Is Alzheimer’s more common, or different, in black Americans? Or do cerebrovascular risk factors account for much of that community's disproportionate dementia burden? There’s too little data to know, because minorities are underrepresented in observational and therapeutic studies on Alzheimer’s disease and related dementias. That may soon change. Researchers across the federally funded Alzheimer’s Disease Centers are being asked to step up recruitment and retention in culturally sensitive, community-building ways. A recent workshop at Washington University, St. Louis, saw lively debate of the issue, and those interested in studying minority recruitment can apply for a R24 grant dedicated to the topic. Read Gabrielle Strobel’s two-part report.
Alzheimer’s Researchers Seek Advice on How to Include African-Americans
On October 10th, nine days before the National Institutes on Aging released a national strategy document on inclusion and representation of minority participants in research into Alzheimer's disease and related dementias (ADRD), 394 stakeholders gathered to discuss the issue at the Charles F. and Joanne Knight Alzheimer’s Disease Research Center at Washington University, St. Louis. Convened by WashU’s John Morris and colleagues, the assembled audience focused on how to boost participation specifically of African-Americans and other black Americans in Alzheimer’s research studies across the country. Representatives of all 30 federally funded Alzheimer’s Disease Centers (ADCs) sat next to patient advocates, funders, clinicians, and scientists who study recruitment and retention of minority participants.
They had frank discussions of what works, what doesn’t, and what needs to be done. The frankness was at times discomforting to some. It also drew praise. “I have been at plenty of meetings on race and research, where things were talked around but never addressed,” said Stephen Thomas, a professor of health services administration at University of Maryland, College Park.
The problem is beyond dispute. Even as black Americans are disproportionately affected by Alzheimer’s and related dementias, they participate in research studies on ADRDs at far below their population fraction of about 13 percent nationally across all age groups. For example, African-Americans contribute only 3.7 percent of autopsy data collected at the National Alzheimer’s Coordinating Center, aka NACC. Even when they do join a study, African-American participants decline tissue sample donation, and leave studies early, at higher rates than whites. “We all agree this is not where we want to be,” said Krista Moulder, executive director of the WashU ADRC.
This underrepresentation means data are lacking on whether AD or other dementias unfold in the same way or differently in black versus white, Latino, or Asian people. Social determinants are thought to be important, and some biological differences may exist. For example, there appear to be differences in CSF tau and sVCAM1, a leukocyte biomarker of brain aging and neuroinflammation. But data sets are tiny; they need replication and deeper exploration in larger, independent samples that do not yet exist (for more on research results, see Part 2 of this series)
African-American underrepresentation is also common in therapeutic trials across disease areas, including Alzheimer’s and cancer (Chen & Wong, ProPublica 2018). The recent Expedition Phase 3 program for solanezumab, for example, included only 1.6 percent African-American participants. Some drug sponsors make additional funds available to recruit black participants, but often, trial sites fail to meet desired quotas. This means when a drug finally works, doctors won’t know if it works as well, or better or worse, for their black patients.
Taking note of the problem, the National Institute of Health in November 2017 tightened policy around the Revitalization Act, which was first issued in 1993 to mandate inclusion of women and minorities. The law was updated once before, in 2000. On including women in dementia research, great strides have been made since then. These days, women typically are at parity in clinical trials and are often a majority in observational studies. For African-Americans, some progress has been made, said Rachel Whitmer of the University of California, Davis. But not enough.
The solution would seem obvious—increase recruitment and retention. But that’s easier said than done. A legacy of exploitation by medical science has left especially older African-Americans distrustful of research, and this feeling is confounded for many by a continuing experience of racism today. “You can’t simply mail a flyer and expect that black people will come to your center,” said Lisa Barnes at Rush University, Chicago.
