# Systemic inflammation, delirium and clinical progression in mild-moderate Alzheimer disease

## TL;DR

The study found that neuroinflammation and delirium, not systemic inflammation, are linked to faster decline in mild-moderate Alzheimer's disease.

## Contribution

This study clarifies that neurodegenerative and delirium markers, not systemic inflammation, predict clinical progression in Alzheimer's.

## Key findings

- Systemic inflammatory biomarkers were not associated with Alzheimer's progression.
- Higher baseline p-tau217 and GFAP were linked to faster cognitive decline.
- Delirium episodes were associated with accelerated dementia severity progression.

## Abstract

Both low-grade systemic inflammation and acute inflammatory events may contribute to Alzheimer Disease (AD) progression. However, studies examining the prognostic utility of systemic inflammatory biomarkers in AD, and how systemic inflammatory events may contribute to clinical trajectories in AD, have yielded conflicting results.

We quantified plasma cytokines/chemokines in 333 individuals with mild-moderate AD at baseline, 12 and 18 months alongside baseline neurodegenerative biomarkers. AD severity was assessed using the Alzheimer Disease Assessment Scale (ADAS-Cog), Clinical Dementia Rating Scale (CDR-Sb) and Disability Assessment for Dementia (DAD).

Systemic inflammatory biomarkers were primarily associated with age/socio-demographic characteristics, remained strikingly stable over time, and were not associated with AD progression. Rather, higher baseline plasma p-tau217 was associated with greater yearly progression on both the ADAS-Cog (β: 2.82; 95% CI: 1.12, 4.52; nominal p = 0.001) and DAD (β: −2.34; 95% CI: −3.86, −0.82; nominal p = 0.003). Higher baseline GFAP was also associated with subsequent decline on both the CDR-Sb (β: 1.02; 95% CI: 0.38, 1.67; nominal p = 0.002) and DAD (β: 1.91; 95% CI: −3.45, −0.37; nominal p = 0.02). Experiencing one or more episodes of delirium was associated with accelerated decline on the CDR-Sb at 18-months (β: 2.63; 95% CI: 1.55, 3.71; adjusted p < 0.001).

Biomarkers of neuroinflammation (GFAP), neurodegeneration (p-tau217) and incident delirium, rather than systemic inflammatory biomarkers, were associated with clinically-significant decline in mild-moderate AD.

10.13039/501100000780European Commission (FP7 grant; 279093); 10.13039/501100004162Meath Foundation (MFRG 121/2021); 10.13039/100010269Wellcome Trust (227946/Z/23/Z & 203930/B/16/Z); Health Research Board (203930/B/16/Z; ECSA-2024-003).