Blood biomarkers differentiate AD-related versus non-AD-related cognitive deficits

Kelsey R. Sewell; Lauren E. Oberlin; Thomas K. Karikari; Marcos Olvera-Rojas; Lu Wan; Jill K. Morris; Paul J. Kueck; Xuemei Zeng; Haiqing Huang; George Grove; Yijun Chen; Tara K. Lafferty; Anuradha Sehrawat; M. Ilyas Kamboh; Anna L. Marsland; Arthur F Kramer; Edward McAuley; Jeffrey M. Burns; Charles H Hillman; Eric D. Vidoni; Chaeryon Kang; Kirk I. Erickson

doi:10.1002/alz.14619

Blood biomarkers differentiate AD-related versus non-AD-related cognitive deficits

Kelsey R. Sewell, Lauren E. Oberlin, Thomas K. Karikari, Marcos Olvera-Rojas, Lu Wan, Jill K. Morris, Paul J. Kueck, Xuemei Zeng, Haiqing Huang, George Grove, Yijun Chen, Tara K. Lafferty, Anuradha Sehrawat, M. Ilyas Kamboh, Anna L. Marsland, Arthur F Kramer, Edward McAuley, Jeffrey M. Burns, Charles H Hillman, Eric D. VidoniChaeryon Kang, Kirk I. Erickson

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

Abstract

INTRODUCTION: The utility of blood-based biomarkers for discriminating Alzheimer's disease (AD)-related versus non-AD-related cognitive deficits in preclinical populations remains poorly understood. Here, we tested the capability of blood markers to detect and discriminate variation in performance across multiple cognitive domains in a cognitively unimpaired sample. METHODS: Participants (n = 648, aged 69.9 ± 3.8, 71% female) underwent a comprehensive cognitive assessment and assays for plasma-based biomarkers amyloid beta (Aβ)1-42/1-40 by mass spectrometry, phosphorylated tau (p-tau) 181 and 217, p-tau217/Aβ1-42, glial fibrillary acidic protein (GFAP), and neurofilament light (NfL). RESULTS: Greater p-tau217 was exclusively associated with poorer episodic memory performance (β = −0.11, SE = 0.04, p =.003), and remained so after covarying for NfL. Higher NfL was non-specifically associated with poorer performance across a range of cognitive domains and remained so after covarying for p-tau217. DISCUSSION: Blood-based biomarkers may differentiate non-AD-related versus AD-related cognitive deficits. This characterization will be important for early intervention and disease monitoring for AD. Highlights: There is heterogeneity in the causes of cognitive decline in aging. AD-related blood biomarkers may help characterize these causes. Elevated p-tau217 was exclusively associated with poorer episodic memory. Elevated NfL was associated with poorer cognition in a broad range of domains. Blood biomarkers may help differentiate AD- and non-AD-related cognitive deficits.

Original language	English (US)
Article number	e14619
Journal	Alzheimer's and Dementia
Volume	21
Issue number	3
DOIs	https://doi.org/10.1002/alz.14619
State	Published - Mar 2025

Keywords

Alzheimer's disease
biomarkers
blood-based biomarkers
cognition
cognitive function

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.14619License: CC BY-NC

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Sewell, K. R., Oberlin, L. E., Karikari, T. K., Olvera-Rojas, M., Wan, L., Morris, J. K., Kueck, P. J., Zeng, X., Huang, H., Grove, G., Chen, Y., Lafferty, T. K., Sehrawat, A., Kamboh, M. I., Marsland, A. L., Kramer, A. F., McAuley, E., Burns, J. M., Hillman, C. H., ... Erickson, K. I. (2025). Blood biomarkers differentiate AD-related versus non-AD-related cognitive deficits. Alzheimer's and Dementia, 21(3), Article e14619. https://doi.org/10.1002/alz.14619

Sewell, KR, Oberlin, LE, Karikari, TK, Olvera-Rojas, M, Wan, L, Morris, JK, Kueck, PJ, Zeng, X, Huang, H, Grove, G, Chen, Y, Lafferty, TK, Sehrawat, A, Kamboh, MI, Marsland, AL, Kramer, AF, McAuley, E, Burns, JM, Hillman, CH, Vidoni, ED, Kang, C & Erickson, KI 2025, 'Blood biomarkers differentiate AD-related versus non-AD-related cognitive deficits', Alzheimer's and Dementia, vol. 21, no. 3, e14619. https://doi.org/10.1002/alz.14619

