Hormone replacement therapy and cognitive performance: The role of homocysteine

Background. Clinical trials have shown that estrogen reduces levels of homocysteine, and recent work has shown that elevated homocysteine increases the risk of incident dementia. However, no studies have investigated whether reduction of homocysteine is a mechanism by which estrogen enhances cognitive functioning. The aim of this study was to examine whether the association between homocysteine and cognitive functioning varies by use of hormone replacement therapy (HRT) in postmenopausal women. Methods. Serum values of homocysteine, HRT status, and two measures of cognitive functioning, the Modified Mini-Mental State Exam (3MSE) and the Delayed Word Recall Test (DELREC), were measured in 1041 elderly women of Latino background. Multiple linear regression models were done to examine whether HRT could modify the effect of homocysteine on cognitive functioning. Results. All findings were adjusted for age, education, income, acculturation, and hysterectomy status. Those subjects on HRT (21%) had 3MSE scores 1.88 points higher (p < .001), DELREC scores 0.12 points higher (p = .06), and homocysteine levels 1.19 μmol/L lower (p < .001) than those not on HRT. Among those not on HRT, the 3MSE was 11.8 points lower and DELREC 1.98 points lower for every 10 μmol/L increase in homocysteine. Among those on HRT, homocysteine was not associated with cognitive functioning. This interaction was not attenuated by further adjustment for lipids, blood pressure, creatinine, folate, Vitamin B₁₂, and cardiovascular disease (p < .001, interaction term coefficient for 3MSE and for DELREC). Conclusions. Women taking HRT may modify the effects of homocysteine levels on cognitive functioning. Further work in randomized clinical trials is needed to examine whether reducing homocysteine levels with HRT can prevent cognitive decline or incident dementia.