<b><i>Introduction:</i></b> Hippocampal atrophy is an established biomarker for conversion from the normal ageing process to developing cognitive impairment and dementia. This study used a novel hypothesis-free machine-learning approach, to uncover potential risk factors of lower hippocampal volume using information from the world’s largest brain imaging study. <b><i>Methods:</i></b> A combination of machine learning and conventional statistical methods were used to identify predictors of low hippocampal volume. We run gradient boosting decision tree modelling including 2,891 input features measured before magnetic resonance imaging assessments (median 9.2 years, range 4.2–13.8 years) using data from 42,152 dementia-free UK Biobank participants. Logistic regression analyses were run on 87 factors identified as important for prediction based on Shapley values. False discovery rate-adjusted <i>p</i> value <0.05 was used to declare statistical significance. <b><i>Results:</i></b> Older age, male sex, greater height, and whole-body fat-free mass were the main predictors of low hippocampal volume with the model also identifying associations with lung function and lifestyle factors including smoking, physical activity, and coffee intake (corrected <i>p</i> < 0.05 for all). Red blood cell count and several red blood cell indices such as haemoglobin concentration, mean corpuscular haemoglobin, mean corpuscular volume, mean reticulocyte volume, mean sphered cell volume, and red blood cell distribution width were among many biomarkers associated with low hippocampal volume. <b><i>Conclusion:</i></b> Lifestyles, physical measures, and biomarkers may affect hippocampal volume, with many of the characteristics potentially reflecting oxygen supply to the brain. Further studies are required to establish causality and clinical relevance of these findings.
