A multivariable mendelian randomisation study of serum lipids and dementia risk within the UK Biobank

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Abstract Background An unfavourable lipid profile has been associated with the increased risk of dementia or Alzheimer’s disease in both observational and genetic studies 1,2 . However, it is challenging to investigate each serum lipid measure individually due to the high correlation between the lipid traits. We aimed to discover causal associations between genetically instrumented serum lipid measures (low‐density lipoprotein cholesterol (LDL‐C), high‐density lipoprotein cholesterol (HDL‐C), triglycerides, apolipoprotein‐A1 (apoA) and apolipoprotein‐B (apoB)) and the risk of dementia. Method We conducted multivariable and univariable Mendelian randomisation (MR) analyses on 329,896 UK Biobank participants (age 37‐73 years) to examine the associations between each serum lipid measure and the risk of dementia. The multivariable approach allows us to assess the association of each lipid measure with the outcome, in cases where the genetic variants used to estimate the exposures are mediated by one another. Result In the univariable MR analyses, we found that genetically determined higher LDL‐C and apoB were both associated with increased risk of dementia, while higher HDL‐C and apoA were associated with decreased risk of dementia. Meanwhile, using multivariable MR analyses, in a model containing LDL‐C, triglycerides and apoB, only apoB remained significantly associated with increased risk of dementia. Conclusion Our findings suggests that when considering the correlation between lipid measures, apoB plays an important role in the previously reported association between serum lipids and increased risk of dementia. References : 1 Iwagami, M, Qizilbash, N, Gregson, J, Douglas, I, Johnson, M, Pearce, N, Evans, S & Pocock, S 2021, 'Blood cholesterol and risk of dementia in more than 1·8 million people over two decades: a retrospective cohort study', The Lancet Healthy Longevity, vol. 2, no. 8, pp. e498‐e506. 2 Zhang, X, Tian, Q, Liu, D, Geng, T, Ge, S, Zheng, D, Wu, L, Song, M, Hou, H, Wang, W & Wang, Y 2020, ‘Causal association of circulating cholesterol levels with dementia: a mendelian randomization meta‐analysis’, Transl Psychiatry, vol. 10, no. 145, https://doi.org/10.1038/s41398‐020‐0822‐x.