Communicating Alzheimer's biomarker results to cognitively unimpaired research participants: Satisfaction, utility, and impact on research attitudes.

Introduction: Recruitment and retention pose a significant challenge to Alzheimer's disease (AD) research. Returning AD biomarker results to participants has been proposed as a means to improve recruitment and retention. We present findings related to participant satisfaction, utility, and impact on research attitudes from the amyloid positron emission tomography (PET) disclosure sub-study within the Wisconsin Registry for Alzheimer's Prevention (WRAP). Methods: Ninety-nine cognitively unimpaired WRAP participants learned their amyloid PET results (mean age ± SD = 72.0 ± 4.8). Measures of reasons for wanting to learn results, study comprehension, result utility, visit satisfaction, research attitudes, and future study enrollment willingness were collected. Between-group, chi-squared analysis was conducted to determine differences by result type (elevated vs. not elevated amyloid PET result) in study comprehension, result utility, and visit satisfaction. Linear mixed-effects modeling was used to evaluate changes in research attitudes and enrollment willingness as a function of time, amyloid result type (elevated/not elevated), and their interaction. Results: The reasons most frequently endorsed for wanting to learn amyloid PET result was a "desire to contribute to research on Alzheimer's disease dementia" and "to inform preventative measures [one] might take (e.g., change diet, exercise, or other lifestyle changes)." Overall, participants reported understanding the results and found learning them useful. Satisfaction with the study visits was overwhelmingly high, with over 80% agreeing with visit usefulness and their satisfaction. Few differences were found between participants who learned an elevated and not elevated result. Over the course of the study, participants who learned an elevated amyloid PET result reported higher willingness to enroll in drug trials (beta: 0.12, p = 0.01) and lifestyle interventions (beta: 0.10, p = 0.02) compared to participants who learned a not elevated result. Discussion: Formal incorporation of disclosure practices may encourage participant recruitment and retention within AD research. Highlights: Participants wanted to learn their amyloid results to contribute to research.Satisfaction with disclosure and post-disclosure visits was high overall.Returning AD biomarkers can increase willingness to participate in research.

Diagnosing Preclinical and Prodromal Neurodegenerative Diseases-The Clinical Is Political.

This Viewpoint describes clinical and political considerations for individuals diagnosed with neurodegenerative conditions during the preclinical or prodromal stage.

Alzheimer's in the modern age: Ethical challenges in the use of digital monitoring to identify cognitive changes.

Pushes toward earlier detection of Alzheimer's disease (AD)-related cognitive changes are creating interest in leveraging technologies, like cellphones, that are already widespread and well-equipped for data collection to facilitate digital monitoring for AD. Studies are ongoing to identify and validate potential "digital biomarkers" that might indicate someone has or is at risk of developing AD dementia. Digital biomarkers for AD have potential as a tool in aiding more timely diagnosis, though more robust research is needed to support their validity and utility. While there are grounds for optimism, leveraging digital monitoring and informatics for cognitive changes also poses ethical challenges, related to topics such as algorithmic bias, consent, and data privacy and security. As we confront the modern era of Alzheimer's disease, individuals, companies, regulators and policymakers alike must prepare for a future in which our day-to-day interactions with technology in our daily life may identify AD-related cognitive changes.

Anticipated Psychological or Behavioral Reactions to Learning Alzheimer Biomarker Results: Associations With Contextual Factors.

