Objective To investigate the association between birth weight and dementia risk and the mediating roles of chronic diseases, and to assess potential biological pathways underlying the birth weight-associated dementia risk based on large-scale proteomics.
Methods We used data from 279743 participants aged 40 to 69 years enrolled in the UK Biobank. Birth weight was categorized into low birth weight (≤ 2500 g), normal birth weight (2500-3999 g), and macrosomia (≥ 4000 g). Multivariable Cox proportional hazards regression models were used to assess the associations between birth weight categories and all-cause dementia and its subtypes (Alzheimer's disease and vascular dementia). Proteomics analyses were conducted to identify proteins and the potential pathways involved.
Results Low birth weight was associated with higher risks for all-cause dementia and its subtypes. The hazard ratios were 1.18 (95% CI, 1.08-1.30) for all-cause dementia, 1.14 (95% CI, 1.00-1.31) for Alzheimer's disease, and 1.22 (95% CI, 1.01-1.48) for vascular dementia. A non-linear relationship was observed between birth weight and dementia risk (P for nonlinearity < 0.001). Certain cardiometabolic diseases in middle-aged adults, such as diabetes, stroke, hypertension, and dyslipidemia, played a significant mediating role in the relationship between low birth weight and dementia risk, with the mediation proportion being 6.3% to 15.8%. Proteomic analyses identified 21 proteins linked to both low birth weight and all-cause dementia risk, which were significantly enriched in the pathways for viral protein interaction with cytokines and cytokine receptors, adipocytokine signaling, and cytokine-cytokine receptor interaction.
Conclusion Low birth weight is positively associated with dementia risk. Cardiometabolic diseases in middle-aged adults may mediate the relationship between low birth weight and dementia risk. A number of proteins and the associated pathways underscore the relationship between low birth weight and dementia risk.
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