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.

Health-related resource use and costs in elderly adults with and without mild cognitive impairment.

OBJECTIVES: To assess differences in resource use and cost between older adults with and without mild cognitive impairment (MCI) over time. DESIGN: Multicenter, longitudinal study. SETTING: Sixty-eight Alzheimer's Disease Cooperative Study (ADCS) sites in the United States. PARTICIPANTS: Two hundred fifty-nine individuals diagnosed with MCI and 107 cognitively normal elderly adults followed annually for 3 years. MEASUREMENTS: The Resource Use Instrument (RUI) was used to capture medical and nonmedical care use. Generalized linear latent and mixed models were used to estimate differences in resource use and costs in older adults with and without MCI after controlling for clinical and demographic characteristics. RESULTS: At baseline, average annual direct medical cost per person was substantially higher for participants with MCI ($6,499) than for those without ($2,969) P < .001). Informal care use was also substantially higher (33% vs 8.4%, P < .001). Results from multivariate analyses of longitudinal data show that, after controlling for participant and informant characteristics, direct medical costs were 44% higher for participants with MCI than for those without. Participants with MCI were almost five times as likely to use informal care as those without. Number of medical conditions and older age were associated with higher medical cost. Worse functional and cognitive status, older age, being married, and being female were associated with higher likelihood of informal care use. Having an adult child informant was associated with higher likelihood of using informal care. CONCLUSION: The RUI captured differences in resource use and costs between individuals with and without MCI. Clinicians who care for individuals with MCI should address informal care needs early in the disease course.

Marketplace of memory: what the brain fitness technology industry says about us and how we can do better.

In the therapeutic void created by over 20 failed Alzheimer's disease drugs during the past decade, a new marketplace of "brain fitness" technology products has emerged. Ranging from video games and computer software to mobile phone apps and hand-held devices, these commercial products promise to maintain and enhance the memory, concentration, visual and spatial skills, verbal recall, and executive functions of individual users. It is instructive to view these products as sociocultural objects deeply imbued with the values and ideologies of our age; consequently, this article offers a critique of the brain fitness technology marketplace while identifying limitations in the capacity of commercial products to realistically improve cognitive health. A broader conception of brain health is presented, going beyond the reductionism of the commercial brain fitness marketplace and asking how our most proximate relationships and local communities can play a role in supporting cognitive and psychosocial well-being. This vision is grounded in recent experiences at The Intergenerational School in Cleveland, OH, a multigenerational community-oriented learning environment that is implementing brain fitness technology in novel ways.

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.

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.

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.

ADCS Prevention Instrument Project: overview and initial results.

One objective of the Alzheimer's Disease Cooperative Study (ADCS) is to develop new or improved instruments and assessment methods for evaluating treatment efficacy in Alzheimer disease (AD) clinical trials. The ADCS Instrument Committee has previously helped to define the state of the art in assessment for AD and Mild Cognitive Impairment clinical trials. We are now entering an exciting era of primary prevention trials to evaluate promising treatments that may delay disease onset and there is a need to develop appropriate instruments for these trials. The ADCS instrument committee has undertaken a project to develop instruments for prevention studies that assess domains known to be important in AD. Prevention trials are long and require large numbers of subjects, making them costly and requiring a high burden of participation for subjects. The current study focused on developing instruments that can be completed at home and in the clinic. The instruments are being evaluated in a cohort of nondemented elderly participating in a 4-year longitudinal study that simulates the design of a primary prevention trial. This report describes the design, baseline characteristics, and some longitudinal outcomes of the study cohort through the completion of the first 2 years of follow-up. We also describe the assessment domains to be measured with our new experimental instruments. This study recruited 644 subjects, 75 years of age and older. Participation in a "book club" that provided free books of interest to elders was offered as a recruitment incentive. Approximately 23% had some mild cognitive symptoms consistent with a Clinical Dementia Rating of 0.5. All subjects received a standardized in-clinic evaluation at baseline, which is repeated annually for 4 years to identify cases suspected of developing dementia and to measure longitudinal change on established clinical assessments. Subjects completed a set of self-administered experimental instruments at home or in the clinic designed to assess cognitive function and behavior, global change, activities of daily living, quality of life, and resource use. An additional "mail-in cognitive function questionnaire" was obtained separately by mail, 1 month before the other assessments. To evaluate the feasibility, efficiency, and validity of the home-based instruments in comparison with acquiring the same information during a clinic visit, subjects were randomized to 1 of 2 conditions in which the baseline and annual follow-up assessments are completed either at home ("home group") or at the study site during their clinic visits ("clinic group"). This initial report describes the ongoing 4-year longitudinal study and provides baseline results, which confirm the feasibility of obtaining home-based clinical information via mail or telephone. Initial results for the experimental instruments and for the book club are reported in separate accompanying articles.

