Plasma proteomic signatures of incident mild behavioral impairment – a longitudinal Singaporean memory clinic study

TL;DR

This study identifies plasma protein markers linked to the development of mild behavioral impairment in older adults, suggesting potential targets for early dementia prevention.

Contribution

The study is the first to identify plasma proteomic signatures associated with incident mild behavioral impairment in a longitudinal memory clinic cohort.

Findings

142 plasma proteins were significantly associated with incident MBI after multivariate adjustment.

Top proteins linked to MBI included TFF3, NPPC, and TNFSF13.

Key biological pathways involved in MBI include extracellular matrix disruption and immune dysregulation.

Abstract

Mild behavioral impairment (MBI) is a diagnostic construct capturing neuropsychiatric symptom burden in pre‐dementia subjects, and has been increasingly recognized as an at‐risk entity for dementia [1,2]. However, prognostic biomarkers and mechanistic underpinnings of incident MBI remain unclear. We therefore utilized a Singaporean memory clinic cohort to evaluate the plasma proteomic signatures of incident MBI.

A Singaporean memory clinic cohort was followed‐up prospectively for 4 years. Dementia‐free subjects who did not have MBI at baseline were included for analysis. All subjects were assessed at baseline and annually using the Neuropsychiatric Inventory (NPI). The definition of incident MBI was made in alignment with the Society to Advance Alzheimer's Research and Treatment of the Alzheimer's Association (ISTAART) criteria, with incident MBI defined as the development of new neuropsychiatric symptoms (defined as an increment in NPI total score of ≥1) over any two consecutive years of follow‐up [3].

Plasma samples were obtained at baseline, and the Olink Explore platform was used to profile 1536 plasma proteins. The associations of plasma proteins with incident MBI were subsequently evaluated using multivariable cox regression models, accounting for multiple testing correction (p‐value < 0.05 and q‐value < 0.1).

Of 219 subjects included for analysis (mean age 71.1±7.6 years, 53% female, 66% hypertensive), 54 (24.7%) subjects developed incident MBI.

We identified 142 proteins (q‐value < 0.1, p‐value < 0.05) which significantly associated with the hazard of incident MBI after multivariate adjustment. The top 3 most associative proteins for incident MBI were TFF3, NPPC and TNFSF13 (Figure 1)

Overrepresentation analysis of all significant proteins revealed diverse biological pathways underpinning incident MBI. The top 3 most significantly over‐represented biological pathways included extracellular matrix disruption and immune dysregulation (Figure 2).

We report plasma proteomic signatures and biological pathways of incident MBI. Future mechanistic studies are required to elucidate the utility of these markers as therapeutic targets for incident MBI and its cognitive sequelae.

References

1. Kan et al, J Clin Psychiatry (2022)

2 Ismail Z et al, J Alzheimers Dis (2021)

3 Ismail Z et al, J Alzheimers Dis (2017)

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