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title = "Blood biomarkers differentiate AD-related versus non-AD-related cognitive deficits",

abstract = "INTRODUCTION: The utility of blood-based biomarkers for discriminating Alzheimer's disease (AD)-related versus non-AD-related cognitive deficits in preclinical populations remains poorly understood. Here, we tested the capability of blood markers to detect and discriminate variation in performance across multiple cognitive domains in a cognitively unimpaired sample. METHODS: Participants (n = 648, aged 69.9 ± 3.8, 71\% female) underwent a comprehensive cognitive assessment and assays for plasma-based biomarkers amyloid beta (Aβ)1-42/1-40 by mass spectrometry, phosphorylated tau (p-tau) 181 and 217, p-tau217/Aβ1-42, glial fibrillary acidic protein (GFAP), and neurofilament light (NfL). RESULTS: Greater p-tau217 was exclusively associated with poorer episodic memory performance (β = −0.11, SE = 0.04, p =.003), and remained so after covarying for NfL. Higher NfL was non-specifically associated with poorer performance across a range of cognitive domains and remained so after covarying for p-tau217. DISCUSSION: Blood-based biomarkers may differentiate non-AD-related versus AD-related cognitive deficits. This characterization will be important for early intervention and disease monitoring for AD. Highlights: There is heterogeneity in the causes of cognitive decline in aging. AD-related blood biomarkers may help characterize these causes. Elevated p-tau217 was exclusively associated with poorer episodic memory. Elevated NfL was associated with poorer cognition in a broad range of domains. Blood biomarkers may help differentiate AD- and non-AD-related cognitive deficits.",

keywords = "Alzheimer's disease, biomarkers, blood-based biomarkers, cognition, cognitive function",

author = "Sewell, \{Kelsey R.\} and Oberlin, \{Lauren E.\} and Karikari, \{Thomas K.\} and Marcos Olvera-Rojas and Lu Wan and Morris, \{Jill K.\} and Kueck, \{Paul J.\} and Xuemei Zeng and Haiqing Huang and George Grove and Yijun Chen and Lafferty, \{Tara K.\} and Anuradha Sehrawat and Kamboh, \{M. Ilyas\} and Marsland, \{Anna L.\} and Kramer, \{Arthur F\} and Edward McAuley and Burns, \{Jeffrey M.\} and Hillman, \{Charles H\} and Vidoni, \{Eric D.\} and Chaeryon Kang and Erickson, \{Kirk I.\}",

note = "This study was funded by a NIH grant (R01AG053952) awarded to Kirk I. Erickson, Jeffrey M. Burns, Arthur F. Kramer, and Edward McAuley and another to Kirk I. Erickson (R35 AG072307). The study also received support from the Clinical and Translational Science Institute at the University of Pittsburgh (UL1\textbackslash{}u2010TR\textbackslash{}u2010001857) and Kansas University infrastructure grants (P30 AG072973 and UL1TR002366).",

year = "2025",

month = mar,

doi = "10.1002/alz.14619",

language = "English (US)",

volume = "21",

journal = "Alzheimer's and Dementia",

issn = "1552-5260",

publisher = "John Wiley \& Sons, Ltd.",

number = "3",

}

TY - JOUR

T1 - Blood biomarkers differentiate AD-related versus non-AD-related cognitive deficits

AU - Sewell, Kelsey R.

AU - Oberlin, Lauren E.

AU - Karikari, Thomas K.

AU - Olvera-Rojas, Marcos

AU - Wan, Lu

AU - Morris, Jill K.

AU - Kueck, Paul J.

AU - Zeng, Xuemei

AU - Huang, Haiqing

AU - Grove, George

AU - Chen, Yijun

AU - Lafferty, Tara K.

AU - Sehrawat, Anuradha

AU - Kamboh, M. Ilyas

AU - Marsland, Anna L.

AU - Kramer, Arthur F

AU - McAuley, Edward

AU - Burns, Jeffrey M.

