicting amyloid positivity in adults with Down syndrome (DS) and examines the impact of apolipoprotein E ε4 (APOE ε4) on test performance. METHODS: Cross-sectional data from 290 adults with DS were analyzed using single molecule array (SIMOA) technology to measure plasma amyloid beta (Aβ)42, Aβ40, neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), tau phosphorylated at threonine 181, and total tau. Amyloid burden was quantified using Pittsburgh Compound B and (18)F-florbetapir Aβ positron emission tomography. Support vector machine analyses were conducted with biomarkers as predictors and age, sex, and APOE ε4 carrier status as covariates. RESULTS: Age, GFAP, and NfL contributed the most to the model performance. The proteomic profile achieved an area under the curve (AUC) of 96\% in models with and without APOE ε4. DISCUSSION: These findings suggest that plasma proteomic biomarkers can effectively identify amyloid positivity in adults with DS and may support clinical triage, monitoring, and selection for clinical trials, independent of APOE ε4 status.",

keywords = "Alzheimer's disease, Down syndrome, amyloid positron emission tomography, blood-based biomarker test, proteomics, support vector machine learning",

author = "Abdullah, \{Lubnaa Badriyyah\} and Fan Zhang and Melissa Petersen and James Hall and Handen, \{Benjamin L.\} and Mark Mapstone and Brad Christian and Elizabeth Head and Sigan Harley and Howard Andrews and Lee, \{Joseph H.\} and Dana Tudorascu and Christy Hom and Shahid Zaman and Brickman, \{Adam M.\} and Diana Rosas and Annie Cohen and Harp, \{Jordan P.\} and Frederick Schmitt and Lauren Ptomey and Burns, \{Jeffrey M.\} and Lott, \{Ira T.\} and Florence Lai and Charles Laymon and Carlos Cruchaga and Sid O'Bryant and Ances, \{Beau M.\}",

note = "Publisher Copyright: {\textcopyright} 2026 The Author(s). Alzheimer's \& Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.",

year = "2026",

month = apr,

doi = "10.1002/alz.71338",

language = "English",

volume = "22",

number = "4",

}

Abdullah, LB, Zhang, F, Petersen, M, Hall, J, Handen, BL, Mapstone, M, Christian, B, Head, E, Harley, S, Andrews, H, Lee, JH, Tudorascu, D, Hom, C, Zaman, S, Brickman, AM, Rosas, D, Cohen, A, Harp, JP , Schmitt, F, Ptomey, L, Burns, JM, Lott, IT, Lai, F, Laymon, C, Cruchaga, C, O'Bryant, S & Ances, BM 2026, 'The association between APOE ε4 carrierships and the detection of amyloid positivity using an Alzheimer's disease proteomic blood test in asymptomatic Down syndrome', Alzheimer's and Dementia, vol. 22, no. 4, e71338. https://doi.org/10.1002/alz.71338

TY - JOUR

T1 - The association between APOE ε4 carrierships and the detection of amyloid positivity using an Alzheimer's disease proteomic blood test in asymptomatic Down syndrome

AU - Abdullah, Lubnaa Badriyyah

AU - Zhang, Fan

AU - Petersen, Melissa

AU - Hall, James

AU - Handen, Benjamin L.

AU - Mapstone, Mark

AU - Christian, Brad

AU - Head, Elizabeth

AU - Harley, Sigan

AU - Andrews, Howard

AU - Lee, Joseph H.

AU - Tudorascu, Dana

AU - Hom, Christy

AU - Zaman, Shahid

AU - Brickman, Adam M.

AU - Rosas, Diana

AU - Cohen, Annie

AU - Harp, Jordan P.

AU - Schmitt, Frederick

AU - Ptomey, Lauren

AU - Burns, Jeffrey M.

AU - Lott, Ira T.

AU - Lai, Florence

AU - Laymon, Charles

AU - Cruchaga, Carlos

AU - O'Bryant, Sid

AU - Ances, Beau M.

PY - 2026/4

Y1 - 2026/4

N2 - INTRODUCTION: This study evaluates plasma-based proteomic profiles for predicting amyloid positivity in adults with Down syndrome (DS) and examines the impact of apolipoprotein E ε4 (APOE ε4) on test performance. METHODS: Cross-sectional data from 290 adults with DS were analyzed using single molecule array (SIMOA) technology to measure plasma amyloid beta (Aβ)42, Aβ40, neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), tau phosphorylated at threonine 181, and total tau. Amyloid burden was quantified using Pittsburgh Compound B and (18)F-florbetapir Aβ positron emission tomography. Support vector machine analyses were conducted with biomarkers as predictors and age, sex, and APOE ε4 carrier status as covariates. RESULTS: Age, GFAP, and NfL contributed the most to the model performance. The proteomic profile achieved an area under the curve (AUC) of 96% in models with and without APOE ε4. DISCUSSION: These findings suggest that plasma proteomic biomarkers can effectively identify amyloid positivity in adults with DS and may support clinical triage, monitoring, and selection for clinical trials, independent of APOE ε4 status.

AB - INTRODUCTION: This study evaluates plasma-based proteomic profiles for predicting amyloid positivity in adults with Down syndrome (DS) and examines the impact of apolipoprotein E ε4 (APOE ε4) on test performance. METHODS: Cross-sectional data from 290 adults with DS were analyzed using single molecule array (SIMOA) technology to measure plasma amyloid beta (Aβ)42, Aβ40, neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), tau phosphorylated at threonine 181, and total tau. Amyloid burden was quantified using Pittsburgh Compound B and (18)F-florbetapir Aβ positron emission tomography. Support vector machine analyses were conducted with biomarkers as predictors and age, sex, and APOE ε4 carrier status as covariates. RESULTS: Age, GFAP, and NfL contributed the most to the model performance. The proteomic profile achieved an area under the curve (AUC) of 96% in models with and without APOE ε4. DISCUSSION: These findings suggest that plasma proteomic biomarkers can effectively identify amyloid positivity in adults with DS and may support clinical triage, monitoring, and selection for clinical trials, independent of APOE ε4 status.

KW - Alzheimer's disease

KW - Down syndrome

KW - amyloid positron emission tomography

KW - blood-based biomarker test

KW - proteomics

KW - support vector machine learning

UR - https://www.scopus.com/pages/publications/105035471152

UR - https://www.scopus.com/pages/publications/105035471152#tab=citedBy

U2 - 10.1002/alz.71338

DO - 10.1002/alz.71338

M3 - Article

C2 - 41964394

AN - SCOPUS:105035471152

SN - 1552-5260

VL - 22

JO - Alzheimer's and Dementia

JF - Alzheimer's and Dementia

IS - 4

M1 - e71338

ER -

The association between APOE ε4 carrierships and the detection of amyloid positivity using an Alzheimer's disease proteomic blood test in asymptomatic Down syndrome

Abstract

Bibliographical note

Funding

UN SDGs

Keywords

ASJC Scopus subject areas

Access to Document

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