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Yet, the role of sex\u2010specific risk factors during midlife, including hormone replacement therapy (HRT) and their interaction with other major risk factors for Alzheimer's Disease, such as apolipoprotein E (APOE)\u2010e4 genotype and age, on brain health remains unclear. We investigated the relationship between HRT (i.e., use, age of initiation and duration of use) and brain health (i.e., cognition and regional brain volumes). We then consider the multiplicative effects of HRT and APOE status (i.e., e2\/e2, e2\/e3, e3\/e3, e3\/e4 and e4\/e4) via a two\u2010way interaction and subsequently age of participants via a three\u2010way interaction. Women from the UK Biobank with no self\u2010reported neurological conditions were included (<jats:italic>N<\/jats:italic>\u2009=\u2009207,595 women, mean age\u2009=\u200956.25\u2009years, standard deviation\u2009=\u20098.01\u2009years). Generalised linear regression models were computed to quantify the cross\u2010sectional association between HRT and brain health, while controlling for APOE status, age, time since attending centre for completing brain health measure, surgical menopause status, smoking history, body mass index, education, physical activity, alcohol use, ethnicity, socioeconomic status, vascular\/heart problems and diabetes diagnosed by doctor. Analyses of structural brain regions further controlled for scanner site. All brain volumes were normalised for head size. Two\u2010way interactions between HRT and APOE status were modelled, in addition to three\u2010way interactions including age. Results showed that women with the e4\/e4 genotype who have used HRT had 1.82% lower hippocampal, 2.4% lower parahippocampal and 1.24% lower thalamus volumes than those with the e3\/e3 genotype who had never used HRT. However, this interaction was not detected for measures of cognition.\u00a0No clinically meaningful three\u2010way interaction between APOE, HRT and age was detected when interpreted relative to the scales of the cognitive measures used and normative models of ageing for brain volumes in this sample. Differences in hippocampal volume between women with the e4\/e4 genotype who have used HRT and those with the e3\/e3 genotype who had never used HRT are equivalent to approximately 1\u20132\u2009years of hippocampal atrophy observed in typical health ageing trajectories in midlife (i.e., 0.98%\u20131.41% per year). Effect sizes were consistent within APOE e4\/e4 group post hoc sensitivity analyses, suggesting observed effects were not solely driven by APOE status and may, in part, be attributed to HRT use. Although, the design of this study means we cannot exclude the possibility that women who have used HRT may have a predisposition for poorer brain health.<\/jats:p>","DOI":"10.1002\/hbm.26612","type":"journal-article","created":{"date-parts":[[2024,2,2]],"date-time":"2024-02-02T13:57:13Z","timestamp":1706882233000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Investigating the synergistic effects of hormone replacement therapy, <scp>apolipoprotein E<\/scp> and age on brain health in the <scp>UK<\/scp> Biobank"],"prefix":"10.1002","volume":"45","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5808-8020","authenticated-orcid":false,"given":"Ananthan","family":"Ambikairajah","sequence":"first","affiliation":[{"name":"Discipline of Psychology, Faculty of Health University of Canberra  Canberra Australian Capital Territory Australia"},{"name":"Centre for Ageing Research and Translation, Faculty of Health University of Canberra  Canberra Australian Capital Territory Australia"},{"name":"National Centre for Epidemiology and Population Health Australian National University  Canberra Australian Capital Territory Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1801-1635","authenticated-orcid":false,"given":"Mizanur","family":"Khondoker","sequence":"additional","affiliation":[{"name":"Norwich Medical School University of East Anglia  Norwich UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward","family":"Morris","sequence":"additional","affiliation":[{"name":"Norfolk and Norwich NHS Trust  Norwich UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5150-6656","authenticated-orcid":false,"given":"Ann\u2010Marie G.","family":"de Lange","sequence":"additional","affiliation":[{"name":"Department of Clinical Neurosciences Lausanne University Hospital (CHUV) and University of Lausanne  Lausanne Switzerland"},{"name":"Department of Psychology University of Oslo  Oslo Norway"},{"name":"Department of Psychiatry University of Oxford  Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5593-1345","authenticated-orcid":false,"given":"Rasha N. M.","family":"Saleh","sequence":"additional","affiliation":[{"name":"Norwich Medical School University of East Anglia  Norwich UK"},{"name":"Department of Clinical and Chemical Pathology, Faculty of Medicine Alexandria University  Alexandria Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9042-4226","authenticated-orcid":false,"given":"Anne Marie","family":"Minihane","sequence":"additional","affiliation":[{"name":"Norwich Medical School University of East Anglia  Norwich UK"},{"name":"Norwich Institute of Healthy Ageing  Norwich UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2214-3788","authenticated-orcid":false,"given":"Michael","family":"Hornberger","sequence":"additional","affiliation":[{"name":"Norwich Medical School University of East Anglia  Norwich 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