Plasma proteomics mediate the association between degenerative joint diseases and dementia risk
Zijian Kang1, Jianzheng Zhang2, Chen Zhu3
1Department of Rheumatology and Immunology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Insights
Degenerative joint diseases (DJD) significantly increase dementia risk, particularly vascular dementia. This link is mediated by specific blood proteins, suggesting inflammation and vascular issues are key mechanisms.
Area of Science:
- Biomedical Science
- Neuroscience
- Gerontology
Background:
- Degenerative joint diseases (DJD) encompass conditions like osteoarthritis and spinal degeneration.
- Dementia, including Alzheimer's disease and vascular dementia, poses a significant public health challenge.
- The relationship between DJD and dementia risk, along with underlying biological mechanisms, requires further investigation.
Purpose of the Study:
- To investigate the association between DJD and the risk of developing dementia.
- To identify proteomic mediators that may explain the link between DJD and dementia.
- To explore potential therapeutic targets for dementia prevention based on these mechanisms.
Main Methods:
- A prospective cohort study of 500,805 UK Biobank participants was conducted.
- DJD diagnoses and dementia outcomes were tracked over a median of 14.45 years.
- Multivariable Cox regression, propensity score matching, and plasma proteomic profiling were used to analyze associations and identify mediators.
Main Results:
- DJD was associated with a significantly increased risk of all-cause dementia (ACD) and vascular dementia (VaD), but not Alzheimer's disease (AD).
- Proteomic analysis identified 18 plasma proteins, including HAVCR1, GDF15, and COL6A3, that significantly mediate the association between DJD and ACD.
- Effect modifications were observed based on age, activity levels, and surgical history.
Conclusions:
- Degenerative joint diseases are independently linked to a higher risk of dementia.
- Systemic proteomic alterations, involving proteins like HAVCR1, GDF15, and COL6A3, mediate this association.
- Inflammation and vascular dysfunction are highlighted as central mechanisms, offering potential avenues for dementia risk stratification and therapeutic intervention.
Objective:
To assess the association between degenerative joint diseases (DJD) and dementia risk and to identify potential proteomic mediators.
Methods:
We conducted a prospective cohort study using data from 500,805 participants in the UK Biobank. Three DJD diagnoses (osteoarthritis [OA], intervertebral disc degeneration [IVDD], and degenerative spinal diseases [DSD]) were identified from the clinical records. Dementia outcomes (all-cause dementia [ACD], Alzheimer's disease [AD], and vascular dementia [VaD]) were tracked over 14.45 years. Multivariable Cox regression models were used to assess DJD-dementia associations, adjusted for demographics, lifestyle, and comorbidities. Propensity score matching (PSM) was employed for validation. Plasma proteomic profiling of 2,923 proteins was performed to identify potential mediators, followed by causal mediation analysis.
Results:
After a median follow-up of 14.45 years, 9,884 participants developed ACD, including 4,404 with AD and 2,224 with VaD. After adjusting for covariates, the DJD group exhibited a significantly elevated risk of ACD (HR: 1.271, 95 % CI: 1.173-1.376) and VaD (HR: 1.587, 95 % CI: 1.323-1.903), but not AD (HR: 1.107, 95 % CI: 0.982-1.248). Subgroup analyses revealed significant effect modifications according to age, activity levels, and surgical procedures. PSM analyses confirmed the robustness of these associations. Proteomic analysis identified plasma proteins associated with both DJDs and ACD risk. Mediation analysis revealed that 18 proteins, including HAVCR1 (mediation proportion 52.6 %, 95 % CI: 39.1 %-78 %), GDF15 (22 %, 95 % CI: 14.5 %-46.8 %), and COL6A3 (14.3 %, 95 % CI: 7.7 %-28.4 %), significantly mediated the association between DJDs and ACD.
Conclusion:
DJDs are independently associated with an increased risk of developing dementia. This correlation is mediated by systemic proteomic alterations. Our findings highlight inflammation and vascular dysfunction as central mechanisms, offering insights into risk stratification and therapeutic targets for preventing dementia.
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