That said, barriers to research participation can be overcome, as illustrated by examples of success that dominated the workshop. In essence, recruiting and retaining minority participants requires a dedicated, sustained, funded effort. Cycles of engaging, giving, and fostering relationships are key, as is cultural competency. “Respect is the minimum. We also must understand the population that we want to study,” said Crystal Glover, also at Rush. A recruiter at the University of Pittsburgh Medical School told Alzforum that with each potential participant, she invests time for multiple personal contacts. She answers their phone calls at all hours, trying to get to know them, learn what’s important in their lives, and address concerns in a personalized way.
The commitment, the money, and the teeth behind recruiting and retaining more minorities are there. At NIA, Cerise Elliott is a program director who focuses on health disparities. This past May, Elliott issued a request for applications for an R24 grant to examine diversity, recruitment, and retention in aging research. Elliott works alongside Carl Hill, director of NIA’s Office of Special Populations. He oversees the Butler-Williams Scholars program, which funds young scientists interested in health disparities in aging. In St. Louis, Hill said that after a slow start, there is now hope that the minority gap can be closed for good. Elliott agreed. “I am thankful we are having this conversation today, so in the future we no longer need it,” she said. “In the future, inclusion, diversity, representation will be part of the scientific process and scientific literature,” Elliott added. Trying to engage a broader audience in their effort, NIA officers on October 23 hosted public discussion on Twitter at #researchdiversity.
To foster a generation of recruitment researchers, the Alzheimer’s Association sponsored 11 junior investigators’ travel to the workshop. Priorities for clinical, neuroscience, and biomarker research were hashed out in advance by working groups sponsored by the Cure Alzheimer’s Fund, and led by Morris and Moulder. Afterwards, WashU’s ADRC has posted a video recording of the workshop on its website. In the near future, Morris said, the organizers will publish a formal report to serve as a reference for the field at large of which recruitment strategies appear to work at some sites in the country already.
The organizers also hope to develop multicenter recruitment and retention protocols that can be formally tested. “Recruitment is a science,” said Barnes, who encouraged the researchers in the room to make a pitch for the R24. Toward that end, Roger Wong, a social work and occupational health researcher who works with Susy Stark at WashU, presented a literature review of published minority recruitment and retention methods in the field. Stark then primed the pump by offering for discussion a straw-man proposal for a multicenter protocol to determine and standardize best practices.
The WashU ADRC has been a leader in including African-Americans in AD research, said Joyce Balls-Berry, Mayo Clinic Rochester, Minnesota. The evening before the workshop, Balls-Berry and Hill spoke at the 13th annual public lecture in honor of Norman R. Seay, a veteran Civil Rights leader in St. Louis. Morris approached Seay soon after taking over WashU’s ADRC in 1997, when he realized he needed to diversify its work. In the year 2000, Seay convened an African-American Advisory Board for the center, on which he still serves. The board helped WashU ADRC grow its African-American representation from 3 percent at the time to 18 percent now (Williams et al., 2010; Williams et al., 2011).
Even so, Morris said, African-Americans participate less fully in WashU studies. More black than white people drop out of WashU studies, and though blood draws and brain scans are increasingly acceptable to black participants, their 38 percent CSF donation rate is half that of non-Hispanic whites. What’s more, fewer black than white people donate their brains for autopsy, at WashU and elsewhere (Boise et al., 2016). “We are not addressing all of the concerns needed for full participation,” Morris said.
In 2004, when the ADRC started an intensive biomarker study that required lumbar puncture, the center’s African-American enrollment plummeted. Two years later, Morris dropped this requirement for blacks only and regained 18 percent representation. “We hope that if we do not require lumbar puncture for enrollment, and if African-Americans participate for some time, we may gain their trust and will be better able to explain the rationale for spinal fluid sampling and answer all questions,” Morris said. The hope is this will generate more CSF donation over time.
What Works? Do Research Before the Research
Looking beyond WashU’s record, ongoing community engagement emerged as the prevailing theme at this workshop. Sites that have built thriving research programs in black communities are doing far more than issuing study invitations, scheduling appointments, and executing assessments. They invest effort getting to know black communities in their catchment area, and meeting some of their needs before they ask prospective participants to join an invasive dementia study. This can take years of active, structured work.
