Ranking the risk factors for Alzheimer’s disease; findings from the UK Biobank study

Abstract

Background: The cause of the most common form of dementia, sporadic Alzheimer’s disease (AD), remains unknown. This may reflect insufficiently powered studies to date for this multi-factorial disorder. The UK Biobank dataset presents a unique opportunity to rank known risk factors and determine novel variables. Methods: A custom machine learning approach for high dimensionality data was applied to explore prospectively associations between AD in a sub-cohort of 156,209 UK Biobank participants aged 60-70 including more than 2,090 who were subsequently diagnosed with AD. Results: After the possession of the APOE4 allele, the next highest ranked risk factors were other genetic variants within the TOMM40-APOE-APOC1 locus. When stratified by their apolipoprotein [[EQUATION]] 4 (APOE4) carrier status, the most prominent risk factors in carriers were AST:ALT ratio, the 'number of treatments/ medications' taken as well as 'time spent in hospital' while protection was conferred by 'Sleeplessness/Insomnia'. In non-carriers, lower socioeconomic status and fewer years of education were highly ranked but effect sizes were small relative to APOE4 carriers. Conclusions: Possession of the APOE4 allele was confirmed as the most important risk factor in AD. Other TOMM40-APOE-APOC1 locus variants further moderate the risk of AD in APOE4 carriers. Liver pathology is a novel risk factor in APOE4 carriers while 'Sleeplessness/Insomnia' is protective in AD irrespective of APOE4 status. Other factors such as 'Number of treatments/ medications' suggest that multimorbidity is an important risk factor for AD. Future treatments aimed at co-morbidities, including liver disease, may concomitantly lower the risk of sporadic AD. Funding Information: This work was supported through the Australian National Health & Medical Research Council (NHMRC)” to [BG]” (APP1163249) and “to [RIL]” (APP1149987), and a University of Sydney SOAR Fellowship “to [GS]”. The Authors also acknowledge the generous philanthropic support of ‘Eve’ (2019 Sydney to Hobart yacht race) supporters [GTS]. Declaration of Interests: BG is a director of Pacific Analytics PTY LTD & SMRTR PTY LTD, Australia, a founding member of the International Cerebral Palsy Genetics Consortium, and a member of the Australian Genomics Health Alliance. All other Authors declare no conflict of interests. Ethics Approval Statement: The research has been conducted using the UK Biobank Resource under Application Number 49777. UK Biobank has approval from the North West Multi-centre Research Ethics Committee (MREC) as a Research Tissue Bank (RTB) approval.