Background: Blood plasma proteins have been associated with Alzheimer's disease (AD), but understanding which proteins are on the causal pathway remains challenging. Objective: Investigate the genetic overlap between candidate proteins and AD using polygenic risk scores (PRS) and interrogate their causal relationship using bi-directional Mendelian randomization (MR). Methods: Following a literature review, 31 proteins were selected for PRS analysis. PRS were constructed for prioritized proteins with and without the apolipoprotein E region (APOE+/-PRS) and tested for association with AD status across three cohorts (n = 6,244). An AD PRS was also tested for association with protein levels in one cohort (n = 410). Proteins showing association with AD were taken forward for MR. Results: For APOE ϵ3, apolipoprotein B-100, and C-reactive protein (CRP), protein APOE+ PRS were associated with AD below Bonferroni significance (pBonf, p < 0.00017). No protein APOE- PRS or AD PRS (APOE+/-) passed pBonf. However, vitamin D-binding protein (protein PRS APOE-, p = 0.009) and insulin-like growth factor-binding protein 2 (AD APOE- PRS p = 0.025, protein APOE- PRS p = 0.045) displayed suggestive signals and were selected for MR. In bi-directional MR, none of the five proteins demonstrated a causal association (p < 0.05) in either direction. Conclusion: Apolipoproteins and CRP PRS are associated with AD and provide a genetic signal linked to a specific, accessible risk factor. While evidence of causality was limited, this study was conducted in a moderate sample size and provides a framework for larger samples with greater statistical power.

Original languageEnglish
Pages (from-to)1825-1839
Number of pages15
Issue number4
Early online date25 Aug 2021
Publication statusPublished - 2021


  • Alzheimer's disease
  • apolipoprotein B-100
  • apolipoprotein E
  • blood proteins
  • C-reactive protein
  • insulin-like growth factor binding protein 2
  • mendelian randomization analysis
  • polygenic trait
  • vitamin D-binding protein


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