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Isoflavones and cognitive function in older women: the SOy and Postmenopausal Health In Aging (SOPHIA) Study

Kritz-Silverstein, Donna PhD; Von Mühlen, Denise MD, PhD; Barrett-Connor, Elizabeth MD; Bressel, Mathias A. B. BS


Objective: This study examines the effects of a dietary supplement of isoflavones on cognitive function in postmenopausal women.

Design: Participants for this 6-month, double-blind, randomized, placebo-controlled clinical trial were women who were in good health, were postmenopausal at least 2 years, and were not using estrogen replacement therapy. Between July 24, 2000, and October 31, 2000, 56 women aged 55 to 74 years were randomized; 2 in the placebo group and 1 in the active treatment group did not complete the 6-month evaluation, and none withdrew because of adverse effects. Women randomized to active treatment (n = 27) took two pills per day, each containing 55 mg of soy-extracted isoflavones (110 mg total isoflavones per day; Healthy Woman: Soy Menopause Supplement, Personal Products Company, McNeil-PPC Inc., Skillman, NJ, USA). Women assigned to placebo (n = 26) took two identical-appearing pills per day containing inert ingredients. Cognitive function tests administered at baseline and follow-up included the following: Trails A and B, category fluency, and logical memory and recall (a paragraph recall test assessing immediate and delayed verbal memory).

Results: At baseline, all women were cognitively intact; there were no significant differences by treatment assignment in age, education, depressed mood, or cognitive function (all P values > 0.10). Compliance was 98% and 97%, respectively, in the placebo and treatment groups; all women took at least 85% of their pills. The women in the treatment group did consistently better, both as compared with their own baseline scores and as compared with the placebo group responses at 6 months. Comparisons of percentage change in cognitive function between baseline and follow-up showed greater improvement in category fluency for women on active treatment as compared with the case of those on placebo (P = 0.02) and showed (nonsignificantly) greater improvement on the two other tests of verbal memory and Trails B.

Conclusion: These results suggest that isoflavone supplementation has a favorable effect on cognitive function, particularly verbal memory, in postmenopausal women.

Many, but not all, epidemiological studies suggest that estrogen replacement therapy (ERT) has beneficial effects on cognitive function in postmenopausal women. 1 Although there are inconsistencies between studies, most observational studies do not report a detrimental effect of ERT on cognitive function. 1 Pooled data from a recent meta-analysis including 2 cohort and 10 case-control studies showed a 34% decreased risk of Alzheimer's disease among users of hormone replacement therapy (HRT). 1 A clinical trial of raloxifene, a selective estrogen receptor modulator (SERM), showed improvement in verbal fluency and recall in women aged 70 years and older, but not in younger women. 2

Phytoestrogens are naturally occurring compounds found in plants that have estrogenic and antiestrogenic effects and have been called “nature's SERMS.”3 Laboratory studies support a beneficial role of isoflavones, one of the major types of phytoestrogens, on cognitive function. For example, phosphorylated tau, which comprises the neurofibrillary tangles found in Alzheimer's brain but not in the normal-aged human brain, were suppressed in the brains of ovariectomized rats fed diets containing soy protein with isoflavones. 4 In another study, estrogen-deficient rats treated for 10 months with one of three levels of soy isoflavones showed a dose-dependent improvement in maze performance. 5

Two observational studies of high soy diets in older adults showed inconsistent results. One study reported that higher midlife tofu consumption among men and their wives was associated with cognitive impairment in later life. 6 However, data on tofu consumption of wives was based on their husbands' responses during interviews conducted in 1965 to 1967 and 1971 to 1974 concerning current tofu consumption, whereas cognitive function was assessed in 1991 to 1993 without information on more recent tofu consumption. Previous research has shown that Asian diets become more Westernized as time since immigration increases. A cross-sectional study of Japanese Americans showed that tofu consumption three or more times per week was associated with lower cognitive function test scores only in women who were current users of ERT, with no associations observed in men or in women who had never used estrogen; in this study, tofu consumption was not associated with change in cognitive function over 2 years. 7 In contrast, a recent clinical trial 8 in 27 college students reported that men and women receiving a high-isoflavone diet for 10 weeks showed improvement in short-term and long-term memory and in mental flexibility, and that women also improved in letter fluency and planning tasks.

To our knowledge, there are no published clinical trials of isoflavones and cognitive function in postmenopausal women. We report here the results of a randomized, placebo-controlled, double-blind trial designed to examine the short-term effects of a dietary isoflavone supplement on cognitive function in postmenopausal women.

From the University of California, San Diego, School of Medicine, Department of Family and Preventive Medicine, Division of Epidemiology, La Jolla, CA.

Received July 1, 2002; revised and accepted October 16, 2002.

This work was supported by an unrestricted gift from Johnson & Johnson and National Institutes of Health grant M01 RR00827.

Address reprint requests to Donna Kritz-Silverstein, PhD, Department of Family and Preventive Medicine, 0631-C, 9500 Gilman Drive, La Jolla, CA 92093-0631, USA. E-mail:

©2003The North American Menopause Society