Uptown and gown:
diversity in partnership with research

Mary Weideman

F rom storefront churches to synagogues, pupusas to pitas, and cafe cortado to espresso, the northern Manhattan neighborhood of Washington Heights/Inwood is the proud possessor of a dazzling array of ethnic and racial cultures. As such, and in partnership with Columbia neuroepidemiologist Richard Mayeux and his research team in the Washington Heights/Inwood Columbia Aging Project, this neighborhood is helping enhance our knowledge of Alzheimer's disease (AD) and related disorders such as Parkinson's disease and stroke.

The qualities of this neighborhood act in synergy with the recognition that many diseases are now thought to result from the interplay between genes and environment. This relationship is subtle and complicated, demanding that teams of epidemiologists and geneticists tease out the true nature of what are now called "complex" disorders. "The unique strength of our research is that we have an ethnically heterogeneous urban community. We can look for [potentially modifiable] risk factors in elderly Caucasians, elderly African-Americans, and elderly Hispanic Americans," says Mayeux, underscoring the fact that different racial, ethnic, and socioeconomic groups harbor different gene pools and varying exposures to environmental risk factors.

Alzheimer's disease is particularly challenging because, genetically, it occurs as either a simple or a complex form. Early-onset familial AD strikes during the third and fifth decades of life as a result of mutations in the genes that code for amyloid precursor protein, presenilin-1, or presenilin-2. This "simple" form of AD, however, accounts for fewer than 5 percent of cases. For most of the 5 million Americans suffering from non-familial AD, the disease strikes after the age of 65, with research implicating a role for both genes and environment.

The gene that codes for apolipoprotein E (ApoE), a protein expressed in the central nervous system, appears to be most strongly implicated in the development of the more complex and common form of AD. The presence of the ApoE gene, however, does not guarantee the development of the disease. "ApoE does not work that way," says Mayeux. "You are at higher risk, but that's only an increase in risk; it's not deterministic. Of patients with AD, about half of them have an ApoE form. It's not even a mutation, it's what we call a polymorphism, a common variant of the gene which, for some reason, is associated with a higher risk of AD." Researchers know that of the alleles associated with ApoE, the ApoE-epsilon 4 variant, or ApoE4, appears to have a major role in the origins of late-onset AD.

Mayeux and others clearly recognize that two people with different genetic backgrounds, or different histories of environmental exposures, will probably differ in their risk of AD -- which brings full circle the particular value of the Washington Heights/Inwood neighborhood. Its dense population, even more diverse than that of the average urban setting, is augmented by socioeconomic strata as well, the latter giving Mayeux's team the opportunity to expand its study of genetic and environmental components to include the impact of various cultural and experiential factors on the development of AD.

In a series of studies spanning nearly a decade, Mayeux's group has demonstrated that environmental factors, such as a history of head injury or depression, increase the probability that AD will develop, while higher levels of education and occupational development are associated with decreased risk. Although African-American populations differ from Hispanic American and Caucasian populations in the degree of risk associated with ApoE, the relationships between the various genotypes, and the differing combinations of ApoE alleles by which they are characterized, are quite complex. The results of numerous studies looking at the combined effects of environmental and genetic risk factors are still being tabulated but show, for example, a tenfold increase in risk of AD when individuals have both the ApoE4 allele and a history of head injury.

Overall, this study will foster the development of a national strategy for treatment of a disease that affects one of the largest-growing segments of our society. It will also help clinicians target future therapies to each person's particular background and needs. An added benefit is that Mayeux's studies reflect a changing clinical research enterprise: a socio-biomedical model in which relations between investigators and volunteers reflect a balanced partnership, with goals more relevant to a broad range of Americans. Mary Sano, a member of Mayeux's research team at Columbia's Sergievsky Center, says: "I think the partnership concept is strongly replacing the [concept of] subject as guinea pig. Moreover, we've attempted to include people of a much broader socioeconomic status."

Establishing a firm footing in collaboration with diverse populations is not an easy task. Be they Holocaust survivors, political exiles, or African-Americans concerned about the now-infamous Tuskegee study (see sidebar), potential participants may have first- or second-hand experiences of studies involving clear abuses of human research subjects. The fact that long-term epidemiologic research is, by its very nature, non-interventional may heighten concerns about trust, even though in the case of AD the disorder is widely recognized to be untreatable at present. "Trust is the key thing. Paper after paper after paper, [other researchers] would ask me, 'These people come into your hospital?' Absolutely not; we go into their homes, we speak their language, we bring the research to them," says Mayeux.

Also essential to establishing trust is an effort to engage the support of neighborhood leaders. This kind of interaction highlighted the 1995 Community Forum on Memory and Growing Older, in which Mayeux and his co-workers, working with community leaders at all levels, discussed their findings within a common-sense context of memory problems and how best to deal with them. Says Mayeux: "I think we do a pretty good job of convincing people that they're contributing to a better tomorrow. This is a particularly unusual community, in the sense that people are very interested in the welfare of others, that what's good for one individual hopefully is good for the entire community." His experience suggests that when scholars inform the public about the long-range purposes and benefits of research, citizens can view a university not as an adversary but as a valued neighbor.

Tuskegee: how not to design a study
Although the United States is not a signatory of the Nuremberg Code, which came directly out of the Nazi experimentation studies, it oversees ethical constraints via the National Institutes of Health Office for Protection from Research Risks (OPRR). During the Tuskegee study, researchers followed the progress of syphilis for more than 30 years in 400 African-American men known to be suffering from the disease before the study's outset. These research participants were not told they had the disease, were not warned of its effects, and were given no treatment.

Following Congressional hearings in 1974, the Belmont Report was issued, specifying ethical constraints for high-risk research participants. Readers wishing more information can read Bad Blood: The Tuskegee Syphilis Experiment by James H. Jones (1993, The Free Press). They may also dial 301-594-0464 to obtain faxed copies of OPRR documents, including the Belmont Report.

-- Mary Weideman


Related links...

  • Taub Center for Alzheimer's Disease Research, Columbia-Presbyterian Medical Center

  • Alzheimer's Disease Cooperative Study, CPMC

  • Washington Heights-Inwood Community Health Information System, CPMC

  • Alzheimer's Disease Review

  • Alzheimer's Association

  • Neurodegeneration, London-based specialty journal


    MARY WEIDEMAN, is a free-lance scientific and medical journalist based in Bethesda, Md. A registered nurse and former NIH biochemist, she has written for Genetic Engineering News, Environmental Health Perspectives, and numerous other publications.

    Photo Credits:
    Street Photo: Photo: Jonathan Smith/Special Effects: Howard R. Roberts