BACKGROUND: As Alzheimer disease (AD) biomarker testing becomes more widely available, adults may opt to learn results. Considering potential reactions to learning biomarker results can guide prebiomarker and postbiomarker testing education and counseling programs. METHODS: Cognitively healthy adults enrolled in observational Alzheimer research responded to a telephone survey about learning AD risk information (n=334; 44% Black or African American; mean age=64.9±7.0). Multiple linear regression models tested if contextual factors predicted anticipated psychological impact (distress, stigma, and cognitive symptoms) or behavior change (planning and risk-reduction). Secondary analyses tested for differences in relationships by racial identity. RESULTS: Internal health locus of control, concern about AD, self-identified sex, education, family dementia history, and belief in AD modifiability predicted anticipated psychological impact. Concern about AD, age, racial identity, belief in AD modifiability, research attitudes, and exposure to brain health-related social norms predicted anticipated behavior change. For Black respondents, there were no sex differences in anticipated distress, whereas there were stronger relationships between health locus of control, brain health social norms, and education on outcomes compared with White respondents. CONCLUSIONS: Results may inform personalized and culturally tailored biomarker testing education and counseling to minimize psychological impacts and increase behavior change related to learning AD risk information.

Informing Disclosure: Efficacy of a Brief Educational Intervention on Research Participants' Knowledge about Alzheimer's Disease Biomarkers.

Recommendations for communicating Alzheimer's disease (AD) biomarkers include pre-disclosure participant education and counseling, to allow individuals to make an informed decision. In a cohort of largely non-Hispanic White, cognitively unimpaired older adults from the Wisconsin Registry for Alzheimer's Prevention, we conducted a structured amyloid PET disclosure process that included knowledge assessment and education. Baseline participant knowledge about AD biomarkers and research was high, but information needs existed around dementia causes, early AD symptoms, genetic information, and psychosocial consequences of disclosure. Knowledge scores increased after education, highlighting the potential of brief educational interventions to improve informed decision-making about biomarker disclosure.

Feasibility of virtual Alzheimer's biomarker disclosure: Findings from an observational cohort.

Introduction: Increased availability of Alzheimer's disease (AD) biomarker tests provides older adults with opportunities to seek out and learn results. We evaluated the feasibility of virtually returning AD biomarker results. Methods: Trained study clinicians disclosed amyloid positron emission tomography (PET) results and provided dementia risk-reduction counseling via televideo to cognitively unimpaired participants already enrolled in AD research (n = 99; mean age ± SD: 72.0 ± 4.8; 67% women; 95% White; 28% amyloid elevated). Results: Our study demonstrated acceptable levels of retention (93%), compliance (98%), adherence (98%), clinician competence (97%), education comprehension (quiz scores 14/15), and virtual visit functionality (rating 9.4/10). Depression, anxiety, and suicidality remained low and did not differ by amyloid result. Discussion: Virtual return of amyloid PET results to cognitively unimpaired research participants is feasible and does not result in increased psychological symptoms. Technological barriers for some participants highlight the need for flexibility. These findings support the use of televideo in AD biomarker disclosure, although our study sample and design have important limitations for generalizability.

Trajectory of clinical symptoms in relation to amyloid chronicity.

Introduction: While it is generally appreciated that amyloid precedes symptomatic Alzheimer's disease (AD) by decades, a greater understanding of this timeline may increase prognostic accuracy, planning, and care of persons who are on the AD continuum. Methods: We examined trajectories of Clinical Dementia Rating-Sum of Boxes (CDR-SB) relative to estimated years of amyloid positivity (A+) in n = 123 participants who were all A+ based on [C-11]Pittsburgh compound B positron emission tomography. Results: The average amyloid chronicity at CDR-SB of 2.5 was 20.1 years. The average trajectory of CDR-SB accelerated after 10 years of elevated amyloid and varied greatly between 10 and 30 years. Exploratory analyses suggested that older age and higher volume of white matter hyperintensities shortened the interval between amyloid onset and cognitive impairment. Discussion: The recontextualization of amyloid burden into the time domain will facilitate studies of disease progression, the influence of co-pathology, and factors that hasten or slow cognitive impairment.

Associations of the Lifestyle for Brain Health index with longitudinal cognition and brain amyloid beta in clinically unimpaired older adults: Findings from the Wisconsin Registry for Alzheimer's Prevention.

