Hormone therapy, dementia, and cognition: the Women’s Health Initiative ten years on

Principle findings on dementia from the Women’s Health Initiative Memory Study (WHIMS) showed that conjugated equine estrogens plus medroxyprogesterone acetate (CEE/MPA) increase dementia risk in women aged 65 years and above, but not risk of mild cognitive impairment. The dementia finding was unexpected, given consistent observational evidence that associates estrogen-containing hormone therapy use with reduced risk of Alzheimer’s disease. It remains controversial whether hormone use by younger postmenopausal women near the time of menopause reduces dementia risk or whether WHIMS findings should be generalized to younger women. Given the challenges of conducting a primary prevention trial to address that question, it is helpful to consider the impact of hormone therapy on cognitive test performance, particularly verbal memory, for its own sake and as a proxy for dementia risk. The WHI Study of Cognitive Aging (WHISCA) showed that CEE/MPA worsened verbal memory, whereas CEE alone had no influence on cognition. These findings have been replicated in several randomized clinical trials. The apparent negative effect of CEE/MPA on verbal memory does not appear to be age-dependent. Additional investigations are needed to understand the impact of other hormonally active compounds on dementia and cognitive outcomes.