# Identification of plasma inflammatory biomarkers for Alzheimer’s disease reveals IFN-γ as a regulator of ACSL1-mediated microglia phenotype

## TL;DR

This study identifies plasma inflammatory biomarkers for Alzheimer’s disease, highlighting IFN-γ as a key player linked to APOE ϵ4 and microglia changes.

## Contribution

The study reveals a novel connection between IFN-γ, APOE ϵ4, and ACSL1-driven microglia in Alzheimer’s disease.

## Key findings

- AD patients showed altered plasma inflammatory profiles with elevated IFN-γ, IL-33, and IL-18.
- IFN-γ was the most informative predictor and was elevated in APOE ϵ4 carriers.
- IFN-γ signaling was enriched in APOE4/4 microglia with high ACSL1 expression.

## Abstract

The identification of plasma biomarkers for the diagnosis of Alzheimer’s disease (AD) has been a longstanding research priority; however, few plasma biomarkers have yet been implemented in routine clinical practice.

This study enrolled 141 participants, including 71 patients with AD, 44 individuals with mild cognitive impairment, and 28 cognitively healthy controls (HC). A total of 16 plasma inflammatory proteins were quantified using multiplex liquid-chip assays, and APOE genotyping was performed. The diagnostic utility of plasma proteins was assessed using the least absolute shrinkage and selection operator (LASSO) with nested cross-validation.

Patients with AD exhibited marked alterations in plasma inflammatory profiles, with elevated levels of IFN-γ, IL-33, and IL-18, and reduced levels of IL-7 and CCL11. Integrating inflammatory markers with clinical variables and APOE genotype substantially improved discrimination between AD and HC, increasing the area under the ROC curve from 0.863 to 0.953. Among all biomarkers, IFN-γ emerged as the most informative predictor and was significantly elevated in AD patients carrying the APOE ϵ4 allele. Analyses of single-nucleus RNA sequencing data further revealed pronounced enrichment of IFN-γ signaling in APOE4/4 AD-associated lipid droplet-accumulating microglia (LDAM), defined by high ACSL1 expression. Notably, IFN-γ stimulation enhanced ACSL1 expression in ApoE4-overexpressing HMC3 microglial cells.

These findings provide a new perspective on the involvement of plasma inflammatory markers for AD diagnosis, and suggest a novel link between IFN-γ and APOE ϵ4-associated AD risk through modulating the ACSL1-driven pathogenic LDAM phenotype.