Introduction: Modifiable health and lifestyle factors increase risk of dementia, but whether modifiable factors, when measured in late-midlife, impact the emergence or progression of Alzheimer's disease (AD) pathophysiologic or cognitive changes remains unresolved. Methods: In initially cognitively unimpaired, late middle-aged participants (N = 1215; baseline age, M [standard deviation] = 59.3 [6.7] years) from the Wisconsin Registry for Alzheimer's Prevention (WRAP), we investigated the influence of the Lifestyle for Brain Health (LIBRA) index, a lifestyle-based dementia risk score, on AD-related cognitive trajectories and amyloid beta (Aß) plaque accumulation. Results: Overall, lower baseline LIBRA, denoting healthier lifestyle and lower dementia risk, was related to better overall cognitive performance, but did not moderate apolipoprotein E ε4 or Aß-related longitudinal cognitive trajectories. LIBRA was not significantly associated with Aß accumulation or estimated age of Aß onset. Discussion: In WRAP, late-midlife LIBRA scores were related to overall cognitive performance, but not AD-related cognitive decline or Aß accumulation in the preclinical timeframe. Highlights: The Lifestyle for Brain Health (LIBRA) index was associated with cognitive performance in late-midlife.LIBRA did not moderate apolipoprotein E ε4 or amyloid-related cognitive decline.LIBRA was not associated with the onset or accumulation of amyloid plaques.

Implications of preclinical Alzheimer's disease biomarker disclosure for US policy and society.

Disclosure of Alzheimer's disease (AD) biomarkers to cognitively unimpaired adults are currently conducted only in research settings. Yet, US Food and Drug Administration approval of a disease-modifying treatment for symptomatic individuals, improved understanding of the "preclinical" phase of disease, and advancements toward more accessible biomarker tests suggest such disclosure will increase in frequency, eventually becoming routine in clinical practice. The changing landscape in AD research to focus on biomarkers has generated debate on the validity and clinical utility of disclosure to cognitively unimpaired adults. This article explores the broader social implications of more widespread AD biomarker disclosure-that is, of individuals learning their risk for developing dementia caused by AD. We identify 10 challenges and offer preliminary solutions. As the field continues to evolve, it is essential to anticipate and address these broader ethical, legal, and social implications of disclosure.

Anticipated reactions to learning Alzheimer's disease biomarker results.

INTRODUCTION: We developed the Alzheimer's Biomarker Survey to assess willingness to enroll in biomarker studies that disclose results and anticipated reactions to an elevated biomarker result. METHODS: Participants included cognitively unimpaired adults enrolled in longitudinal AD studies (n = 334, mean age = 64.8 ± 7.7, 44% non-Hispanic Black or African American). Exploratory and confirmatory factor analyses determined the latent structure comprising anticipated reactions to learning AD biomarker results. Measurement invariance was tested across racial groups. RESULTS: Two models comprising behavior change and psychological impact fit well for the total sample and the two racial groups. The 2-factor behavior change model assessed constructs of planning and dementia risk-reduction. The 3-factor psychological impact model assessed constructs of distress, cognitive symptoms, and stigma. Both models exhibited measurement invariance across racial groups. DISCUSSION: The 28-item Anticipated Reactions to AD Biomarker Disclosure scale is a reliable and valid measure of anticipated reactions when communicating AD biomarker results to research participants.

What Influences the Willingness of Blacks and African Americans to Enroll in Preclinical Alzheimer's Disease Biomarker Research? A Qualitative Vignette Analysis.

