Objective: The effect of systemic hormone therapy (HT) on dementia risk is unclear. Our aim was to investigate the association between HT and dementia.

Study design: This register-based study consists of a nested case-control study and a co-twin control design, which controls for familial confounding, including shared genetics.

Main outcome measures: Through Danish national registries from 1995 to 2011, we identified: a) 2700 female singletons with incident dementia and 13,492 matched controls; b) 288 female twins with incident dementia and co-twins without dementia. Data on HT and education were retrieved, and analyses were performed using conditional logistic regression and McNemar's chi(2)-test. HT use decreased dramatically after the Women's Health Initiative study results were published in 2002, and the analyses were stratified accordingly to account for potentially different HT user characteristics.

Results: The odds ratio (OR) for the association between systemic HT and dementia was 1.05, 95% CI = [0.93-1.19] in singletons and 2.10, 95% CI = [0.99-4.46] in twins. A statistically significant association was found for systemic HT before 2003 in both populations, with an OR of 1.14, 95% CI = [1.01-1.28] in singletons and an OR of 2.20, 95% CI = [1.04-4.65] in twins.

Conclusion: Using Danish nationwide registries and controlling for education and for familial factors in a subsample, systemic HT was found to be associated with increased dementia risk if used before 2003, when HT was more commonly prescribed.