The work is necessary because the barriers to research participation among African-Americans are manifold. One is lingering distrust of medical institutions, said Balls-Berry. It was engendered not only by the infamous Tuskegee project that withheld syphilis treatment from infected men in Alabama, but also by other instances of abusive medical experimentation on African-Americans, especially their boys (e.g., Washington H, Medical Apartheid, 2008). “We still feel the consequences,” said Glover.
For many African-Americans, the cultural memory of medical science evokes fear. This is a far cry from the feeling of empowerment, and agency in a shared fight against a common foe, that researchers like to associate with study participation. Barriers to joining research exist at the systemic, community, institutional, interpersonal, and even intrapersonal level, Glover said. They stem from stigma and low self-esteem, educational disparities, or lack of transportation, to name a few. In essence, the barriers mean that successful research inclusion, to many African-American people, is a broader concept that requires listening to them and even making their needs an integral part of the process. Balls-Berry, Hill, and Glover all urged the audience to acknowledge the silencing that has resulted from historical oppression and continuing health disparities.
Some centers have made this work. In the Chicago metropolitan area, Barnes has built two cohort studies that together enrolled 1,000 African-Americans without dementia into observational research. Called Minority Aging Research Study (MARS) and Rush Clinical Core (CORE), they require annual clinical/cognitive exams using batteries harmonized with other studies at Rush so that results can be compared across race.
How about biomarkers? Barnes considers them a priority. “As we move in our field toward a biological definition of AD, in which the disease is defined by pathology that can be documented by postmortem autopsy or biomarkers, we have to ask what does this mean for older African-Americans who are not usually included in biomarker studies? There are few biomarker studies with African-Americans, and at Rush we are working hard to change that,” Barnes said. MARS and CORE do not request CSF, but everyone gives blood. Brain donation, which is optional, is creeping up as participants become engaged and build trust together with the researchers. Thus far, more than half of participants have expressed interest, a similar rate as at WashU, and 70 brains have come to autopsy, Barnes said.
Barnes stressed that researchers must work in the community before making organ requests. Her team uses Glover’s NGAGE model, which stands for Network, Give first, Advocate for research, Give back, Evaluate. In practice, this means meeting with African-American community leaders, partnering in health fairs, engaging early study participants as “ambassadors,” sharing research updates with individual participants and the community, and doing pre- and post-enrollment surveys. The Rush team fosters bidirectional community relationships through a range of activities that support the community’s needs. A social worker on the team connects people to services. Indeed, Elliott encouraged the audience to include funds for a social worker and community support services in their R24 NIA grant application.
Barnes highlighted the cyclical nature of this “research-before-the-research.” Engaging and supporting the community builds opportunities to educate, encouraging interest to join a study down the line. Regardless of whether a person agrees to a specific test, answering every one of their questions builds the trust that allows the scientist to explain how their blood will be used, or why lying in a scanner will eventually benefit the volunteer, their loved ones, or the wider African-American community.
Equally important is sustainability, Barnes said. To make staying with the study easier for participants, her research staff visit them in their homes for cognitive and clinical exams, and the study pays transportation for brain-imaging visits. The team has a retention specialist whose job it is to come up with creative ways to foster people’s motivation to return; this can take the form of tokens of appreciation, checking in between visits, greeting cards for special occasions, etc.
Finally, it’s critical that the staff be culturally competent. At least some of them should be African-American, and all must be comfortable working in prospective participants’ neighborhoods. At the St. Louis workshop, a black recruiter spoke about motivating community elders to visit the center, only to have a perceived insensitivity on the part of white center staff make them turn back. It helps if the staff is aware of social and cultural risk factors of the participants they interact with, perhaps birth region, early life conditions, and quality of education. Participants, investigators, and staff should know each other. When Barnes started MARS in 2004, she visited every study volunteer at home. “Research participation is a lived experience. It is what works for us in Chicago,” Barnes said.