BACKGROUND: Alzheimer's disease (AD) begins with an asymptomatic "preclinical" phase, in which abnormal biomarkers indicate risk for developing cognitive impairment. Research is increasingly focused on validating biomarkers to improve reliable diagnosis and timely clinical treatment of AD. Most preclinical biomarker research lacks adequate representation of Black/African American and other racially and ethnically minoritized individuals, limiting the applicability of data to these groups. This may exacerbate existing disparities by hindering diagnosis and treatment among racially and ethnically minoritized individuals. OBJECTIVE: Understand the factors influencing willingness of Blacks/African Americans to participate in AD biomarker research and identify opportunities to improve enrollment. METHODS: We enrolled Blacks/African Americans (N = 145) between 46-85 years of age who had previously participated in AD research. Participants gave open-ended responses to a vignette describing a hypothetical biomarker research study. Using qualitative content analysis, we identified themes that motivated and discouraged enrollment in AD biomarker research. RESULTS: Participant responses were categorized into several themes. Themes motivating participation included a desire to know their biomarker results and to support research. Major themes discouraging participation included concerns about potential negative psychological outcomes to learning one's increased risk for AD, doubt about the usefulness of testing, and worry about the potential physical harms of testing. CONCLUSION: Understanding themes motivating and discouraging AD preclinical biomarker research participation may inform research material development, approach to community engagement, and/or trial design to increase enrollment of Blacks/African Americans.

Cardiology clinic patient attitudes toward and potential personal utility of genetic testing: Findings from a unique multiracial clinical sample.

As more is understood about the hereditary nature of disease risk, the utility of genetic testing within cardiovascular medicine is increasingly being explored. Although testing may afford more personalized risk stratification, there is a paucity of information regarding patient knowledge, attitudes, and beliefs toward genetic testing among cardiology patients. Participants (n = 530) recruited primarily from a cardiology clinic filled out a 41-item written questionnaire assessing knowledge, beliefs, and attitudes toward genetic testing, motivators and detractors for considering genetic testing, and perceived likelihood for behavior change after hypothetical genetic testing risk stratification. Path analysis was used to test the hypothetical models predicting the likelihood of getting a genetic test and making behavior changes following genetic testing. The patient population was late-middle-aged (59.0 ± 14.5 years), majority women (61.5%), and about half reported having a bachelor's degree. 58.1% of participants self-identified as White, 25.7% as African American or Black, 6.8% as Spanish, Latino, or Hispanic, 3.0% as Asian or Pacific Islander, and 0.5% as Native American. Gender (being a woman) and more years of education were related to greater knowledge about genetic testing. Racial identity and years of education were related to beliefs about genetic testing. Beliefs, but not knowledge, were related to more positive attitudes and a higher likelihood of pursuing genetic testing. Positive attitudes were related to greater perceived personal control (PPC). Furthermore, attitudes and PPC were related to higher likelihood of lifestyle change after genetic testing. These results highlight the need to integrate the experiences of racialized communities into education/counseling efforts. Most educational counseling efforts lack a nuanced discussion of social determinants of health or beliefs. In addition to factual information, educational counseling must also address people's beliefs, concerns, and the intersecting experiences and identities, which shape patients' relationships with the evolving landscape of healthcare and personalized medicine.

Predictors of Willingness to Enroll in Hypothetical Alzheimer Disease Biomarker Studies that Disclose Personal Results.

INTRODUCTION: We examined factors related to willingness to enroll in hypothetical Alzheimer disease (AD) biomarker studies. METHODS: Using linear regression, we assessed the relationship among enrollment willingness and demographics, family dementia history, research attitudes, concern about AD, experiences of discrimination, and belief in AD risk modifiability. Inductive coding was used to assess qualitative data. RESULTS: In middle-aged and older adult AD research participants (n=334), willingness to enroll in biomarker studies was driven by biomarker collection method, research attitudes, and disclosure of personal results. Predictors of willingness were similar for Black and White participants. Themes associated with increased willingness included a desire to learn biomarker results and support research. DISCUSSION: Research attitudes were an important predictor of biomarker study willingness regardless of race. As seen elsewhere, Black participants were more hesitant to participate in biomarker research. Disclosure of biomarker results/risk can bolster willingness to enroll in biomarker studies, particularly for Black participants.

