Thyroid function and the risk of Alzheimer’s disease: A Mendelian Randomisation study

Background Observational epidemiological studies propose that variations in thyroid function are associated with the risk of dementia; however, there have been inconsistent findings regarding the direction of the association. It is still unclear whether these associations are causal or not. We aim to test whether genetically determined variation within the normal range of thyroid function and hypothyroidism are causally associated with the risk of Alzheimer’s disease (AD). Methods Mendelian Randomisation (MR) analyses_using genetic instruments associated with normal range TSH and FT4 levels. Secondary analyses included investigation of the role of hypothyroidism. Bidirectional MR was conducted to address the presence of a potential reverse causal association. Summary statistics were obtained from the ThyroidOmics Consortium and the latest available GWAS meta-analyses. Results MR analyses show a causal association between normal range TSH levels and decreased risk of AD (OR = 0.98, 95% CI=0.97-0.99, p = 0.01). There was no evidence for a causal association between FT4 or hypothyroidism and Alzheimer’s disease. Bidirectional MR did not show any effect of Alzheimer’s disease on TSH or FT4. Conclusions This Mendelian Randomisation study shows for the first time a causal association between normal-range thyroid function and AD. Future studies should clarify the underlying pathophysiological mechanisms. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial NA ### Funding Statement The Barts Biomedical Research Centre funded by the UK National Institute for Health Research (NIHR) has supported COVID related research. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: NA All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data information is provided in the manuscript. * FT4 : Free thyroxine IVW : Inverse variance weighted LD : Linkage disequilibrium MR : Mendelian Randomisation OR : Odds ratio SD : Standard deviation SNP : Single nucleotide polymorphism TSH : Thyroid stimulating hormone