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Accumulating evidence indicates that the pathophysiological process underlying Alzheimer disease—including protein aggregation, synaptic dysfunction, and neuronal loss—begins years if not decades prior to the onset of clinical symptoms and functional limitation. This long prodromal period represents our greatest hope for effective therapeutic intervention as well as a domain of serious ethical concern. Interventions to arrest or even to delay the neurodegenerative process could profoundly reduce the anticipated societal burden of Alzheimer disease in an aging global population,1 especially if initiated prior to the development of functional impairment. However, successfully implementing such a strategy will likely require the identification and targeting of people who are cognitively normal but have evidence for underlying neurodegeneration—initially only for recruitment into clinical trials to test the utility of preventive strategies, but eventually (it is hoped) for the broad delivery of such interventions should they be proved effective. New molecular diagnostic techniques now allow for in vivo detection of abnormal levels of the disease biomarkers amyloid-β and tau, using positron emission tomography (PET) or cerebrospinal fluid analysis. But given the remaining uncertainties about the clinical meaning and predictive power of these techniques, it remains controversial whether or how test results can be responsibly disclosed to cognitively normal individuals.2,3 In this issue of JAMA Neurology , Mozersky and colleagues4 present early work addressing how cognitively normal adults interpret a finding of elevated brain amyloid-β in the context of enrollment for the Anti-Amyloid Treatment in Asymptomatic Alzheimer Study (A4 study). The design of the A4 study itself illustrates the ethical challenges at play. This clinical trial addresses whether administration of solanezumab (a humanized monoclonal antibody targeting amyloid-β aggregation) can prevent cognitive decline among cognitively normal adults with elevated brain amyloid-β as measured using PET with the radiotracer florbetapir.5 Prevailing appropriate use criteria advise against clinical use of amyloid imaging in asymptomatic individuals, citing “a significant potential for patients and families to make inaccurate assumptions about risk and future outcomes on the basis of amyloid PET results.”6(p483) However, in the A4 study, prospective participants are screened using amyloid PET, and evidence of amyloid accumulation is an inclusion criterion for enrollment. Thus, the trial design not only requires that amyloid imaging be performed but also effectively requires that the results of such imaging be disclosed to participants (as well as to prospective participants who are excluded as having negative imaging results). Recognizing these challenges, the A4 investigators have implemented a rigorous process for disclosure of imaging results, appropriately emphasizing the ambiguity and limitations of amyloid imaging as an individual predictor of future clinical disease.7 The article by Mozersky et al4 presents findings from an A4 trial substudy, which uses semistructured telephone interviews with research participants who have elevated amyloid-β on PET to elicit their understanding of the significance of the findings. A slight majority of participants (27 of 50) anticipated their finding of elevated amyloid-β, perhaps unsurprising in a group volunteering for a study of Alzheimer disease prevention in which elevated amyloid-β is a condition for enrollment. Likely more important given ethical concerns over biomarker disclosure, participant responses indicated that the A4 study investigators successfully communicated the prognostic uncertainty associated with imaging results. A strength of qualitative research is its ability to elicit stakeholder beliefs or concerns that may not have been initially anticipated. In this case, a sizable proportion of participants (20 of 50) expressed dissatisfaction with the categorical characterization of results as “elevated” or “not elevated,” in some cases desiring more specific information about how elevated their own results were relative to the threshold for inclusion in the A4 study. The authors speculate that concern for more fine-grained interpretation of results may be more salient for cognitively normal individuals undergoing predictive testing than for symptomatic patients seeking an explanation for current symptoms. However, their finding is echoed in another recent study of clinical amyloid imaging in symptomatic patients with dementia and mild cognitive impairment.8 In that work by Grill and colleagues, several caregivers expressed an expectation that PET images could be used as a measure of disease severity—a similar wish for granularity that is considered an inappropriate application of amyloid imaging given the absence of data to support such inferences.6 The findings of these 2 groups together suggest that, in addition to counseling regarding prognostic uncertainties with amyloid imaging, closer attention must be paid to advising prospective participants about the presently limited, categorical interpretation of these tests. Overall, the findings of Mozersky and colleagues4 are broadly reassuring regarding research participants’ ability to understand the prognostic uncertainty of amyloid imaging. Related article Opinion