A randomized controlled trial of disclosing genetic risk information for Alzheimer disease via telephone.

PurposeTelephone disclosure of genetic test results can improve access to services. To date, studies of its impact have focused on return of Mendelian risk information, principally hereditary cancer syndromes.MethodsIn a multisite trial of Alzheimer disease genetic risk disclosure, asymptomatic adults were randomized to receive test results in person or via telephone. Primary analyses examined patient outcomes 12 months after disclosure.ResultsData from 257 participants showed that telephone disclosure occurred 7.4 days sooner and was 30% shorter, on average, than in-person disclosure (both P < 0.001). Anxiety and depression scores were well below cutoffs for clinical concern across protocols. Comparing telephone and in-person disclosure protocols, 99% confidence intervals of mean differences were within noninferiority margins on scales assessing anxiety, depression, and test-related distress, but inconclusive about positive impact. No differences were observed on measures of recall and subjective impact. Subanalyses supported noninferiority on all outcomes among apolipoprotein E (APOE) ɛ4-negative participants. Subanalyses were inconclusive for APOE ɛ4-positive participants, although mean anxiety and depression scores were still well below cutoffs for clinical concern.ConclusionTelephone disclosure of APOE results and risk for Alzheimer disease is generally safe and helps providers meet demands for services, even when results identify an increased risk for disease.

Disclosing Pleiotropic Effects During Genetic Risk Assessment for Alzheimer Disease: A Randomized Trial.

BACKGROUND: Increasing use of genetic testing raises questions about disclosing secondary findings, including pleiotropic information. OBJECTIVE: To determine the safety and behavioral effect of disclosing modest associations between apolipoprotein E (APOE) genotype and coronary artery disease (CAD) risk during APOE-based genetic risk assessments for Alzheimer disease (AD). DESIGN: Randomized, multicenter equivalence clinical trial. (ClinicalTrials.gov: NCT00462917). SETTING: 4 teaching hospitals. PARTICIPANTS: 257 asymptomatic adults were enrolled, 69% of whom had 1 AD-affected first-degree relative. INTERVENTION: Disclosure of genetic risk information about AD and CAD (AD+CAD) or AD only (AD-only). MEASUREMENTS: Primary outcomes were Beck Anxiety Inventory (BAI) and Center for Epidemiologic Studies Depression Scale (CES-D) scores at 12 months. Secondary outcomes were all measures at 6 weeks and 6 months and test-related distress and health behavior changes at 12 months. RESULTS: At 12 months, mean BAI scores were 3.5 in both the AD-only and AD+CAD groups (difference, 0.0 [95% CI, -1.0 to 1.0]), and mean CES-D scores were 6.4 and 7.1 in the AD-only and AD+CAD groups, respectively (difference, 0.7 [CI, -1.0 to 2.4]). Both confidence bounds fell within the equivalence margin of ±5 points. Among carriers of the APOE ε4 allele, distress was lower in the AD+CAD groups (difference, -4.8 [CI, -8.6 to -1.0]) (P = 0.031 for the interaction between group and APOE genotype). Participants in the AD+CAD groups also reported more health behavior changes, regardless of APOE genotype. LIMITATIONS: Outcomes were self-reported by volunteers without severe anxiety, severe depression, or cognitive problems. Analyses omitted 33 randomly assigned participants. CONCLUSION: Disclosure of pleiotropic information did not increase anxiety or depression and may have decreased distress among persons at increased risk for 2 conditions. Providing risk modification information about CAD improved health behaviors. Findings highlight the potential benefits of disclosure of secondary genetic findings when options exist for decreasing risk. PRIMARY FUNDING SOURCE: National Human Genome Research Institute.

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

INTRODUCTION: Conventional multisession genetic counseling is currently recommended when disclosing apolipoprotein E (APOE) genotype for the risk of Alzheimer's disease (AD) in cognitively normal individuals. The objective of this study was to evaluate the safety of brief disclosure protocols for disclosing APOE genotype for the risk of AD. METHODS: A randomized, multicenter noninferiority trial was conducted at four sites. Participants were asymptomatic adults having a first-degree relative with AD. A standard disclosure protocol by genetic counselors (SP-GC) was compared with condensed protocols, with disclosures by genetic counselors (CP-GC) and by physicians (CP-MD). Preplanned co-primary outcomes were anxiety and depression scales 12 months after disclosure. RESULTS: Three hundred and forty-three adults (mean age 58.3, range 33-86 years, 71% female, 23% African American) were randomly assigned to the SP-GC protocol (n = 115), CP-GC protocol (n = 116), or CP-MD protocol (n = 112). Mean postdisclosure scores on all outcomes were well below cut-offs for clinical concern across protocols. Comparing CP-GC with SP-GC, the 97.5% upper confidence limits at 12 months after disclosure on co-primary outcomes of anxiety and depression ranged from a difference of 1.2 to 2.0 in means (all P < .001 on noninferiority tests), establishing noninferiority for condensed protocols. Results were similar between European Americans and African Americans. CONCLUSIONS: These data support the safety of condensed protocols for APOE disclosure for those free of severe anxiety or depression who are actively seeking such information.

