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      Reactions to learning a “not elevated” amyloid PET result in a preclinical Alzheimer’s disease trial

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          Abstract

          Background

          The experiences of biomarker-ineligible cognitively normal persons can inform trial conduct and the translation of preclinical Alzheimer’s disease (AD) into clinical practice.

          Methods

          We interviewed 33 persons whose “not elevated” brain amyloid imaging biomarker result made them ineligible for a preclinical AD trial.

          Results

          Most participants ( n = 17) reported being informed that they did not demonstrate adequately elevated amyloid to qualify, whereas some ( n = 14) reported being told they had no amyloid or plaques. Relief ( n = 17) and disappointment related to not being able to participate ( n = 12) were the most common reactions to results. Nearly all participants would have made healthy lifestyle changes if they had received an “elevated” result, would have another scan, and would participate in another AD prevention trial.

          Conclusions

          Although some participants may misconstrue results, disclosure of a “not elevated” amyloid result in the research setting causes little behavior change; willingness to participate in AD research remains.

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          Most cited references19

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          Subthreshold amyloid predicts tau deposition in aging

          Current approaches to the early detection of Alzheimer's disease (AD) rely upon classifying individuals as “positive” or “negative” for biomarkers related to the core pathology of β-amyloid (Aβ). However, the accumulation of Aβ begins slowly, years before biomarkers become abnormal. We used longitudinal [ 11 C] Pittsburgh Compound B PET scanning and neuropsychological assessment to investigate the earliest changes in AD pathology and how it affects memory in cognitively normal older humans ( N = 71; mean age 75 years; 35% male). We used [ 18 F] AV-1451 PET scanning at the end of the observation period to measure subsequent tau deposition in a subset of our sample ( N = 37). We found evidence for an inverted-U relationship between baseline Aβ levels and Aβ slope in asymptomatic older adults, suggesting a slowing of Aβ accumulation even in cognitively normal adults. In participants who were nominally amyloid negative, both the rate of amyloid accumulation and the baseline levels of Aβ predicted early tau deposition in cortical Braak regions associated with AD. Amyloid measures were only sensitive to memory decline as baseline levels of Aβ increased, suggesting that pathological accumulation occurs before impacting memory. These findings support the necessity of early intervention with amyloid-lowering therapies even in those who are amyloid negative. SIGNIFICANCE STATEMENT The progressive nature of Alzheimer's disease (AD) necessitates the earliest possible detection of pathological or cognitive change if disease progression is to be slowed. We examined cognitively normal older adults in whom AD pathology is starting to develop, with the goal of early detection of AD pathology or cognitive changes. We found amyloid measures to be sensitive early on in predicting subsequent early tau deposition. Further, it appears that rates of amyloid accumulation already begin to slow in preclinical AD, suggesting that it is a relatively late stage of AD progression. Thus, it is crucial to examine older adults early, before amyloid levels have saturated, to intervene to slow disease progression.
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            Memory decline accompanies subthreshold amyloid accumulation

            Objective Extensive cortical β-amyloid (Aβ positivity) has been linked to cognitive decline, but the clinical significance of elevations in Aβ within the negative range is unknown. Methods We examined amyloid and cognitive trajectories (memory, executive function) in 142 cognitively normal older individuals enrolled in the Alzheimer's Disease Neuroimaging Initiative who were Aβ-negative at baseline and who had at least 2 [ 18 F]-florbetapir PET scans over 3.9 ± 1.4 years. We determined whether Aβ accumulation was associated with longitudinal changes in memory or executive function. Results Among baseline-negative individuals, florbetapir slope (mean annual increase 0.002 ± 0.008 standardized uptake value ratio units/y) was not related to age, sex, education, APOE4 status, baseline memory or executive function, temporoparietal glucose metabolism, baseline hippocampal volume, or hippocampal volume change; but it was related to higher baseline cortical florbetapir, indicating that Aβ accumulation was ongoing at baseline in those who accumulated during the study. Over the course of follow-up, 13 individuals converted to florbetapir+ and 14 nearly nonoverlapping individuals converted to mild cognitive impairment or Alzheimer disease. Amyloid accumulation among baseline-negative individuals was associated with poorer longitudinal memory performance ( p = 0.019), but it was not associated with changes in executive function. Reducing the sample to individuals with at least 3 timepoints to estimate the florbetapir slope strengthened the relationship further between florbetapir accumulation and memory decline ( p = 0.007). Conclusions Memory decline accompanies Aβ accumulation in otherwise healthy, Aβ-negative older adults. Amyloid increases within the negative range may represent the earliest detectable indication of pathology with domain-specific cognitive consequences.
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              Safety of disclosing amyloid status in cognitively normal older adults.

              Disclosing amyloid status to cognitively normal individuals remains controversial given our lack of understanding the test's clinical significance and unknown psychological risk.
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                Author and article information

                Contributors
                jgrill@uci.edu
                cgcox@uci.edu
                kristin.harkins@uphs.upenn.edu
                jason.karlawish@uphs.upenn.edu
                Journal
                Alzheimers Res Ther
                Alzheimers Res Ther
                Alzheimer's Research & Therapy
                BioMed Central (London )
                1758-9193
                22 December 2018
                22 December 2018
                2018
                : 10
                : 125
                Affiliations
                [1 ]ISNI 0000 0001 0668 7243, GRID grid.266093.8, Institute for Memory Impairments and Neurological Disorders, , University of California, Irvine, ; 3204 Biological Sciences III, Irvine, CA USA
                [2 ]ISNI 0000 0001 0668 7243, GRID grid.266093.8, Institute for Clinical and Translational Science, , University of California, Irvine, ; Irvine, CA USA
                [3 ]ISNI 0000 0001 0668 7243, GRID grid.266093.8, Department of Psychiatry and Human Behavior, , University of California, Irvine, ; Irvine, CA USA
                [4 ]ISNI 0000 0001 0668 7243, GRID grid.266093.8, Department of Neurobiology and Behavior, , University of California, Irvine, ; Irvine, CA USA
                [5 ]ISNI 0000 0004 1936 8972, GRID grid.25879.31, Penn Memory Center, University of Pennsylvania, ; Philadelphia, PA USA
                [6 ]ISNI 0000 0004 1936 8972, GRID grid.25879.31, Department of Medicine, , University of Pennsylvania, ; Philadelphia, PA USA
                [7 ]ISNI 0000 0004 1936 8972, GRID grid.25879.31, Department of Medical Ethics and Health Policy, , University of Pennsylvania, ; Philadelphia, PA USA
                [8 ]ISNI 0000 0004 1936 8972, GRID grid.25879.31, Department of Neurology, , University of Pennsylvania, ; Philadelphia, PA USA
                Author information
                http://orcid.org/0000-0002-4215-7589
                Article
                452
                10.1186/s13195-018-0452-1
                6303934
                30579361
                bc3d4ff2-8a70-4c0f-89ab-c4c4a0d776d8
                © The Author(s). 2018

                Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 11 September 2018
                : 26 November 2018
                Funding
                Funded by: National Institute on Aging (US)
                Award ID: AG016573
                Categories
                Research
                Custom metadata
                © The Author(s) 2018

                Neurology
                disclosure,preclinical,asymptomatic,alzheimer’s disease,prevention
                Neurology
                disclosure, preclinical, asymptomatic, alzheimer’s disease, prevention

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