Liqin ZhaoLiqin Zhao, Ph.D.
Research Assistant Professor of Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, recipient of a 2005 New Investigator Research Grant

Research focus

I often think about a very emotional conversation with a close friend regarding his 69-year-old father, who had just been diagnosed with early-stage Alzheimer's disease and had failed his driver's license exam. My friend was deeply hurt by the mean way in which his father communicated with him after failing the exam. “He is perfectly fine in all other areas, and I can't believe that he was so mean to me,” my friend repeated, even after I had spent hours explaining to him how a human brain's structure and function can be altered by Alzheimer's and that these changes can affect the individual's judgment and the way they communicate and act.

Impact of Association funding
The Alzheimer's Association opened a door to help turn my passion into reality. The New Investigator Research Grant (NIRG) from the Alzheimer's Association enabled me to pursue my own ideas and conduct the basic science research that has led to the discovery of a promising therapy for Alzheimer's. This novel therapy is being studied in a clinical trial funded by the National Institute on Aging (NIA).

Many months later, my friend was able to put these feelings behind him, but then was overwhelmed with emotion as he witnessed the disease slowly taking his father away from their family. While living in a nursing home over the next five years, his father continued to worsen until he could no longer recognize the people around him, even family members.

Those conversations with my friend solidified my passion for Alzheimer's research and finding a cure so others would not experience the emotional struggles my friend had experienced. The Alzheimer's Association opened a door to help turn my passion into reality. The New Investigator Research Grant (NIRG) from the Alzheimer's Association enabled me to pursue my own ideas and conduct the basic science research that has led to the discovery of a promising therapy for Alzheimer's. This novel therapy is being studied in a clinical trial funded by the National Institute on Aging (NIA).

Despite the attention given to Ronald Reagan, Charlton Heston, Sargent Shriver and other men who developed Alzheimer's, elderly women are still by far the principle victims of the disease, accounting for 68 percent of cases. Both basic science and clinical research suggest that ovarian estrogens may help prevent neurodegeneration in women. The loss of estrogen during menopause could be a risk factor for cognitive impairment and dementia such as Alzheimer's. Moreover, research suggests that timely initiation of an estrogen-containing hormone therapy (HT) could help prevent Alzheimer's and alleviate other estrogen deficiency–associated symptoms in menopausal and postmenopausal women. However, since current forms of HT may increase women's risk of breast cancer, stroke and blood clots, it's imperative that we develop an alternative HT that is both effective and safe.

Soy foods vs. soy extracts

Over the past decade, a group of plant-derived, non-steroidal estrogen-like compounds, known as phytoestrogens, have been found to have similar functional activity to ovarian estrogens and have received enormous attention by both researchers and clinicians. This increased interest in phytoestrogens has been attributed in large part to the health-promoting effects suggested by epidemiological studies of soy-based foods, which are rich in phytoestrogens and regularly consumed in Asian countries. For example, a number of epidemiological studies conducted in populations across the continents revealed a 2.5 times lower prevalence of Alzheimer's in Japan and China than in North America and Europe, where individuals consume less than 1 milligram of phytoestrogens per day compared with 20‒80 milligrams per day in Asian individuals.

Moreover, epidemiological studies suggest that this difference in phytoestrogen intake may also contribute to differences in the incidence of other sex hormone–related disorders seen in Asian versus North America and European populations. In particular, recent statistics show that only 25 percent of Japanese and 18 percent of Chinese menopausal and postmenopausal women experience hot flashes compared with 85 percent of North American and 70 percent of European women. In addition, historically, breast and prostate cancer rates in Asia have been much lower than in Western countries. These positive observational findings, however, lack confirmation from well-controlled, randomized clinical trials, which have produced inconsistent and inconclusive data.

Growing up in China and then living in the United States has given me a firsthand opportunity to appreciate the differences in the diets between these two distant parts of the world. Capitalizing upon such knowledge, I hypothesized that the discrepancies between observational studies focusing on soy-derived foods and interventional studies examining soy-derived extracts could have originated from the differences between the natural forms of soy foods and pharmacological preparations of soy extracts.

The bottom line is that soy foods and soy extracts are not the same. In recent years, many soy extract products have become available over the counter. Most of these are advertised as dietary supplements for use by women to lessen menopausal symptoms such as hot flashes. However, these supplements are unregulated by the U.S. Food and Drug Administration, so their safety and efficacy are questionable. The greatest problem is that the processing of soy extract products is not standardized. An analysis of a number of commercial soy extract supplements revealed an abundance of substances of unknown origin. Some of these substances may have been created through the extraction process. In this process, the organic solvents and high temperatures used may cause chemical reactions leading to the generation of substances not naturally present in soy. These substances could produce an undesirable effect, counteracting the favorable health-giving properties of other substances in the supplement.

A novel therapy

Funding from the Alzheimer's Association enabled me to test this hypothesis and attempt to develop a phytoestrogen formulation that is safe and effective. The research included screening a database of 25,000 phytoestrogens and resulted in the discovery of a formulation we've called phyto-β-SERM that was found to be neuroprotective. A nine-month study of female mice engineered to develop Alzheimer's that were given the formulation provided additional support for the therapeutic potential of the formulation in slowing or reducing the cognitive decline and neurophysiological changes associated with Alzheimer's. In contrast, mice receiving a commercial soy extract–containing diet did not show these improvements.

To my tremendous excitement, these benchside scientific discoveries have led to an NIA-funded, recently launched, first-in-humans pilot trial of phyto- β-SERM. The trial evaluates the formulation's safety, its effect on hot flashes and cognition in menopausal and postmenopausal women and how it is absorbed, distributed, and metabolized (its pharmacokinetics) in the body. The trial consists of two studies to be completed in the next three years. The Phase I study is designed to determine the pharmacokinetics of the formulation and which doses are safe and well-tolerated. The Phase IIA study is a proof-of-concept study that will continue to examine safety and best dosages but also examine the formulation's effect on hot flashes and cognition. The success of these early stage human studies will lay important foundations for later stage, long-term efficacy studies in Alzheimer's patients.

Moving research forward

For many years, one of the largest unmet medical needs in the health of menopausal and postmenopausal women has been an estrogen therapy that is both effective and safe. I am hopeful that my research could lead to a breakthrough to fill the gap. The formulation may also help preserve cognitive function in men.

In addition to its tremendous impact on my research, the NIRG award from the Alzheimer's Association has monumentally advanced my career as an independent Alzheimer's researcher. I was appointed to a research faculty position soon after I received this honorable award, and the funded research has resulted in several peer-reviewed publications and two U.S. patent applications. No words can describe how grateful I am to the Alzheimer's Association for its instrumental role in making this happen.

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