Digging Deeper: What Can We Really Learn about Dementia from History?

In response to Finch and Burstein's provocative argument that the advanced dementias may result from environmental toxins and lifestyle factors associated with post-industrial societies, we call for a more rigorous historical approach, emphasizing the importance of situating ancient texts more fully in their historical and cultural context. Such an approach would also entail consideration of the declining relative rates of dementia in Western countries, which have been linked to population health-level factors and policies that appear to have reduced the risk of dementia by directly and indirectly influencing the social determinants of brain health.

Disclosure of APOE genotype for risk of Alzheimer's disease.

BACKGROUND: The apolipoprotein E (APOE) genotype provides information on the risk of Alzheimer's disease, but the genotyping of patients and their family members has been discouraged. We examined the effect of genotype disclosure in a prospective, randomized, controlled trial. METHODS: We randomly assigned 162 asymptomatic adults who had a parent with Alzheimer's disease to receive the results of their own APOE genotyping (disclosure group) or not to receive such results (nondisclosure group). We measured symptoms of anxiety, depression, and test-related distress 6 weeks, 6 months, and 1 year after disclosure or nondisclosure. RESULTS: There were no significant differences between the two groups in changes in time-averaged measures of anxiety (4.5 in the disclosure group and 4.4 in the nondisclosure group, P=0.84), depression (8.8 and 8.7, respectively; P=0.98), or test-related distress (6.9 and 7.5, respectively; P=0.61). Secondary comparisons between the nondisclosure group and a disclosure subgroup of subjects carrying the APOE epsilon4 allele (which is associated with increased risk) also revealed no significant differences. However, the epsilon4-negative subgroup had a significantly lower level of test-related distress than did the epsilon4-positive subgroup (P=0.01). Subjects with clinically meaningful changes in psychological outcomes were distributed evenly among the nondisclosure group and the epsilon4-positive and epsilon4-negative subgroups. Baseline scores for anxiety and depression were strongly associated with post-disclosure scores of these measures (P<0.001 for both comparisons). CONCLUSIONS: The disclosure of APOE genotyping results to adult children of patients with Alzheimer's disease did not result in significant short-term psychological risks. Test-related distress was reduced among those who learned that they were APOE epsilon4-negative. Persons with high levels of emotional distress before undergoing genetic testing were more likely to have emotional difficulties after disclosure. (ClinicalTrials.gov number, NCT00571025.)

Making the Case for the Accelerated Withdrawal of Aducanumab.

U.S. Food and Drug Administration-s (FDA) approval of aducanumab (Aduhelm® in the US) as a treatment for mild cognitive impairment of the Alzheimer type and Alzheimer-s disease has raised such major concerns about efficacy, safety, FDA processes, and regulatory capture that Biogen-s license to market this biologic should be immediately withdrawn. Aducanumab has not demonstrated benefit to patients, failed to meet regulatory guidelines, and is likely to cause both individual and societal harm.

The evolving classification of dementia: placing the DSM-V in a meaningful historical and cultural context and pondering the future of "Alzheimer's".

Alzheimer's disease is a 100-year-old concept. As a diagnostic label, it has evolved over the 20th and 21st centuries from a rare diagnosis in younger patients to a worldwide epidemic common in the elderly, said to affect over 35 million people worldwide. In this opinion piece, we use a constructivist approach to review the early history of the terms "Alzheimer's disease" and related concepts such as dementia, as well as the more recent nosological changes that have occurred in the four major editions of the Diagnostic and Statistical Manual since 1952. A critical engagement of the history of Alzheimer's disease and dementia, specifically the evolution of those concepts in the DSM over the past 100 years, raises a number of questions about how those labels and emergent diagnoses, such as Neurocognitive Disorders and Mild Cognitive Impairment, might continue to evolve in the DSM-V, due for release in 2013.

Ethical issues in early diagnosis and prevention of Alzheimer disease.

This paper considers ethical issues related to early diagnosis and all forms of prevention of Alzheimer disease and related conditions. It offers a critical view of the current state of scientific, clinical, and social responses to the growing number of older people with cognitive challenges, and suggests how priorities going forward should be different from those receiving most attention today. We begin with a review of global policy efforts, consider the fundamental goals of prevention, examine issues surrounding early diagnosis, explore more deeply values associated with efforts to prevent age associated cognitive decline, and conclude by considering often unexplored ethical issues that contextualize the field and should influence our approaches to the future.

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

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 ethnicity-specific 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 Americans. CONCLUSION: The Risk Evaluation and Education for Alzheimer Disease study provides an instructive example of a process to develop risk assessment protocols that are sensitive to the implications of genetic testing for multiple ethnic groups with differing levels of risk.

Health state valuation in mild to moderate cognitive impairment: feasibility of computer-based, direct patient utility assessment.