ADCS Prevention Instrument Project: quality of life assessment (QOL).

Information about quality of life (QOL) is valuable in evaluating pharmaceutical agents but it is not adequately assessed in many dementia drug trials. In prevention trials, following participants to conversion to AD requires QOL scales appropriate for both normal and cognitively impaired individuals. Our objective was to evaluate the utility of several scales for subject or informant QOL assessment: Quality of Life-AD; Quality of Life Activity Inventory; SF-36; SF-12 (a shortened version of the SF-36); and Satisfaction with Life Scale. Measurements were collected from 644 subject-study partner pairs, half of whom completed the instruments at the clinic and half at home. Three-month test-retest data were collected. Scales administered at home or in clinic did not differ significantly. Subject self-ratings showed a wide range for all scales. Test-retest intraclass coefficients ranged from 0.67 to 0.77. Moderately high interscale associations suggest that the scales are measuring common aspects of QOL but are not equivalent. Furthermore, they differed with respect to associations with demographic variables and QOL determinants. We conclude that the QOL scores at baseline show sufficient range and reliability to suggest they will have utility in tracking QOL through conversion to dementia.

ADCS Prevention Instrument Project: pharmacoeconomics: assessing health-related resource use among healthy elderly.

BACKGROUND: The Prevention Instrument project of the Alzheimer's Disease Cooperative Study (ADCS) seeks to develop instruments to assess treatment efficacy including potential economic benefit. The Resource Use Inventory (RUI) is an instrument that has been used to capture resource utilization and costs in populations with Alzheimer disease (AD). However, resource utilization and costs for healthy, cognitively intact elderly as they begin to demonstrate cognitive deterioration are not well understood. In addition, the loss that relates to the subjects' own time as they transition through cognitive impairment is not well documented. OBJECTIVES: To evaluate the utility of the RUI in a sample of cognitively intact elderly individuals living in the community and enrolled in AD prevention trials. METHODS: The RUI was administered to 644 subjects and their study partners either at home or in the clinic. For half of each sample, 3-month retesting was carried out. The RUI consisted of 9 questions. The first part of the RUI captured subjects' use of direct medical care (eg, hospitalizations) and nonmedical care (eg, home health aides). The second part of the RUI captured the time caregivers spend providing care to the subjects. The third part of the RUI captured subjects' participation in volunteer work and employment. The assessment interval for each question was the past 3 months. RESULTS: The percentage of RUI forms returned incomplete or inaccurate for both in-clinic and at-home groups was extremely low. There were no differences in utilization rates between in-clinic and at-home group for all items in the RUI. Except for use of outpatient procedures, tests, or treatments, there were no differences in utilization rates between subjects who filled out the RUI with the help of their study partners or by themselves. Items in the RUI were sensitive to subjects' cognitive and functional status and demographic characteristics. CONCLUSIONS: Home-based completion of the RUI by participants in an AD prevention study is feasible, and seems to provide data that are reliable and valid. The instrument will be useful for tracking resource and time use through transition from healthy to cognitive impairment.

Genetic risk assessment for adult children of people with Alzheimer's disease: the Risk Evaluation and Education for Alzheimer's Disease (REVEAL) study.

As genetic risk factors continue to be identified for common, complex adult-onset diseases, it will become increasingly important to understand if, how, and when to translate these discoveries into clinical practice. This article provides an overview of and results to date from the REVEAL study, a multisite randomized clinical trial (n = 162) examining the impact of a genetic risk assessment program, including apolipoprotein E genotype disclosure, for adult children of people with Alzheimer's disease. The study's rationale and procedures are described, including the generation of numerical lifetime risk curves for use in the education and counseling protocol. Findings are summarized across numerous study questions, including (1) who seeks genetic risk assessment and why, (2) how apolipoprotein E results affect risk perceptions, (3) the psychological impact of genetic risk assessment, and (4) how risk information affects participants' subsequent health and insurance behaviors.

Antiaging medicine and mild cognitive impairment: practice and policy issues for geriatrics.

The claim that aging itself is treatable or even preventable has repeatedly been made over the centuries. Antiaging medicine is the current leader of approaches that even claim that geriatrics as a discipline will become increasingly unnecessary. The concept of mild cognitive impairment (MCI) as a condition intermediate between normal cognitive aging and Alzheimer's disease highlights the conceptual and practical difficulty of differentiating aging from disease. What should geriatricians and their organizations make of scientifically mainstream attempts to decelerate, arrest, or compress aspects of the normal human aging, including the brain aging process? This article reviews the political, philosophical, practice-related, and economical implications of antiaging medicine for geriatrics using MCI as a practical example. It concludes by suggesting actions that geriatricians should consider to strengthen their profession and to improve patient care in response to the challenges of longevity medicine.