In North Carolina, Goldie Byrd, while working at North Carolina A&T State University in Greensborough, created its Center for Outreach in Alzheimer’s, Aging, and Community Health. COAACH enables recruitment as part of a broader mission to improve literacy, care, training, and research on aging-related diseases. At the St. Louis workshop, Byrd, who last September became director of the Maya Angelou Center for Health Equity at Wake Forest University in nearby Winston-Salem, reviewed the prep work required to be able to start genetics research. Though ApoE4 is more frequent in African-Americans than non-Hispanic whites, the allele increases AD risk less in African-Americans than it does in whites. Not enough samples exist to work out the reason for this apparent contradiction, or to explore AD genetics in African-Americans more broadly.
A geneticist by training, Byrd knew she needed to put community before genetics research. She ran a feasibility study with 500 intergenerational local people. Two-thirds were under 40, and three-quarters had less education than a bachelor’s degree. Lo and behold, a majority said they wanted to participate in research, with the number reaching 85 percent among 18- to 24-year-olds. They were motivated by having a relative with the disease, and the younger people by monetary compensation. “These surveys are much more positive than the common perception that African-Americans won’t participate. They want to,” Byrd told the audience. Pedigrees of local families showed that some have a high burden of Alzheimer’s, yet they are not fully aware of the disease’s role in their family, Byrd said.
Having established both need and motivation, Byrd in 2013 created COACCH with a grant from the Merck Foundation. Its all-black staff host support groups, educational luncheons, galas, town hall meetings, an annual caregiver education conference, celebrity events, and a program that connects family members to web-based resources and health information. “Our recruitment went through the roof,” Byrd said. People stick with it, too. Retention stands above 90 percent, as people derive a sense of dignity and meaning from their work with the center.
In Atlanta, a successful recruitment hub is called Registry for Remembrance. Built as a partnership between the Emory University ADRC and its local community, the registry informs black elders about cognitive disorders and engages them in ADRD research. Speaking in St. Louis, William Hu at Emory noted that the registry started in response to focus groups that, like Byrd, had found black citizens in and around Atlanta were interested in volunteering for AD research. By 2011, it had enrolled 130 participants. The post-2008 NIA funding crunch delayed comprehensive phenotyping until 2012, when Hu got an R21 grant in for that purpose.
Hu noted that while he is keen to get to know his study participants personally, early registry members who champion the study in their community are more effective recruiters. Like Barnes and Byrd, Hu found that returning information in the form of newsletters, forums, and luncheons is critical to retain volunteers. He found differences to Glover and Balls-Berry’s experience in that his volunteers rarely bring up Tuskegee when they decline biomarker procedures. Hu showed that fear of side effects from a lumbar puncture, and claustrophobia about entering a scanner, were the only two factors that prompted more black than white research volunteers at Emory to say no (Howell et al., 2016).
In Portland, creating a culture of belonging was the primary goal of Raina Croff at the Layton Aging and Alzheimer’s Disease Center at Oregon Health & Science University. Croff approached engaging African-Americans in brain health research from a cultural perspective. She heard from black elders that gentrification had displaced them from their former Portland neighborhood to less-walkable suburbs, cutting them off from their social networks and physical activity. So Croff’s all-black team developed maps of 72 walks in those formerly black neighborhoods, annotated the maps with markers celebrating black history there from 1940 to 2010, and put them on iPads for small groups of volunteers to use together. Croff measured health indicators such as mood and cognitive status before and after the walking program. Besides improving mood and MoCA scores, the group walks engendered in the participants a sense of belonging and pride in the center’s work, which may motivate further participation in subsequent research studies (Croff et al, 2018).
