No Cognitive Benefit of Raloxifene in Women with Alzheimer's

Megan Brooks

November 05, 2015

Treatment with the selective estrogen receptor modulator raloxifene did not improve cognitive function compared with placebo in a small pilot study of older women with Alzheimer's disease (AD).

"Estrogens have a number of effects that could affect brain processes relevant to [AD]," Victor W. Henderson, MD, director of the Alzheimer's Disease Research Center at Stanford University in California, told Medscape Medical News.

"Raloxifene was interesting to us from two perspectives. First, it works through estrogen receptors, but its effects are not just those of an estrogen. Second, raloxifene is the only compound with clinical trial evidence to suggest it might reduce the likelihood of developing cognitive impairment in healthy older women. We wanted to see whether it might also improve cognitive symptoms of women who already have [AD]," Dr Henderson explained.

The study was published online November 4 in Neurology.

No Meaningful Benefit

Forty-two women (mean age, 76 years) with late-onset mild to moderate AD were randomly allocated to high-dose (120 mg/d) oral raloxifene or identical placebo for 12 months. The dose was chosen on the basis of findings from the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, in which reductions in risk for mild cognitive impairment were seen at 120 mg daily but not 60 mg daily, the investigators say.

All 42 women were included in intention-to-treat analyses and 39 women contributed 12-month outcomes.

There was no significant difference between raloxifene and placebo for the primary outcome: change in the Alzheimer's Disease Assessment Scale, cognitive subscale, at 12 months (standardized difference, 0.03; 95% confidence interval, –0.39 to 0.44; two-tailed P = .89).

Secondary analyses of dementia rating, activities of daily living, and behavior, as well as caregiver burden and distress, also failed to suggest "meaningful benefit, although power to detect treatment effects was limited," the investigators say.

Nonsignificant differences favoring raloxifene on some verbal memory tasks were evident but could have been due to chance, they say. Nonetheless, raloxifene has been reported to benefit verbal memory in older postmenopausal women without dementia, "and future studies might examine raloxifene effects within this cognitive domain more closely," they note.

One woman in the raloxifene group experienced a possibly related serious adverse event: ischemic stroke followed by death. "Raloxifene is linked to fatal stroke in women at high risk defined by the Framingham stroke score. In future trials, high stroke risk could be considered exclusionary," the researchers report.

"The take-home message from this relatively small, 1-year study is that raloxifene does not have a large, or even a medium, effect on cognition in women with Alzheimer disease," Dr Henderson told Medscape Medical News. "However, we were not able to exclude the possibility of a small cognitive effect."

The researchers caution that their findings should not be generalized to populations or outcomes not studied in this trial, including the effects of raloxifene on cognition in women without dementia, on risk for AD, or effects of other selective estrogen receptor modulators on cognitive outcomes.

They also note that recruitment was "more difficult than anticipated, and the study sample did not reflect the racial and ethnic diversity of the general population."

Mark Espeland, PhD, professor, Public Health Sciences-Department of Biostatistics at Wake Forest Baptist Medical Center, Winston-Salem, North Carolina, who reviewed the analysis for Medscape Medical News, said he agrees with the authors' conclusions.

"While the little overall evidence of benefit and the difficulties in recruitment do not rule out the potential that a future trial could be conducted and may find positive results, the data that are presented likely diminish enthusiasm towards mounting such a trial and the expectation that raloxifene would emerge as a promising intervention," Dr Espeland commented.

The study was supported by the National Institutes of Health (NIH). Eli Lilly and Co. provided study drug and placebo without charge or restriction. Dr Henderson has received research support from the NIH. A complete list of author disclosures is available at www.neurology.org.

Neurology. Published online November 4, 2015. Abstract

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