# Elevated serum inflammasome adaptor protein ASC is associated with white matter hyperintensities in vascular cognitive impairment

## TL;DR

Higher levels of a protein called ASC in the blood are linked to brain changes seen in vascular cognitive impairment, suggesting a potential new target for treatment.

## Contribution

Identifies serum ASC as a novel biomarker for vascular cognitive impairment and its progression.

## Key findings

- Serum ASC levels were elevated in vascular cognitive impairment subgroups compared to controls.
- ASC levels correlated with white matter hyperintensities, a marker of cerebrovascular disease.
- Dysregulated inflammasome activation may contribute to vascular cognitive impairment pathology.

## Abstract

Alzheimer’s disease (AD) and vascular dementia (VaD) exhibit distinct neuropathological hallmarks, with AD defined by cortical amyloid plaques and neurofibrillary tangles, while VaD arises primarily from cerebrovascular disease (CeVD). However, CeVD frequently coexists with AD, and both conditions fall within the spectrum of vascular cognitive impairment (VCI). Notably, chronic neuroinflammation is a shared mechanistic link between AD and VaD. Inflammasomes, multi-protein complexes that sense cellular damage and orchestrate inflammatory responses, have been implicated in preclinical models of both diseases. However, their translational potential in the clinical setting remains underexplored. Here, we investigate the inflammasome adaptor protein, apoptosis associated speck-like protein containing a CARD (ASC), as a novel serum biomarker for CeVD, cognitive decline and VCI progression. A total of 531 participants (123 non-cognitively impaired, 208 cognitive impaired, no dementia and 200 with dementia) were included from a Singapore-based clinical cohort. All subjects underwent comprehensive clinical, neuropsychological and neuroimaging assessments. Serum samples were collected, and ASC was measured using a microfluidics immunoassay platform. Compared to controls, serum ASC levels were increased in the VCI clinical subgroups, namely, cognitive impaired, no dementia with CeVD, AD with CeVD and VaD. Multivariate analyses using CeVD neuroimaging markers showed associations between serum ASC and white matter hyperintensities, but not with lacunes or cerebral microbleeds. Mediation analyses similarly showed that the association between ASC and VCI subgroups may be largely explainable by severity of concomitant CeVD, specifically white matter hyperintensities volume. Our findings indicate that elevated serum ASC levels may reflect a state of inflammasome activation in VCI, particularly in individuals with extensive white matter hyperintensities. These results underscore the potential role of dysregulated inflammasome activation not only as a pathogenic factor but also as a potential therapeutic target for VCI.

Chai et al. report that higher serum inflammasome adaptor protein ASC were associated with vascular cognitive impairment and dementia, which may be largely mediated by concomitant cerebrovascular disease, specifically white matter hyperintensities. Their findings suggest the roles of dysregulated inflammasome as pathogenic factor and therapeutic target for vascular cognitive impairment.

Graphical Abstract