Exploring the causal risk factors behind dementia

Abstract

Numerous risk factors for dementia have been identified, spanning genetic determinants, environmental influences, and other health conditions. Yet, the intrinsic causal relationships between these factors and dementia remain elusive. Understanding those mechanisms driving dementia could help develop effective prevention and intervention strategies for the disease. Four studies were conducted to investigate the causal mechanisms underlying dementia. Firstly, a colocalization study was undertaken to identify causal genes that were common to dementia and related traits. This study revealed evidence for shared aetiology between dementia and related health conditions. Secondly, we used Mendelian randomization (MR) analysis to investigate whether elevated anti-varicella-zoster virus (VZV) immunoglobulin G (IgG) levels—a biomarker indicating prolonged viral exposure—could lead to dementia onset in later life. Unfortunately, this study did not find significant evidence of a causal relationship. Subsequently, we expanded our investigation through a phenome-wide MR study to assess the causal role of the anti-VZV IgG levels for a wide range of health traits, which uncovered several causal associations. Finally, a causal network analysis was performed, integrating all previously reported risk factors of dementia to examine how known modifiable risk factors collectively contribute to dementia’s causal pathway. My research identified potential causal risk factors for dementia across multiple domains from genetic risk factors to multiple environmental causal pathways. However, these causal findings require further validation, such as external and laboratory validations. Additionally, the exploratory scope of the current study is limited by the capabilities of the methodologies. Methodological improvements for faster processing speed, larger dataset accommodation, along with the integration of various data modalities, are desirable.

Date of Award	15 Feb 2024
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Kenneth Muir (Co Supervisor), Artitaya Lophatananon (Co Supervisor) & Hui Guo (Main Supervisor)