BACKGROUND: Most patients with dementia will, at some point, need a proxy health care decision maker. It is unknown whether persons with various degrees of cognitive impairment can reliably report their health-related preferences. METHODS: The authors performed health state valuations (HSVs) of current and hypothetical future health states on 47 pairs of patients with mild to moderate cognitive impairment and their caregivers using computer-based standard gamble, time tradeoff, and rating scale techniques. RESULTS: Patients' mean (SD) age was 74.6 (9.3) years. About half of the patients were women (48%), as were most caregivers (73%), who were on average younger (mean age= 66.2 years, SD= 12.2). Most participants were white (83%); 17% were African American. The mean (SD) Mini-Mental State Examination (MMSE) score of patients was 24.2 (4.6) of 30. All caregivers and 77% of patients (36/47) completed all 18 components of the HSV exercise. Patients who completed the HSV exercise were slightly younger (mean age [SD]= 74.1 [8.5] v. 75.9 [11.8]; P = 0.569) and had significantly higher MMSE scores (mean score [SD] = 25.0 [4.3] v. 21.4 [4.4]; P = 0.018). Although MMSE scores below 20 did not preclude the completion of all 18 HSV ratings, being classified as having moderate cognitive impairment was associated with a lower likelihood of completing all scenario ratings (44% v. 82%). Patient and caregiver responses showed good consistency across time and across techniques and were logically consistent. CONCLUSION: Obtaining HSVs for current and hypothetical health states was feasible for most patients with mild cognitive impairment and many with moderate cognitive impairment. HSV assessments were consistent and reasonable.

Global perspectives on dementia and art: An international discussion about changing public health policy.

In an era of global environmental deterioration and income inequity, public health faces many challenges, including the growing number of individuals, especially older people, with chronic diseases. Dementia is increasingly being seen not just as a biomedical problem to solve but as a public and community challenge to address more broadly. Concepts like prevention, brain health, and quality of life/well-being are receiving more attention. The engagement of community in addressing these challenges is being seen as critical to successful social adaptation. Arts programs are reinvigorating cultural responses to the growing number of older people with cognitive challenges. The humanities offer ways of understanding the power of words and stories in public discourse and a critical lens though which to view political and economic influences. In this paper, we report on a panel held in London on the occasion of the conference at the Royal Society for Public Health in March, 2017, in which the authors presented. Key issues discussed included problem framing, the nature of evidence, the politics of power and influence, and the development of effective interventions. In this paper, we review the rejection of two policies, one on dementia and one on the arts and humanities in public health, by the American Public Health Association; the emergence of policies in the UK; and some of the state of the art practices, particularly in training, again focusing on the UK.

Empirical assessment of a research advance directive for persons with dementia and their proxies.

OBJECTIVES: To evaluate a research advance directive for persons with established dementia diagnoses and their family caregivers or proxies. DESIGN: Prospective randomized, controlled trial. SETTING: Three clinics, one each in Ohio, Kentucky, and Illinois. PARTICIPANTS: At the end of separate interviews about enrollment choices in five types of hypothetical research projects, 149 persons with established dementia diagnoses and their family proxies were randomized to jointly complete the Planning Ahead Together (PAT) document, a research advance directive (n=69) or to remain in the control group (n=80). INTERVENTION: The directive was assessed at two points: immediately after sample members received naturally occurring invitations to participate in other studies and again 2 years after initial enrollment. MEASUREMENTS: Personal enrollment rates, reported ease of enrollment decision for patients and proxies, and proxy comfort were compared between the experimental and control groups. RESULTS: Forty-one dyads were reinterviewed immediately after consent discussions for other trials. Forty-seven patients and 106 proxies were interviewed at 2-year follow-up. There was no evidence immediately after a trial enrollment opportunity or in the follow-up interview that the research advance directive (PAT) assisted patients or proxies. Enrollment rates, decision ease, and proxy comfort and certainty were similar in the PAT and control groups. CONCLUSION: Patient and proxy experience making hypothetical decisions in the interview may have affected enrollment decisions by the PAT and control groups. Although the low number of recruitment attempts and the natural attrition of the geriatric population limit conclusions about effectiveness that may be drawn from this unique data set, the feasibility of a research advance directive is clearly demonstrated.

Quality of life: the bridge from the cholinergic basal forebrain to cognitive science and bioethics.

Our paper on loss of neurons in the Nucleus Basalis of Meynert (now considered part of the cholinergic basal forebrain) in Alzheimer disease (AD) stimulated scientific interest in this little studied brain region. Our subsequent studies associated pathology in the basal forebrain with other dementias, such as Parkinson's disease, and with neurotransmitter receptor changes, such as in nicotinic receptors. We and many others worked to develop medications to treat AD through cholinergic mechanisms and eventually four cholinesterase inhibitors were approved. However the effect sizes of currently available drugs are modest and ethical issues in conducting research in dementia are challenging. In Cleveland we came to focus on the goals of improving quality of life and the importance on non-pharmacological approaches to treatment. International efforts were organized to improve the efficiency of drug development and to focus on important cultural and pharmacoeconomic issues. Eventually I became concerned about the very way we conceive AD and related concepts like MCI (mild cognitive impairment). As the hundredth anniversary of the first case approaches I am helping to organize meetings to reflect deeply on what we have learned and how to imagine creating a more positive future for persons affected by what I used to call AD.