Disclosure of preclinical Alzheimer's disease biomarker results in research and clinical settings: Why, how, and what we still need to know.

Disclosure of personal disease-related information to asymptomatic adults has been debated over the last century in medicine and research. Recently, Alzheimer's disease (AD) has been conceptualized as a continuum that begins with a "preclinical" stage in which biomarkers are present in the absence of cognitive impairment. Studies have begun assessing the safety, psychological, and behavioral effects of disclosing both AD-related genetic and biomarker information to cognitively unimpaired older adults. Yet, debate continues over the appropriate circumstances and methods for returning such information. This article outlines concerns with and rationale for AD biomarker disclosure and summarizes findings from prior studies. Overall, this article aims to describe and respond to key questions concerning disclosure of amyloid positron emission tomography scan results to asymptomatic adults in a research setting. Moving forward, such conditions are important to consider as interventions target the preclinical phase of AD and normalize disclosing biomarker information to cognitively unimpaired persons.

Prescription Medications and Co-Morbidities in Late Middle-Age are Associated with Greater Cognitive Declines: Results from WRAP.

The present study investigated: 1) sex differences in polypharmacy, comorbidities, self-rated current health (SRH), and cognitive performance, 2) associations between comorbidities, polypharmacy, SRH, and objective measures of health, and 3) associations of these factors with longitudinal cognitive performance. Analyses included 1039 eligible Wisconsin Registry for Alzheimer's Prevention (WRAP) participants who were cognitively unimpaired at baseline and had ≥2 visits with cognitive composites, self-reported health history, and concurrent medication records. Repeated measures correlation (rmcorr) examined the associations between medications, co-morbidities, SRH, and objective measures of health (including LIfestyle for BRAin Health Index (LIBRA), and depression). Linear mixed-effect models examined associations between medications, co-morbidities, and cognitive change over time using a preclinical Alzheimer's cognitive composite (PACC3) and cognitive domain z-scores (executive function, working memory, immediate learning, and delayed recall). In secondary analyses, we also examined whether the number of medications interacted with co-morbidities and whether they modified age-related cognitive trajectories. The number of prescribed medications was associated with worse SRH and a higher number of self-reported co-morbidities. More prescribed medications were associated with a faster decline in executive function, and more comorbidities were associated with faster PACC3 decline. Those with a non-elevated number of co-morbidities and medications performed an average of 0.26 SD higher (better) in executive function and an average of 0.18 SD higher on PACC3 than those elevated on both. Associations between medications, co-morbidities, and executive function, and PACC3 suggest that persons with more co-morbidities and medications may be at increased risk of reaching clinical levels of impairment earlier than healthier, less medicated peers.

Amyloid and tau imaging biomarkers explain cognitive decline from late middle-age.

This study investigated differences in retrospective cognitive trajectories between amyloid and tau PET biomarker stratified groups in initially cognitively unimpaired participants sampled from the Wisconsin Registry for Alzheimer's Prevention. One hundred and sixty-seven initially unimpaired individuals (baseline age 59 ± 6 years; 115 females) were stratified by elevated amyloid-ß and tau status based on 11C-Pittsburgh compound B (PiB) and 18F-MK-6240 PET imaging. Mixed effects models were used to determine if longitudinal cognitive trajectories based on a composite of cognitive tests including memory and executive function differed between biomarker groups. Secondary analyses investigated group differences for a variety of cross-sectional health and cognitive tests, and associations between 18F-MK-6240, 11C-PiB, and age. A significant group × age interaction was observed with post hoc comparisons indicating that the group with both elevated amyloid and tau pathophysiology were declining approximately three times faster in retrospective cognition compared to those with just one or no elevated biomarkers. This result was robust against various thresholds and medial temporal lobe regions defining elevated tau. Participants were relatively healthy and mostly did not differ between biomarker groups in health factors at the beginning or end of study, or most cognitive measures at study entry. Analyses investigating association between age, MK-6240 and PiB indicated weak associations between age and 18F-MK-6240 in tangle-associated regions, which were negligible after adjusting for 11C-PiB. Strong associations, particularly in entorhinal cortex, hippocampus and amygdala, were observed between 18F-MK-6240 and global 11C-PiB in regions associated with Braak neurofibrillary tangle stages I-VI. These results suggest that the combination of pathological amyloid and tau is detrimental to cognitive decline in preclinical Alzheimer's disease during late middle-age. Within the Alzheimer's disease continuum, middle-age health factors likely do not greatly influence preclinical cognitive decline. Future studies in a larger preclinical sample are needed to determine if and to what extent individual contributions of amyloid and tau affect cognitive decline. 18F-MK-6240 shows promise as a sensitive biomarker for detecting neurofibrillary tangles in preclinical Alzheimer's disease.

