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

Michael Allwright; Hamish D Mundell; Andrew N McCorkindale; Richard I Lindley; Paul J Austin; Boris Guennewig; Greg T Sutherland

doi:10.1016/j.nbas.2023.100081

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

Aging Brain. 2023 Jun 17:3:100081. doi: 10.1016/j.nbas.2023.100081. eCollection 2023.

Authors

Michael Allwright¹, Hamish D Mundell², Andrew N McCorkindale², Richard I Lindley³, Paul J Austin¹, Boris Guennewig¹, Greg T Sutherland²

Affiliations

¹ Brain and Mind Centre and School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2006, Australia.
² Charles Perkins Centre and School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Camperdown, NSW 2006, Australia.
³ Westmead Applied Research Centre, Sydney Medical School, University of Sydney, NSW 2006 and George Institute for Global Health, Newtown, NSW 2042, Australia.

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 $epsilon$ 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-APOE 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.

Keywords: Alzheimer’s disease; Apolipoprotein E; Liver; Machine learning; Multimorbidity; UK Biobank.