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Background <p>Observational studies have reported associations between retinal thickness and Alzheimer’s disease (AD); however, the causal relationship remains uncertain.</p> Objective <p>To investigate the potential causal relationships between retinal thickness and AD, and circulating total-tau levels using Mendelian randomization (MR) and genetic colocalization analyses.</p> Methods <p>Summary-level data of genome-wide association studies on retinal nerve fiber layer (RNFL) and ganglion cell-inner plexiform layer (GC-IPL) thickness, AD and circulating total-tau levels were utilized for causal analysis. The inverse-variance weighted (IVW) method served as the primary analytical approach, supplemented by MR-Egger, robust adjusted profile score, maximum likelihood, and weighted median methods. Sensitivity analyses were conducted to ensure robustness. Genetic colocalization analysis was utilized to identify potential shared causal variants.</p> Results <p>The IVW estimates from the discovery MR analysis indicated no statistically significant causal effect of genetically predicted RNFL or GC-IPL thickness on AD or circulating total-tau levels, and exploratory reverse MR analysis found no causal link either (P<sub>IVW</sub> &gt; 0.05). Replication bidirectional MR analysis produced consistent negative results (P<sub>IVW</sub> &gt; 0.05). Sensitivity analyses demonstrated robustness across all MR methods. Genetic colocalization analysis identified no shared causal variants between RNFL or GC-IPL thickness and AD or circulating total-tau (posterior probability H4 &lt; 0.75). Post-hoc power analysis revealed severely limited statistical power for forward MR analyses.</p> Conclusion <p>Our study found no statistically significant genetic causal associations between retinal thickness, AD, and total-tau levels. However, severely limited statistical power precludes definitive exclusion of small causal effects. Future studies with substantially larger sample sizes are needed to achieve adequate statistical power for definitive conclusions. Since all GWAS datasets were restricted to European ancestry, caution is required when generalizing these findings, and replication in diverse populations is encouraged.</p>

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Evaluating causal links between retinal thickness, Alzheimer’s disease, and circulating total-tau: evidence from Mendelian randomization and colocalization analysis

  • 期刊论文

  • 发表日期：

    2026年1月10日

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  • Dandan Sheng,
  • Song Wang,
  • Zheng Xiao,
  • Weiping Liu,
  • Bo Xiao,
  • Luo Zhou

摘要

Background

Observational studies have reported associations between retinal thickness and Alzheimer’s disease (AD); however, the causal relationship remains uncertain.

Objective

To investigate the potential causal relationships between retinal thickness and AD, and circulating total-tau levels using Mendelian randomization (MR) and genetic colocalization analyses.

Methods

Summary-level data of genome-wide association studies on retinal nerve fiber layer (RNFL) and ganglion cell-inner plexiform layer (GC-IPL) thickness, AD and circulating total-tau levels were utilized for causal analysis. The inverse-variance weighted (IVW) method served as the primary analytical approach, supplemented by MR-Egger, robust adjusted profile score, maximum likelihood, and weighted median methods. Sensitivity analyses were conducted to ensure robustness. Genetic colocalization analysis was utilized to identify potential shared causal variants.

Results

The IVW estimates from the discovery MR analysis indicated no statistically significant causal effect of genetically predicted RNFL or GC-IPL thickness on AD or circulating total-tau levels, and exploratory reverse MR analysis found no causal link either (PIVW > 0.05). Replication bidirectional MR analysis produced consistent negative results (PIVW > 0.05). Sensitivity analyses demonstrated robustness across all MR methods. Genetic colocalization analysis identified no shared causal variants between RNFL or GC-IPL thickness and AD or circulating total-tau (posterior probability H4 < 0.75). Post-hoc power analysis revealed severely limited statistical power for forward MR analyses.

Conclusion

Our study found no statistically significant genetic causal associations between retinal thickness, AD, and total-tau levels. However, severely limited statistical power precludes definitive exclusion of small causal effects. Future studies with substantially larger sample sizes are needed to achieve adequate statistical power for definitive conclusions. Since all GWAS datasets were restricted to European ancestry, caution is required when generalizing these findings, and replication in diverse populations is encouraged.