# Non-compacted, PET-insensitive amyloid states increase after systemic inflammation and predict neuritic damage across Aβ pathology models and Alzheimer patients

## TL;DR

Systemic inflammation leads to changes in amyloid structures in Alzheimer's models and patients, causing neuritic damage that is not captured by standard PET scans.

## Contribution

Shows that non-compacted amyloid states, not detected by PET, are linked to neuritic damage and worsened by inflammation.

## Key findings

- Systemic LPS in mice shifts Aβ aggregates to a less compacted state, increasing neuritic dystrophy.
- Non-compacted amyloid and microgliosis predict neuritic damage in both mouse models and AD patients.
- Amyloid-PET measures fail to capture non-compacted amyloid states associated with disease severity.

## Abstract

Neuroinflammation is a key modulator of Alzheimer’s disease (AD) risk, yet the impact of non-genetic inflammatory risk factors – such as systemic inflammation – remains poorly defined. Building on our previous work, here we show that 9 months after systemic lipopolysaccharide (LPS) challenge in APP23 mice, microglia-plaque interaction is disturbed and shifts Aβ aggregates toward a less compacted state, as revealed by conformation-sensitive amyloid dyes. Importantly, these structural changes are associated with increased plaque-associated neuritic dystrophy, phenocopying the effects of microglial risk genes. Generalising these findings, we show that across aging in APP23 and APPPS1 mice, and in AD patient tissue, non-compacted amyloid and microgliosis – but not compacted amyloid – are consistent predictors of neuritic damage. Notably, both in mouse and human tissue, ex vivo amyloid-PET signal largely reflects compacted but not non-compacted amyloid load. Our findings suggest that genetic and environmental risk factors converge on shared mechanisms of impaired microglial-plaque interaction and amyloid restructuring, and that commonly used amyloid-PET measures insufficiently capture amyloid states that define the severity of neuritic damage, with important implications for clinical trials in AD.