AU - Hillman, Charles H

AU - Vidoni, Eric D.

AU - Kang, Chaeryon

AU - Erickson, Kirk I.

N1 - This study was funded by a NIH grant (R01AG053952) awarded to Kirk I. Erickson, Jeffrey M. Burns, Arthur F. Kramer, and Edward McAuley and another to Kirk I. Erickson (R35 AG072307). The study also received support from the Clinical and Translational Science Institute at the University of Pittsburgh (UL1\u2010TR\u2010001857) and Kansas University infrastructure grants (P30 AG072973 and UL1TR002366).

PY - 2025/3

Y1 - 2025/3

N2 - INTRODUCTION: The utility of blood-based biomarkers for discriminating Alzheimer's disease (AD)-related versus non-AD-related cognitive deficits in preclinical populations remains poorly understood. Here, we tested the capability of blood markers to detect and discriminate variation in performance across multiple cognitive domains in a cognitively unimpaired sample. METHODS: Participants (n = 648, aged 69.9 ± 3.8, 71% female) underwent a comprehensive cognitive assessment and assays for plasma-based biomarkers amyloid beta (Aβ)1-42/1-40 by mass spectrometry, phosphorylated tau (p-tau) 181 and 217, p-tau217/Aβ1-42, glial fibrillary acidic protein (GFAP), and neurofilament light (NfL). RESULTS: Greater p-tau217 was exclusively associated with poorer episodic memory performance (β = −0.11, SE = 0.04, p =.003), and remained so after covarying for NfL. Higher NfL was non-specifically associated with poorer performance across a range of cognitive domains and remained so after covarying for p-tau217. DISCUSSION: Blood-based biomarkers may differentiate non-AD-related versus AD-related cognitive deficits. This characterization will be important for early intervention and disease monitoring for AD. Highlights: There is heterogeneity in the causes of cognitive decline in aging. AD-related blood biomarkers may help characterize these causes. Elevated p-tau217 was exclusively associated with poorer episodic memory. Elevated NfL was associated with poorer cognition in a broad range of domains. Blood biomarkers may help differentiate AD- and non-AD-related cognitive deficits.

AB - INTRODUCTION: The utility of blood-based biomarkers for discriminating Alzheimer's disease (AD)-related versus non-AD-related cognitive deficits in preclinical populations remains poorly understood. Here, we tested the capability of blood markers to detect and discriminate variation in performance across multiple cognitive domains in a cognitively unimpaired sample. METHODS: Participants (n = 648, aged 69.9 ± 3.8, 71% female) underwent a comprehensive cognitive assessment and assays for plasma-based biomarkers amyloid beta (Aβ)1-42/1-40 by mass spectrometry, phosphorylated tau (p-tau) 181 and 217, p-tau217/Aβ1-42, glial fibrillary acidic protein (GFAP), and neurofilament light (NfL). RESULTS: Greater p-tau217 was exclusively associated with poorer episodic memory performance (β = −0.11, SE = 0.04, p =.003), and remained so after covarying for NfL. Higher NfL was non-specifically associated with poorer performance across a range of cognitive domains and remained so after covarying for p-tau217. DISCUSSION: Blood-based biomarkers may differentiate non-AD-related versus AD-related cognitive deficits. This characterization will be important for early intervention and disease monitoring for AD. Highlights: There is heterogeneity in the causes of cognitive decline in aging. AD-related blood biomarkers may help characterize these causes. Elevated p-tau217 was exclusively associated with poorer episodic memory. Elevated NfL was associated with poorer cognition in a broad range of domains. Blood biomarkers may help differentiate AD- and non-AD-related cognitive deficits.

KW - Alzheimer's disease

KW - biomarkers

KW - blood-based biomarkers

KW - cognition

KW - cognitive function

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U2 - 10.1002/alz.14619

DO - 10.1002/alz.14619

M3 - Article

C2 - 40110626

AN - SCOPUS:105001035501

SN - 1552-5260

VL - 21

JO - Alzheimer's and Dementia

JF - Alzheimer's and Dementia

IS - 3

M1 - e14619

ER -

Blood biomarkers differentiate AD-related versus non-AD-related cognitive deficits

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