An Interview with Patrick A. Griffith, M.D.
Professor of Clinical Medicine
Chief, Division of Neurology
Morehouse School of Medicine
Member, Dana Alliance for Brain Initiatives
Your research and advocacy work focuses on understanding why minorities appear to be at higher risk for Alzheimer’s disease and related dementias. What have we learned from research to date?
Patrick A. Griffith: This is a controversial area. The research is ongoing, so the current thinking may or may not change as more data accumulates. One of the research programs that I follow most closely is an international study comparing a group of native Africans (Yoruba tribe) in Ibadan, Nigeria with a group of African-Americans in Indianapolis, the so-called Indianapolis-Ibadan Dementia Project. The researchers are following community-dwelling individuals who are cognitively normal at the time of enrollment, and tracking which among them go on to develop dementia. They’ve published two reports so far, five years apart, finding in both instances a lower prevalence and lower incidence of Alzheimer’s disease (AD) in the Ibadan cohort.
Epidemiological data from two observational U.S. studies support this. The first, from a research group at Columbia University led by [Dana Alliance Member] Richard Mayeux, M.D., has found a higher prevalence of AD in Hispanics and African-Americans in northern Manhattan compared to African-Americans in Indianapolis and Africans in Ibadan. The difference is relatively small between the New York City group and the Indianapolis group, but there is a major difference between those two and the Nigerian cohort.
The second is the ongoing Multi-Institutional Research in Alzheimer’s Genetic Epidemiology (MIRAGE) study, a database kept by Lindsay Farrer, Ph.D., at Boston University (BU), and its offshoot MIRAGE-STAR (Special Targeting of African-Americans with Alzheimer’s and their Relatives). In the latter, Robert Green, M.D., a BU neuro-epidemiologist, led the enrollment of persons living in Atlanta, Ga., Birmingham, Ala. and Charleston, S.C. The lifetime cumulative risk of developing AD was higher in African-Americans compared to whites for both men and women.
Why is there a difference? Some people initially felt that it was due to differences in life expectancy, but that’s not the case. The percentage of individuals living past age 65 is more or less the same in the Indianapolis and Ibadan groups. Others have speculated that genetic differences may be the reason, specifically differences in the presence of the ApoE-4 allele, a risk promoter gene linked to late-onset Alzheimer’s. If you inherit two copies of the E-4 gene, you have a 95 percent chance of developing late-onset AD by age 85. But there seems to be no significant difference between E-4 prevalence in the Ibadan cohort compared to the Indianapolis cohort.
It’s not life expectancy, and it’s not the ApoE-4 allele. The question researchers are trying to answer is: what is accounting for this difference? Is it diet? Is it environmental? Is it lifestyle? These questions continue to be debated in the literature and in scientific circles.
What is the current thinking about what might be accounting for the higher prevalence and incidence of Alzheimer’s and dementia in ethnic minorities here in the United States?
PAG: There seems to be something about living in a developed country. There is currently no consensus among researchers in the field about what may account for the higher prevalence and incidence of Alzheimer’s and dementia in ethnic minorities in the United States. Therefore, we learn from studies comparing similar groups outside the United States. In addition to the Indianapolis-Ibadan study, there is data from an ongoing study tracking dementia prevalence in eastern India. It turns out that the prevalence in rural India is very similar to the prevalence in Ibadan, Nigeria. So this is another developing country with low prevalence. In India, they think it may be due to dietary influences, because a lot of the people there are vegetarian and eat curry frequently. Indian curry has an ingredient called curcumin, an antioxidant that some studies have suggested may be protective against dementia.
These emerging data suggest that in developing countries the rate of dementia is low. There is something about how the disease develops in North America, England, Australia, and other developed countries that is different than how it develops in developing countries. One important issue is whether this may be in part due to the fact that there is more stroke-related dementia (also called vascular dementia or multi-infarct dementia) diagnosed in developing countries. My own thinking is that it’s probably not that.
These observations would seem to point to some kind of multi-factorial influence (i.e., combinations of dietary, gene expression, and/or environmental factors). The question that I would like to see answered is: when does the prevalence change? In other words, if you have low prevalence in an African cohort, does it change in first-generation immigrants to developed countries? If Yoruba Nigerians from Ibadan were to immigrate to New York or Indianapolis, does their risk for Alzheimer’s change in that same generation, or does the risk become increased only in subsequent generations? If it changes in subsequent generations, that would suggest that maybe there are lifestyle, dietary, or environmental factors that come into play in the United States to account for the difference. Is it because food is grown, processed, and consumed differently, or are there other factors that have not yet been identified by epidemiologists who study disease trends in populations?
Another possible explanation is exercise. In developing countries, people tend to be more physically active, not in the sense of “working out,” but because there is typically less access to automobiles and public transportation. It is not yet clear how nongenetic factors affect risk.