In New York City, Jennifer Manly of Columbia University has built trusting relationships with participants in the Washington-Heights Inwood Community Aging Project, which has been recruiting African-Americans in northern New York City since 1989. Like Barnes, Manly visited participants in their homes in her early work with WHICAP. Getting to know them personally gave her an opening to ask about their childhood and youth, where Manly places the origin for social determinants of dementia (see Part 2).—Gabrielle Strobel
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- Williams MM, Meisel MM, Williams J, Morris JC. An interdisciplinary outreach model of African American recruitment for Alzheimer's disease research. Gerontologist. 2011 Jun;51 Suppl 1:S134-41. PubMed.
- Boise L, Hinton L, Rosen HJ, Ruhl MC, Dodge H, Mattek N, Albert M, Denny A, Grill JD, Hughes T, Lingler JH, Morhardt D, Parfitt F, Peterson-Hazan S, Pop V, Rose T, Shah RC. Willingness to Be a Brain Donor: A Survey of Research Volunteers From 4 Racial/Ethnic Groups. Alzheimer Dis Assoc Disord. 2016 Oct 24; PubMed.
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Do African-Americans Have More, or Different, Alzheimer’s Disease? Too Little Data to Tell
- Alzheimer’s disease is twice as common among African-Americans than non-Hispanic whites. Or is it?
- African-Americans have greater cerebrovascular risk factors. Do those lead to AD, or to vascular or mixed dementia?
- African-Americans have differences in their CSF and ApoE. What do they mean?
- African-Americans live with adverse social determinants of health. Do they lead to Alzheimer’s as currently defined?
This is but a sampling of the scientific questions that researchers, patient advocates, and other stakeholders grappled with on October 10 at Washington University in St Louis. They met for a federally funded workshop called African-American Participation in AD Research: Effective Strategies. The sparse nature of the data available thus far to answer these and other questions highlighted that scientists across the country would be well-advised to emulate and expand local efforts that have been effective in engaging this important minority population (see Part 1 of this series).
According to a Brookings Institution analysis of projections by the U.S. Census Bureau, black people over 65 currently make up 9 percent of the U.S. population, and their share will grow to 13 percent by 2060 (Frey et al., 2012). These demographics mask higher population fractions in parts of large cities such as New York or Chicago, and mid-size cities such as St. Louis, Detroit, and many other urban areas. And yet black people consistently make up a far lower proportion of participants in observational studies and clinical trials, meaning even basic questions remain unanswered for this population.
For starters, whether Alzheimer’s is more common in African-Americans remains unclear. Some population-based or memory clinic cohorts report a black AD incidence twice that of whites (e.g. Tang et al., 2001; Weuve et al., 2018). But other recent data suggest racial differences may not be as large as previously thought. Rachel Whitmer of the University of California, Davis, School of Medicine, studies electronic health records of patients in the Kaiser Permanente health care system. This approach allows her to tap new populations unlikely to participate in research, such as rural people or people with diabetes-related low-blood-sugar episodes who are too sick to join studies. Analyzing dementia incidence between the years 2000 to 2013 among 274,283 members of Kaiser Permanente, Whitmer was surprised to discover that while Asian Americans, at 15 percent, had the lowest rate of all racial groups, the difference between blacks (26 percent) and whites (19.3 percent) was smaller than she had expected (Mayeda et al., 2016).
The issue remains obscure because some studies use all-cause dementia or a clinical diagnosis as an outcome, while others use an etiological definition of Alzheimer’s disease marked by its signature postmortem neuropathology or biomarkers. Equating different forms of dementia makes it difficult to isolate cerebrovascular from amyloid- and tau-related pathways, cautioned David Knopman from the Mayo Clinic, Rochester, Minnesota. The use in dementia diagnosis of cognitive testing against population norms may further skew prevalence numbers on African-Americans, some of whom underperform on those tests as a result of growing up with educational disparities (Barnes and Bennett, 2014).
