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. 2025 Mar;21(3):e14619.
doi: 10.1002/alz.14619.

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

Kelsey R Sewell  1   2 , Lauren E Oberlin  1   3 , Thomas K Karikari  4 , Marcos Olvera-Rojas  5 , Lu Wan  1 , Jill K Morris  6   7 , Paul J Kueck  6   7 , Xuemei Zeng  4 , Haiqing Huang  1 , George Grove  4 , Yijun Chen  8 , Tara K Lafferty  4 , Anuradha Sehrawat  4 , M Ilyas Kamboh  9 , Anna L Marsland  4 , Arthur F Kramer  10   11   12 , Edward McAuley  11   13 , Jeffrey M Burns  7 , Charles H Hillman  10   14 , Eric D Vidoni  7 , Chaeryon Kang  4   15 , Kirk I Erickson  1
Affiliations

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

Kelsey R Sewell et al. Alzheimers Dement. 2025 Mar.

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.

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Conflict of interest statement

Thomas K. Karikari, Yijun Chen, and Xuemei Zeng are inventors on a University of Pittsburgh patent regarding the IPMS assay for Aβ peptides. Thomas K. Karikari serves a consultant for Quanterix, outside the submitted work. All other authors have no conflicts to disclose. Author disclosures are available in the supporting information.

Figures

FIGURE 1
FIGURE 1
Flow diagram depicting sample size for each analysis. Aβ1‐42/1‐40, plasma amyloid beta 1‐42/1‐40 ratio; IGNITE, Investigating Gains in Neurocognition in an Intervention Trial of Exercise; GFAP, glial fibrillary acidic protein; NfL, neurofilament light; p‐tau, phosphorylated tau.
FIGURE 2
FIGURE 2
Linear regression between biomarkers and cognitive outcomes controlling for age, sex, years of education, race, study site, BMI, and CIRS‐G total score. Only the cognitive domain with the largest effect size for each biomarker is illustrated here; others can be found in Figure S3. BMI, body mass index; CIRS‐G, Cumulative Illness Rating Scale for Geriatrics; GFAP, glial fibrillary acidic protein; NfL, neurofilament light; p‐tau, phosphorylated tau.
See this image and copyright information in PMC

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