How might so-called vascular risk factors—like diabetes, hypertension and high cholesterol—contribute to the higher prevalence and incidence of Alzheimer’s disease in minority populations in the U.S. and other developed countries?
PAG: Most epidemiologists agree that the two biggest risk factors for AD are aging and family history. In terms of family history, the predominant group is the one where there is a clear genetic cause, as with early-onset Alzheimer’s and a family of genes called presenilins. Then there is another group where the disease may run in families, but we haven’t yet found the particular gene or gene mutations responsible for the phenotype seen in African-related groups (African-Caribbean, African-American, etc.). Several minority communities are in that second group. In those cohorts, is the problem a mutated gene, or some combination of genes? Or is it related to vascular risk factors such as diabetes, high blood pressure, or high cholesterol? What attributable risk does each factor cause? Is hypertension more significant than diabetes or is it the co-occurrence of these conditions that is problematic? Are there common or unique biomarkers to the type of dementia that appears in these populations? These issues have not been sorted out.
While it has not been proven, the clinical sense is that vascular risk factors are probably different in minorities vs. whites. Researchers are debating whether or not cognitive impairment in an elderly person is stroke-related, so-called “pure” Alzheimer’s, or a mixture of both (called mixed dementia). Many people think that these exist on a continuum or a spectrum. Pure Alzheimer’s refers to the presence of particular degenerative processes confirmed by histologic changes of varying density seen in selected brain regions upon autopsy. The changes include plaques, which are outside of neurons and are primarily related to a protein called beta amyloid, and neurofibrillary tangles, which occur inside neurons and are primarily related to a protein called tau.
As far back as 1906, Alois Alzheimer observed these plaques and tangles in the first reported case of the disease, though he didn’t know they were due to amyloid and tau protein. Today, plaques and tangles are well-documented as the key features underlying AD, and they seem to occur in certain parts of the brain more than others.
The problem is that many people start to accumulate plaques and tangles just as a matter of getting old. The question is: what else besides aging turns the brain toward Alzheimer’s disease in some instances and toward vascular dementia in others? The sense is that in some people, little “silent” strokes in the brain, even though they are clinically undetectable, predispose a person to a more aggressive form of AD.
There is an ongoing multi-center international study being led by Vladimir Hachinski, M.D., London Health Sciences Center in London, Ontario, in collaboration with the National Institute of Neurological Disorders and Stroke. This study developed harmonization criteria for vascular cognitive impairment that may help answer these questions eventually. The researchers are following people diagnosed with vascular cognitive impairment (where brain damage results from problems with the blood vessels in the brain) to determine how many go on to develop “pure” vascular dementia and how that is differentiated from mixed dementia and cerebrovascular disease.
It’s well documented that these kinds of vascular risk factors are more common in African-Americans. Is that the case for other minorities as well?
PAG: A few researchers are beginning to look at other minority groups. For example, Helena Chui, M.D., and colleagues from the University of Southern California are following an Asian-American cohort in California along with a group in Hawaii. Her study is called the Honolulu-Asia Aging Study. One of the researchers, Helen Petrovitch, M.D., is following Japanese-American males. Another group at the University of Pittsburgh, led by Mary Ganguli, M.D., is tracking dementia incidence in a rural population in eastern India.
While there is progress being made, at this point a lot of us have more questions than answers. We’re getting one set of information from the epidemiologists who do population studies, and we’re getting a different set of information from the clinicians who are trying to follow these groups over long periods of time to understand the differences. Unraveling all of this is very much a work in progress.
What are the barriers to better assessment and treatment of dementia in minority populations?
PAG: Unfortunately, African-Americans and Hispanics tend to come to the attention of physicians only in the middle or later stages of the illness, when behavioral problems such as agitation, aggression, or wandering start to manifest. That is a much more difficult stage to treat, because the disorder has already progressed. The medications we currently have that are FDA-approved work best in the earlier stages, and should be started as early as possible.
Whether this phenomenon of seeking treatment later than would be ideal is due to educational barriers, financial barriers, or cultural barriers is being debated. The cultural aspect is interesting, because in a lot of minority settings, the family may be more likely to ignore signs of forgetfulness, thinking that they are just a matter of getting older and not really a problem.
Clinicians who provide healthcare services to minority families are trying to get them to recognize that memory problems are never normal, and if family members have episodes of “senility” or whatever they might term it, then they should be evaluated medically as soon as possible.
How far can education go toward overcoming these barriers to earlier diagnosis and treatment?
PAG: That’s the heart of the matter. Some researchers now identify a condition called Mild Cognitive Impairment (MCI), but many believe MCI is really an early stage of Alzheimer’s. This begs the question: if you educate everyone, including minorities, to recognize MCI, do you then treat them at that point? And if so, what will you treat them with? Most people agree that the centrally acting cholinesterase inhibitors that are currently FDA-approved should at least be tried in MCI. The problem is that none of these drugs are curative, and they only modestly affect the progression of symptoms.