One attempt at understanding environmental influences on dementia came from Sujuan Gao, a biostatistician at Indiana University School of Medicine, Indianapolis. Gao summarized incidence results from a longstanding study comparing brain aging in some 4,100 African-Americans from around Indianapolis to 4,400 Yoruba people in the city of Ibadan, Nigeria. The study enrolled a first wave of volunteers in 1992 and a second in 2001, and has conducted up to seven follow-up observations with them by now. Led in the U.S. by Hugh Hendrie, also at University of Indiana, this observational cohort put the incidence of Alzheimer’s disease among African-Americans in Indiana at more than twice that of the Nigerian volunteers. In addition, their measures of hypertension, diabetes, stroke, smoking, cholesterol, and body-mass index were higher than those of the Yoruba.
Intriguingly, the later-born cohort enrolled in 2001 had a steep reduction in AD incidence relative to the first cohort among African-Americans, but stayed constant in the Yoruba. What had changed, Gao asked? For the second Indiana cohort, years of education and white-collar jobs had gone up, while rural upbringing and smoking had gone down. The participants’ hypertension and diabetes rates had risen, but they received medical treatment for those risk factors.
Analyzing each factor individually, Gao showed that blood-pressure-lowering medication in particular brought down risk of AD. Statin treatment did, too, though it was unclear if the protection worked through lowering blood cholesterol levels, as those remained high.
Diabetes was more frequent and more severe among the American than Nigerian study participants. When the researchers added participants’ electronic health records to the study’s own data, they discovered that people who were developing dementia had a notable decline in their previously elevated blood glucose levels during the five years before they became symptomatic. A subsequent comparison with white people in the U.S. showed that this pre-dementia blood glucose decline appeared to be particular to African-Americans (Hendrie et al., 2017; Hendrie et al., 2018). In an ongoing WashU biomarker study (see below), the plasma glucose marker hemoglobin A1c was elevated at baseline in cognitively normal African-Americans relative to otherwise matched non-Hispanic whites, but no follow-up data are available yet to assess change over time.
Taken together, Gao believes that the declining rates of dementia among African-Americans in the Indiana-Ibadan cohort reflect both improved life course determinants and better medical management of cerebrovascular risk factors, especially hypertension.
Whitmer noted that previous studies have underestimated the effect of high blood pressure on cognitive aging in African-Americans, because a shorter life expectancy exacerbates their underrepresentation in epidemiological aging studies (Mayeda et al., 2016). A selective survival bias occurs because health disparities accelerate aging in African-Americans, said Jennifer Manly of Columbia University, New York. This shortens life span in some, for example due to complications of hypertension; which, in turn, distorts racial comparisons of cognitive function in old age (Zahodne et al., 2016; Barnes and Bennett, 2014). Manly considers longer education to be the factor that may have had the greatest impact in the later-born Indiana-Ibadan cohort. Her analyses of the longstanding observational Washington Heights-Inwood Community Aging Project (WHICAP) cohort in north Manhattan also showed less memory decline in later-born people who received more education.
At the workshop, Lisa Barnes of Rush University, Chicago, briefly previewed emerging results from her ongoing cohort studies of brain aging in African-Americans in the Chicago metropolitan area (see Part 1). Her data tend to support the importance of both cerebrovascular health and cognitive reserve due to life course factors. Barnes’ team sees that black participants appear to be particularly vulnerable to microinfarcts, i.e., microvascular lesions in the brain that are visible on MRI. Compared with white participants in comparable studies at Rush, dementia in African-Americans rose more steeply with the number of microinfarcts they had.
What about neuropathology? Brain donation rates are increasing in the Rush study, though the 70 autopsies conducted to date still offer only a small data set. Thus far, Barnes said, pathology comparisons between racial groups indicate that black study volunteers without dementia at baseline are not much different from whites. Among people who had dementia, however, more blacks than whites had mixed pathology consisting of amyloid plaques, neurofibrillary tangles, infarcts, Lewy bodies, and arteriolar sclerosis; fewer blacks than whites had “pure” AD, i.e., only plaques and tangles (Barnes et al., 2015).
