Plasma inflammatory biomarker profiles across the Alzheimer's disease spectrum in the Bio-Hermes cohort

Zain Hussain; Dominic Ng; Samuel Leighton; Fani Deligianni; Craig Ritchie; Jonathan Cavanagh

doi:10.1002/alz.71257

Plasma inflammatory biomarker profiles across the Alzheimer's disease spectrum in the Bio-Hermes cohort

Zain Hussain^*, Dominic Ng, Samuel Leighton, Fani Deligianni, Craig Ritchie, Jonathan Cavanagh

^*Corresponding author for this work

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

Abstract

INTRODUCTION
Inflammation contributes to Alzheimer's disease (AD), but its stage-specific and amyloid-dependent patterns remain unclear.

METHODS
We analyzed 964 participants from the Bio-Hermes cohort (cognitively normal [CN] = 404, mild cognitive impairment [MCI] = 302, mild AD = 258). Plasma levels of 32 cytokines, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) were quantified alongside core AD biomarkers. Associations with cognition, amyloid, apolipoprotein E (APOE) ε4, and clinical outcomes were assessed using analysis of covariance, partial correlations, and regression models.

RESULTS
Twenty-four cytokines, NfL, and GFAP differed across cognitive groups. Amyloid stratification revealed a core amyloid-independent profile (14 cytokines + NfL) and a broader amyloid-specific profile including GFAP, interleukin (IL)-1β, and IL-18, implicating microglial inflammasome and astrocytic activation. Stage-dependent patterns suggested inflammation may act as early driver, concurrent process, or late amplifier. Paradoxical associations (e.g., eotaxin-2, IL-2R with better memory) and APOE ε4-linked immune differences indicated context-dependent roles.

DISCUSSION
This exploratory study reveals biologically plausible, inflammatory heterogeneity in AD and highlights plasma cytokine profiles as candidate biomarkers and therapeutic targets, warranting investigation.

Original language	English
Article number	e71257
Number of pages	14
Journal	Alzheimer's and Dementia
Volume	22
Issue number	3
DOIs	https://doi.org/10.1002/alz.71257
Publication status	Published - 12 Mar 2026

Keywords

Alzheimer's disease
Amyloid
APOE ε4
Biomarkers
Cytokines
Inflammation

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title = "Plasma inflammatory biomarker profiles across the Alzheimer's disease spectrum in the Bio-Hermes cohort",

abstract = "INTRODUCTION Inflammation contributes to Alzheimer's disease (AD), but its stage-specific and amyloid-dependent patterns remain unclear. METHODS We analyzed 964 participants from the Bio-Hermes cohort (cognitively normal [CN] = 404, mild cognitive impairment [MCI] = 302, mild AD = 258). Plasma levels of 32 cytokines, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) were quantified alongside core AD biomarkers. Associations with cognition, amyloid, apolipoprotein E (APOE) ε4, and clinical outcomes were assessed using analysis of covariance, partial correlations, and regression models. RESULTS Twenty-four cytokines, NfL, and GFAP differed across cognitive groups. Amyloid stratification revealed a core amyloid-independent profile (14 cytokines + NfL) and a broader amyloid-specific profile including GFAP, interleukin (IL)-1β, and IL-18, implicating microglial inflammasome and astrocytic activation. Stage-dependent patterns suggested inflammation may act as early driver, concurrent process, or late amplifier. Paradoxical associations (e.g., eotaxin-2, IL-2R with better memory) and APOE ε4-linked immune differences indicated context-dependent roles. DISCUSSION This exploratory study reveals biologically plausible, inflammatory heterogeneity in AD and highlights plasma cytokine profiles as candidate biomarkers and therapeutic targets, warranting investigation.",

keywords = "Alzheimer's disease, Amyloid, APOE ε4, Biomarkers, Cytokines, Inflammation",

author = "Zain Hussain and Dominic Ng and Samuel Leighton and Fani Deligianni and Craig Ritchie and Jonathan Cavanagh",

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doi = "10.1002/alz.71257",

language = "English",

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journal = "Alzheimer's and Dementia",

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T1 - Plasma inflammatory biomarker profiles across the Alzheimer's disease spectrum in the Bio-Hermes cohort

AU - Hussain, Zain

AU - Ng, Dominic

AU - Leighton, Samuel

AU - Deligianni, Fani

AU - Ritchie, Craig

AU - Cavanagh, Jonathan

PY - 2026/3/12

Y1 - 2026/3/12

N2 - INTRODUCTION Inflammation contributes to Alzheimer's disease (AD), but its stage-specific and amyloid-dependent patterns remain unclear. METHODS We analyzed 964 participants from the Bio-Hermes cohort (cognitively normal [CN] = 404, mild cognitive impairment [MCI] = 302, mild AD = 258). Plasma levels of 32 cytokines, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) were quantified alongside core AD biomarkers. Associations with cognition, amyloid, apolipoprotein E (APOE) ε4, and clinical outcomes were assessed using analysis of covariance, partial correlations, and regression models. RESULTS Twenty-four cytokines, NfL, and GFAP differed across cognitive groups. Amyloid stratification revealed a core amyloid-independent profile (14 cytokines + NfL) and a broader amyloid-specific profile including GFAP, interleukin (IL)-1β, and IL-18, implicating microglial inflammasome and astrocytic activation. Stage-dependent patterns suggested inflammation may act as early driver, concurrent process, or late amplifier. Paradoxical associations (e.g., eotaxin-2, IL-2R with better memory) and APOE ε4-linked immune differences indicated context-dependent roles. DISCUSSION This exploratory study reveals biologically plausible, inflammatory heterogeneity in AD and highlights plasma cytokine profiles as candidate biomarkers and therapeutic targets, warranting investigation.

AB - INTRODUCTION Inflammation contributes to Alzheimer's disease (AD), but its stage-specific and amyloid-dependent patterns remain unclear. METHODS We analyzed 964 participants from the Bio-Hermes cohort (cognitively normal [CN] = 404, mild cognitive impairment [MCI] = 302, mild AD = 258). Plasma levels of 32 cytokines, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) were quantified alongside core AD biomarkers. Associations with cognition, amyloid, apolipoprotein E (APOE) ε4, and clinical outcomes were assessed using analysis of covariance, partial correlations, and regression models. RESULTS Twenty-four cytokines, NfL, and GFAP differed across cognitive groups. Amyloid stratification revealed a core amyloid-independent profile (14 cytokines + NfL) and a broader amyloid-specific profile including GFAP, interleukin (IL)-1β, and IL-18, implicating microglial inflammasome and astrocytic activation. Stage-dependent patterns suggested inflammation may act as early driver, concurrent process, or late amplifier. Paradoxical associations (e.g., eotaxin-2, IL-2R with better memory) and APOE ε4-linked immune differences indicated context-dependent roles. DISCUSSION This exploratory study reveals biologically plausible, inflammatory heterogeneity in AD and highlights plasma cytokine profiles as candidate biomarkers and therapeutic targets, warranting investigation.

KW - Alzheimer's disease

KW - Amyloid

KW - APOE ε4

KW - Biomarkers

KW - Cytokines

KW - Inflammation

U2 - 10.1002/alz.71257

DO - 10.1002/alz.71257

M3 - Article

C2 - 41816922

SN - 1552-5260

VL - 22

JO - Alzheimer's and Dementia

JF - Alzheimer's and Dementia

IS - 3

M1 - e71257

ER -

Plasma inflammatory biomarker profiles across the Alzheimer's disease spectrum in the Bio-Hermes cohort

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