KLOTHO heterozygosity attenuates APOE4-related amyloid burden in preclinical AD.

OBJECTIVE: To examine whether the KLOTHO gene variant KL-VS attenuates APOE4-associated ß-amyloid (Aß) accumulation in a late-middle-aged cohort enriched with Alzheimer disease (AD) risk factors. METHODS: Three hundred nine late-middle-aged adults from the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center were genotyped to determine KL-VS and APOE4 status and underwent CSF sampling (n = 238) and/or 11C-Pittsburgh compound B (PiB)-PET imaging (n = 183). Covariate-adjusted regression analyses were used to investigate whether APOE4 exerted expected effects on Aß burden. Follow-up regression analyses stratified by KL-VS genotype (i.e., noncarrier vs heterozygous; there were no homozygous individuals) evaluated whether the influence of APOE4 on Aß was different among KL-VS heterozygotes compared to noncarriers. RESULTS: APOE4 carriers exhibited greater Aß burden than APOE4-negative participants. This effect was stronger in CSF (t = -5.12, p < 0.001) compared with PiB-PET (t = 3.93, p < 0.001). In the stratified analyses, this APOE4 effect on Aß load was recapitulated among KL-VS noncarriers (CSF: t = -5.09, p < 0.001; PiB-PET: t = 3.77, p < 0 .001). In contrast, among KL-VS heterozygotes, APOE4-positive individuals did not exhibit higher Aß burden than APOE4-negative individuals (CSF: t = -1.03, p = 0.308; PiB-PET: t = 0.92, p = 0.363). These differential APOE4 effects remained after KL-VS heterozygotes and noncarriers were matched on age and sex. CONCLUSION: In a cohort of at-risk late-middle-aged adults, KL-VS heterozygosity was associated with an abatement of APOE4-associated Aß aggregation, suggesting KL-VS heterozygosity confers protections against APOE4-linked pathways to disease onset in AD.

Occupational-like organophosphate exposure disrupts microglia and accelerates deficits in a rat model of Alzheimer's disease.

Occupational exposure to organophosphate pesticides, such as chlorpyrifos (CPF), increases the risk of Alzheimer's disease (AD), though the mechanism is unclear. To investigate this, we subjected 4-month-old male and female wild-type (WT) and TgF344-AD rats, a transgenic AD model, to an occupational CPF exposure paradigm that recapitulates biomarkers and behavioral impairments experienced by agricultural workers. Subsequent cognition and neuropathology were analyzed over the next 20 months. CPF exposure caused chronic microglial dysregulation and accelerated neurodegeneration in both males and females. The effect on neurodegeneration was more severe in males, and was also associated with accelerated cognitive impairment. Females did not exhibit accelerated cognitive impairment after CPF exposure, and amyloid deposition and tauopathy were unchanged in both males and females. Microglial dysregulation may mediate the increased risk of AD associated with occupational organophosphate exposure, and future therapies to preserve or restore normal microglia might help prevent AD in genetically vulnerable individuals exposed to CPF or other disease-accelerating environmental agents.