Genetically, too, no large differences between African-Americans and Caucasian people have emerged. The genetic architecture of aging-related cognitive decline is similar overall. Advanced sequencing techniques are yielding some variants, for example in the ABCA7 gene. But none have jumped out for a large effect size or high frequency. Neither have any picked up momentum by repeated confirmation in independent sample sets, or caught researchers’ imaginations for suggesting a tangible biological mechanism that might be unique to African-Americans (e.g. Raj et al., 2017; Mez et al., 2017; Cukier et al., 2016; Kunkle et al., 2017).
Goldie Byrd of Wake Forest University, Winston-Salem, North Carolina, a co-author on many of these papers, told Alzforum that she suspects differences in ADRD between black and white Americans have less to do with genetics and more with the long-term health consequences of living with racism. Some researchers at the workshop called for more research on neuronal, vascular, and immunological mechanisms of chronic stress.
What about biomarkers? Little is known about differences in African-Americans specifically because available data sets are so small, said John Morris of Washington University St. Louis, who hosted the workshop. However, researchers presented unpublished findings that spurred much interest.
One study is being led by William Hu of Emory University, Atlanta. Hu recalled that his interest in biologic differences was sparked during his neurology residency at the University of Pennsylvania in Philadelphia, where researchers incorporate CSF tests into their diagnostic workups for people with clinical signs of Alzheimer’s disease. “Often, African-Americans did not have the CSF results that would make me comfortable telling them they had AD. This made me curious,” Hu said. Did they have something else that presented clinically as AD? Was it vascular dementia mixed with AD? Or was there something truly different in how their AD developed?
Once at Emory, Hu started a biomarker study with the university’s research registry for African-Americans. It currently follows 135 older black people whose cognition ranges from normal to mild dementia. Hu has two papers under review or in preparation; at the workshop he only hinted at the overall finding. While some CSF analytes are the same among black and white participants—Aβ42, NfL, sICAM-1, sAPPα, and sAPPβ—other markers differ. These include total tau, phospho-tau 181, the neuroinflammation marker vascular cell adhesion molecule 1 (sVCAM-1, July 2018 conference news), the endopeptidase neprilysin, and others.
A previous data freeze on 65 registry participants is published. It indicated that while otherwise matched black and white volunteers had comparable levels of CSF Aβ42 and Aβ42/Aβ40 ratio, black participants had lower levels of CSF tau and more white-matter hyperintensities. That paper suggested that cerebrovascular factors tend to play a larger role in cognitive impairment in African-Americans than in Caucasians (Howell et al, 2017). The new data support this trend. “We now have many analytes that are different between older healthy African-Americans and whites,” Hu said in St. Louis.
Converging evidence from WashU is currently in press. In St. Louis, WashU’s Morris showed a cross-sectional analysis of 903 participants 45 and older, including 87 African-Americans, all of whom were comprehensively assessed from 2004 to 2015 with at least one MRI, amyloid PET, and CSF assays for Aβ42 and tau. This presentation did not include neurovascular CSF analytes such as sVCAM-1; even so, the canonical AD CSF signature confirmed and expanded Hu’s finding of same Aβ42 but lower tau.
The St. Louis area cohort, too, showed no difference in amyloid burden by race. In both black and white people, deposition increased with age. It was higher in ApoE4 carriers and as people approached the onset of dementia. The hippocampus was smaller in symptomatic people of both races. That said, CSF tau was different. Both total tau and phospho-tau were significantly lower in African-Americans than whites. Both analytes rose in the expected overall pattern, in that when a person was symptomatic his or her CSF tau was elevated. But the numeric tau values were always lower in African-Americans than in otherwise matched non-Hispanic whites.
