PHILADELPHIA – Leuprolide acetate, in combination with an acetylcholinesterase inhibitor, helped to preserve cognitive function in Alzheimer’s disease patients in an exploratory study.
The study is small and the results are modest. But they do warrant further investigation in a larger group, Dr. Richard L. Bowen said at the Clinical Trials Conference on Alzheimer’s Disease.
Leuprolide acetate is an agonist of gonadotropin-releasing hormone (GnRH). Dr. Bowen, a family physician in Charleston, S.C., has long postulated that luteinizing hormone, which is highly present in Alzheimer’s brains – especially in the hippocampus – predisposes to cognitive decline. Some preclinical evidence exists to support the idea that luteinizing hormone may modulate amyloid precursor processing predisposing to amyloid plaque formation. Leuprolide’s effect of indirectly down-regulating the secretion of luteinizing hormone by desensitizing GnRH receptors improved cognition in a mouse model of Alzheimer’s, Dr. Bowen noted.
But it was actually a conversation about an Alzheimer’s patent with prostate cancer that sparked his 10-year work on leuprolide. “As a family practice physician, I was doing an annual exam on a postmenopausal woman, talking about the risks and benefits of hormone replacement therapy. She mentioned that her husband, who had Alzheimer’s, had been getting ‘some kind of hormone therapy’ for his prostate cancer. And she said very specifically that since he’d been on it he had not gotten any worse, and in fact, had improved a little,” he said in an interview.
This started Dr. Bowen to thinking about the relationship between gonadotropin suppression and its possible link to neurons and cognition. “Gonadotropins are very important in cell division and very high in fetal life – obviously important for fetal development, when you do want lots of cell division.”
Estrogen and testosterone eventually take center stage in human life, effectively shutting down gonadotropin production – for a while, at least. But when estrogen levels fall at menopause, gonadotropins rise again. “This could predispose terminally differentiated neurons – which aren’t supposed to divide – to cell division, thus, death.”
His theory holds that such a process could also increase amyloid burden. “This does seem to pan out in cellular and animal models, where the expression of gonadotropins in the brain perfectly correlates with amyloid deposition. It’s a coherent model of this disease that speaks to why and when we develop it.”
In 2004, Dr. Bowen and his colleagues published a paperdemonstrating that neuroblastoma cells exposed to luteinizing hormone showed a significant increase in amyloid precursor protein and a resultant increase in amyloidogenic processing.
That same paper found that leuprolide treatment in an ovariectomized Alzheimer’s mouse model decreased amyloid expression, suggesting that luteinizing hormone, not estrogen, drove the change.
At the meeting, he reported a 48-week, dose-ranging study of 109 women with mild to moderate Alzheimer’s. They received either placebo or leuprolide acetate injections with a low dose (11.25 mg) or high dose (22.5 mg), which were carried out over 12 weeks, with cognitive assessments conducted at regular intervals during the remainder of the study.
The primary endpoints were scores on the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog) and the Alzheimer’s Disease Cooperative Study Clinical Global Impression of Change (ADCS-CGIC). Secondary endpoints included the Neuropsychiatric Inventory, Alzheimer’s Disease Cooperative Study-Activities of Daily Living Inventory (ADCS-ADL), Burden Interview, and ADCS-CGI Severity Rating.
There were no significant between-group differences in the ADAS-cog or the ADCS-CGIC scores in the entire group. But a preplanned subgroup analysis turned up an intriguing finding in the 78 patients who were also taking an acetylcholinesterase inhibitor (AChEI).
Although they didn’t improve cognitively, patients taking the combination of an AChEI and leuprolide held their scores at baseline level in the ADAS-cog and ADCS-CGIC throughout the 36-week follow-up period. At 48 weeks, mean ADAS-cog score declined by 3.3 in the placebo group, 4.1 in the low-dose combination group, and 0.18 in the high-dose combination group.
Results were similarly significant on the ADCS-CGIC measure, with mean declines of 63% and 82% in the placebo and low-dose groups, respectively, compared with a 38% decline in the high-dose group.
The subgroup analysis found no differences on the other measures.
Dr. Bowen said the results of his study are even more intriguing when viewed in light of a studypublished by investigators at the Dana Farber Cancer Institute that showed a 50% reduction in Alzheimer’s incidence in men who had received leuprolide for prostate cancer.
“This was remarkably similar to what we saw in our own 12-year Medicare database review,” which examined incident Alzheimer’s after prostate cancer, gallbladder surgery, hernia repair, and enlarged prostate. “Again, the decrease in the risk of developing Alzheimer’s associated with prostate cancer was about 50%.”