Incorporating ethnicity into genetic risk assessment for Alzheimer disease: the REVEAL study experience

Abstract

Purpose: To describe how investigators in a multisite randomized clinical trial addressed scientific and ethical issues involved in creating risk models based on genetic testing for African American participants. Methods: The following informed our decision whether to stratify risk assessment by ethnicity: evaluation of epidemiological data, appraisal of benefits and risks of incorporating ethnicity into calculations, and feasibility of creating ethnicityspecific risk curves. Once the decision was made, risk curves were created based on data from a large, diverse study of first-degree relatives of patients with Alzheimer disease. Results: Review of epidemiological data suggested notable differences in risk between African Americans and whites and that Apolipoprotein E genotype predicts risk in both groups. Discussions about the benefits and risks of stratified risk assessments reached consensus that estimates based on data from whites should not preclude enrolling African Americans, but population-specific risk curves should be created if feasible. Risk models specific to ethnicity, gender, and Apolipoprotein E genotype were subsequently developed for the randomized clinical trial that oversampled African Researchers are identifying a growing number of genetic markers that are associated with increased or decreased risk for common, complex diseases. Consequently, the development of genetic risk assessment and risk communication strategies are areas of critical importance, especially given that laypersons often have a difficult time in understanding probabilistic information. 1,2 Protocols for disclosing genetic information have been developed and refined for various forms of cancer, 3-6 but similar efforts have been made only recently for other diseases. 7,8 One area of recent focus is Alzheimer disease (AD).AD is the most common form of dementia among the elderly, affecting an estimated five million individuals in the United States. Well over 10 million Americans are expected to have the condition by 2050 as the population continues to age. 9 Many risk factors are well-characterized, including age and family history, 10 -14 whereas many others are under investigation, including education level, 15,16 head trauma, 17,18 high blood pressure, 19 caloric intake, and high cholesterol. 20,21 Regarding genetic factors, rare mutations on genes coding for amyloid precursor protein, presenilin 1, and presenilin 2 have been identified that are deterministic for early-onset AD. 22 Apolipoprotein E (APOE), in contrast, affects susceptibility to AD and has three major forms. APOE ⑀3, the most common allele, is found in over half the US population. The ⑀4 allele is associated with increased risk for AD whereas the ⑀2 allele has a protective effect. 23,24 The ⑀4 allele is neither necessary nor sufficient for AD though, and individuals with the ⑀2 allele still have risk for AD. APOE variants are also associated with other conditions such as hyperlipoproteinemia and atherosclerosis 25 and may play a role in the development of ma...

A randomized noninferiority trial of condensed protocols for genetic risk disclosure of Alzheimer's disease

“…We selected European-American or African-American for enrollment because we had sufficient data to create ethnicity-specific risk models for these groups that incorporated APOE genotype. 5 Given ambiguous data about the relationship between APOE and AD for other ethnicities, 6,7 however, we excluded other populations.…”

“…5 The study was designed as a non-inferiority trial, despite inherent limitations of this approach, 14 because the goal of the study was develop a protocol that markedly reduced clinical service demands rather than one that improved outcomes that had already been shown to be safe. 1 The study was conducted at sites in academic medical centers in Boston, Cleveland, New York and Washington, DC.…”

“…1,5,15 In brief, all subjects were shown a single graph with gender and race-specific risk curves and were told their APOE genotype and numeric estimates of their cumulative lifetime (potential range: 13–77%) and remaining risk for AD (cumulative incidence from current age to the age of 85 years). A genetic counselor disclosed results to subjects in the SP-GC arm and in one condensed protocol arm (CP-GC), while a study physician disclosed results in the other condensed protocol arm (CP-MD).…”

Factors Affecting Recall of Different Types of Personal Genetic Information about Alzheimer's Disease Risk: The REVEAL Study

“…Disclosure of the APOE test results was performed by a genetic counselor during either a second in-person appointment or a telephone call. During disclosure, in sessions that lasted 16 minutes on average, genetic counselors verbally disclosed participants’ results using a scripted template, emphasizing participants’ genotypes, number of risk-increasing alleles, and numerical lifetime risk estimates expressed as percentages as described in prior reports [12-15]. Participants were also given written materials that included a risk curve depicting their lifetime risk for AD and a summary statement containing their APOE genotype, their estimated lifetime risk of AD, and the factors used to calculate their lifetime risk (see Supplementary Materials).…”

Interaction of Double-stranded RNA-dependent Protein Kinase (PKR) with the Death Receptor Signaling Pathway in Amyloid β (Aβ)-treated Cells and in APPSLPS1 Knock-in Mice

“…This neuronal loss distribution closely parallels the strong intraneuronal A␤ immunostaining and intracellular thioflavin-S-positive material but does not correlate with extracellular deposits (26). Therefore, we worked only with 3-month-old mice to examine abnormalities of death receptor signaling before neuronal loss.…”