Alcohol-related dementia (360G-Wellcome-306069_Z_23_Z)

Alcohol-related dementia has suffered research neglect despite high clinical need. My recent work has found evidence for a causal role of alcohol consumption on dementia, yet lack of pathophysiological knowledge is currently limiting clinical translation of these findings. The research proposed here aims to identify and characterize key pathways by which exposure to alcohol leads to dementia. Clarity of these relationships is vital given the widespread population exposure to alcohol and the lack of disease-modifying treatments for dementia. The key goals are: 1\. Examine if alcohol affects risk and course of common and rarer dementia subtypes. 2\. Establish whether genetic variation influences the susceptibility of drinkers to dementia. 3\. Identify causal molecular pathways driving alcohol’s impact on dementia. I will use a combination of large-scale electronic health records, epidemiological, neuroimaging and multi-omics datasets from the US, UK, Estonia and China. The consequent statistical power will allow triangulation of observational and pseudo-experimental (Mendelian randomization) approaches to improve causal inference. Outcomes: Findings from this work will generate fundamental insights into how alcohol can lead to dementia. I will determine whether dementia with an alcohol aetiology merits specific identification and management. Characterization of molecular pathways will pave the way for potential therapeutic strategies.