Curiously, ApoE appeared to have the opposite effect on CSF tau in African-Americans than in whites. Among white people, as expected, CSF t-tau and p-tau are higher in those who carry the APOE4 AD risk allele than those who do not. Among African-Americans the opposite is true, whereby CSF t-tau and p-tau measurements came in lower when a person carried APOE4. This difference is intriguing because studies by other groups have reported that APOE4 does not boost AD risk equally across race. Even though ApoE4 is more frequent in African-Americans, it does not appear to drive up their AD risk much (e.g., Evans et al., 2003; Weuve et al., 2018).
At the workshop, scientists debated in the auditorium and hallways what Hu and Morris’s data might mean. Potential interactions between ApoE, tau, cholesterol, and neuroinflammatory pathways in microglia have become an active area of study (e.g. July 2018 conference news; Kang et al., 2018). Might there be a factor in African-Americans that protects against the downstream effect of amyloid deposition, or of ApoE, on tau? If so, this could point to a yet-unknown molecular mechanism that could yield therapeutic targets for Alzheimer’s disease. Alas, the Emory and WashU CSF data sets, while the largest available at this point, are still far too small to draw conclusions, Morris and Hu agreed. “We need a national cohort,” Hu said. The two centers are now collaborating.
A larger data set would also allow researchers to better understand layers of diversity among people of color in the U.S. more broadly. For example, recent black immigrants from Caribbean countries have quite different early life experiences than African-Americans whose families have been in the U.S. for generations, said Jonathan Jackson of Massachusetts General Hospital, Boston. Life experience could influence CSF measures; as could socioeconomic circumstances. Hu noted that participants from around the more affluent Emory University Medical School area may differ from those around Atlanta’s Grady Memorial Hospital, which serves an urban population with greater health disparities. The African-American participants in the WashU cohort had on average 13 years of education, which exceeds their average across the country, said Manly.
For her part, Manly considers adverse life course factors going back to childhood to be root causes for racial disparities in health and cognition as people age. On home visits to WHICAP participants, Manly learned that well over half of them were born in southern states in the U.S. She subsequently documented large education disparities. Black people born in the South had fewer years of school, fewer school days per year, and poorer-quality schools than white people born in the South, or than people born in northern states.
Childhood disadvantage carries forward into poor health in multiple ways. For example, Whitmer cited her group’s analysis of 7,423 members of Kaiser Permanente Northern California, including 1,354 black people. It found that being born in a southern U.S. state, in addition to being linked to stroke, also came with a higher risk of dementia, particularly among African-Americans, even though they had since moved to California. A subsequent analysis linking birth in a high infant mortality area to dementia risk reinforced the larger point that place of birth has enduring consequences on dementia risk (Gilsanz et al., 2017; Gilsanz et al., 2018).
While this workshop focused on African-Americans, understanding diversity in ADRD research is a broader challenge. For one thing, Latinos have even higher rates of dementia than black Americans (e.g., Mayeda et al., 2016). For another, diversity across urban and rural populations, socioeconomic status and cognitive reserve, is difficult to capture. “We want to have breadth, i.e., large populations that are diverse racially, educationally, and geographically. But we also want depth, i.e., brain images, plasma, and CSF. Doing both is hard,” Whitmer said.
In AD therapeutic trials, where efficacy signals have been hard to discern, trialists generally want more tightly defined patient groups selected with biomarkers and phenotypic data that allow them to stratify trial results. They caution that more diversity, if it is poorly understood, may increase noise in the trial data. To understand diversity in Alzheimer’s disease, scientists at the WashU workshop called for larger longitudinal cohorts that track both AD and cerebrovascular biomarkers in diverse populations starting in mid-life, and for adding biomarker outcomes to existing aging cohorts.—Gabrielle Strobel
- Alzheimer’s Researchers Seek Advice on How to Include African-Americans
- VCAM1: Gateway to the Aging Brain?
- ApoE Has Hand in Alzheimer’s Beyond Aβ, Beyond the Brain
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