What about starting treatment earlier? Might we be able to prevent the development of AD? That is the hope, but unfortunately a lot of the antioxidants that have been touted as potentially preventative have turned out to be ineffective. The most recent one to fail is ginkgo biloba, based on a large six-year study investigating its effectiveness in delaying or preventing the onset of Alzheimer’s disease.
Some people say, why not just control the vascular risk factors? If we know somebody has a family history of cognitive problems, we recommend doing everything possible to ensure that they don’t develop diabetes, high cholesterol, or hypertension. Or if they do develop one of those conditions, they should be treated aggressively as soon as they are diagnosed. Of course, there are similar barriers to the early and effective treatment of these conditions, especially in minorities, as there are with early identification and treatment of Alzheimer’s.
Is there anything wrong with the fact that the same messages are being expounded to minorities as to Caucasians?
PAG: I think there is, and educational and financial barriers play a major role. A published study from Emory University’s nursing group and neurology department compared African-Americans presenting to a public, inner-city hospital, to African-Americans who went to a hospital next to the Emory campus in an upper-middle class area of Atlanta. The researchers found a clear delay in the presentation of possible dementia patients at the inner-city hospital compared to those at the hospital next to Emory. Why might that be?
It may be that the African-Americans who go to the hospital near Emory are better educated and therefore better informed about early identification of Alzheimer’s, so when they notice problems with memory, they take their loved one in to get evaluated sooner. In contrast often those persons who receive care at the inner-city hospital may not be as well educated or as well off financially.
What role might physician education play in improving early identification and treatment of minorities?
PAG: That is another factor that is hard to quantify. It may be that the physicians examining patients in settings such as the inner-city hospital may be unwittingly contributing to delays in diagnosis and treatment.
In the usual setting in which many minority patients receive healthcare, there is likely to be high volume. That’s because minorities are more likely to be receiving medical care from primary care physicians, who typically see lots of people and may have less time to spend with individual patients. This begs the question as to whether there is appropriate reimbursement for such physicians to screen patients for signs of dementia, and if so, what would be the appropriate tests or screening tools that should be used?
Most physicians use something called the Mini-Mental State Exam (MMSE), which is a test that was validated and originated by two geriatric psychologists in Baltimore. Some psychologists who test minority groups, such as Yaakov Stern, Ph.D., and Jennifer Manley, Ph.D., at Columbia University, contend that minority patients tend to test lower on the MMSE because the Baltimore study subjects on whom the test was validated were largely college-educated and white.
It’s a matter of the families needing to be advocates and seeking out medical care for their loved one early on, and for the physicians taking care of elderly patients to look for problems as early as possible.
Minorities continue to be under-represented in clinical trials. Do you see evidence that this situation is changing?
PAG: I think it is changing slowly, but it is still a big issue. The two individuals who are likely to encourage minority patients to participate in a clinical trial are the primary care physician and the faith-based advisor (e.g., clergy member or minister). You have to gain the trust of those two individuals.
Being a minority researcher is not enough in terms of convincing a minority patient to participate in a clinical trial. There has been increasing interest in focusing educational efforts on healthcare providers who serve minorities, as well as on the faith-based community. The Alzheimer’s Association has been very supportive of educational outreach to the clergy and ministers, for example, as well as to primary care physicians.
Is the long shadow of the infamous Tuskegee experiments still haunting minority research today?
PAG: I think it’s there, but it is not as much of a deterrent. I don’t know if the average patient knows about Tuskegee, but it always comes up as an issue in clinical trial recruitment of minority populations. It’s clear that educated, historically astute physicians and ministers who serve minorities are very much aware of Tuskegee and know about President Clinton’s apology, etc. That is not missed on the better informed minority individual.
I think the important issue is that the potential study participant has to be assured first of privacy. In the same way that they are protective of their elders’ cognitive problems, they don’t want it known in their social setting that they have a family member who is having problems. In contrast, I think in the white community, although there also may be some reluctance, there are clear examples of people who have been brave enough to talk about their dementia openly, to not try to hide it. You have the role models of Ronald Reagan, for instance, or Rita Hayworth, so there may be less reticence about going to seek help.
What we as researchers and advocates have to do is assure not only the minority-serving primary care physician but also the patient that not everybody who is forgetful has Alzheimer’s; they have to be tested and screened. We have to emphasize that there is good evidence that being treated as early as possible delays the eventuality of needing nursing home placement. We need to clearly communicate that this is a poorly understood condition that seems to occur among older individuals, but we’re still trying to understand who gets it, in what proportions, how fast it progresses, and what we can do about it. That’s why I say it is still a work in progress.