Alzheimer’s Disease Research in the Bay Area and Beyond

At least 4.5 million people in the U.S. suffer from Alzheimer’s disease(AD), and the number is expected to climb beyond 12 million by 2050. AD observes no ethnic boundaries, and an even greater increase will likely occur in China as living conditions, health care, and longevity improve in this most populous country on earth.

AD places astonishing financial and emotional burdens on its victims, their families, and society. AD already costs an estimated $100 billion per year in the U.S. alone. It is easy but frightening to imagine what the expected rise in AD cases will do to the cost of health care in the near future. Major medical breakthroughs are urgently needed to prevent this disease from robbing our society of its resources—including the wisdom of our elders.

At first glance, the situation may seem bleak. Most clinical trials of AD treatments have failed, and no truly effective therapeutic strategies have emerged. In fact, AD is a Pandora’s box of obstacles. Its cause is most likely multifactorial, and therapies must be developed to deal with these different factors, taking into account the different ways people respond to disease based on their genetic makeup. One person may develop AD because she inherited two alleles for apolipoprotein E4 and suffered a head injury. Another person because he inherited a mutated presenilin gene that cranks up the production of toxic amyloid-β (Aβ) proteins in the brain. The well-publicized cardiovascular side effects of popular anti-inflammatory drugs illustrate the pitfalls of drug development. Even treatments that work well and have minimal side effects in animals and small groups of patients can “lose” efficacy or turn out to be unsafe when given to thousands of people with diverse genetic backgrounds.

Fortunately, disease-related neuroscience has never advanced more rapidly than now, which gives reason for great hope. Our understanding of AD and disease processes in general has improved greatly, and the research tools now becoming available will provide many new approaches to the study of disease. The convergence of disease-oriented basic research and clinical research promise exactly the sort of breakthroughs we so desperately need.

Recent developments in the Bay Area can be expected to greatly facilitate these efforts and to promote the identification of better AD treatments.

GIND and UCSF investigators planning new outreach efforts. From left to right: Li Gan, Yadong Huang, Lennart Mucke, Craig Hou, and Fen-Biao Gao.

First, the relocation of the Gladstone Institute of Neurological Disease(GIND) to Mission Bay brings AD research to this burgeoning enterprise. In turn, we gain access to promising new technologies, including cutting-edge approaches to drug screening, medicinal chemistry, and magnetic resonance imaging. GIND investigators have launched major efforts to shed light on the etiologic diversity of AD and to better predict which patients might benefit from particular therapeutic interventions. These initiatives include the comparative investigation of multiple AD-related factors, the study of interactions between drugs, genes and gender, and the large-scale analysis of gene-expression profiles with DNA and protein arrays.

Second, together with Dr. Bruce Miller and other collaborators at UCSF, we proposed to establish a new Alzheimer’s Disease Research Center (ADRC) in San Francisco. In a highly competitive process, ours was the only new center approved for NIH funding in 2004. The clinical investigations and trials supported by this entity will be carried out primarily at UCSF’s Memory and Aging Center. They will provide Bay Area residents access to the best in dementia care and give Gladstone investigators exciting new opportunities to translate their discoveries into treatments. Two particularly promising pilot projects at Gladstone, one focusing on brain inflammation and the other on the protein tau, have already been jump-started with ADRC support. Since funds for pilot projects are very limited, major efforts will have to be made to expand the support for these trailblazing research initiatives.

Finally, the GIND is developing an international outreach program for AD and related conditions. Conducting research in other countries has a long tradition at Gladstone. The Turkish Heart Study of the Gladstone Institute of Cardiovascular Disease has revealed information that has helped Turks and others around the world. The Gladstone Institute of Virology and Immunology has recently begun an African AIDS initiative.

We have chosen to focus on Asia and the Pacific Islands. China has the fastest growing population of elderly peoplein the world. Yet, the resources available for the differential diagnosis and management of dementia in this and other Asian countries are still limited, and AD research in China is just beginning to take off. The GIND and UCSF are in an excellent position to help advance and accelerate this process. The Memory and Aging Center takes care of many Asians and PacificIslanders with AD in the Bay Area and has already established several new initiatives to address the specific needs of these patients and their families. The GIND has a keen interest in how neurological disease processes interact with different genes and ethnic backgrounds. Moreover, three of our investigators and a large proportion of our trainees and research staff are Asian, which should greatly facilitate the exchange of ideas, educational efforts, technologies, research materials, and clinical specimens. I hope that others in the Bay Area and beyond will find this program worthy of support by other means.

AD is a global threat. Unfortunately, many costly clinical trials for Alzheimer’s disease have yielded disappointing results. The disease is likely influenced by many genetic and environmental factors, and responsive subpopulations may be obscured by others who do not respond to the treatment. Identifying markers to help match the right patients with the right treatments is a major challenge .

Because the etiology of AD is heterogeneous and many drugs have a relatively narrow therapeutic window, the most effective treatment of this disease will likely involve the combination of drugs with mechanistically distinct actions. The advantages of this strategy have been demonstrated in other multifactorial diseases, for example, hypertension and atherosclerosis.

Recognizing the formidable challenges of this disease, we can also have reason to hope. Our understanding of the disease grows daily. Our research tools continually improve and refine our ability to explore new avenues. New ideas come from fertile collaborations. Researchers at Gladstone are particularly well positioned to pursue a variety of therapeutic avenues. That research will benefit people around the world.