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INTRODUCTIONInformation on the psychosocial impact of Alzheimer's disease (AD) biomarker testing in adults at risk of AD is needed to inform best practices for communicating biomarker results.METHODSNinety‐nine cognitively unimpaired older adults learned amyloid positron emission tomography (PET) results (mean age = 72.0 ± 4.8, 95% White, 28% elevated amyloid). Linear mixed‐effects regression models were used to test the main effects and interaction of PET result × time on psychosocial outcomes up to 6 months after learning results.RESULTSA significant interaction of PET result × time was observed for concern about AD (β = 0.28, p = 0.02) and intrusive thoughts and avoidance (β = ‐0.82, p < 0.001). A main effect of PET result was observed for AD test‐related distress (β = 12.09, p < 0.001).DISCUSSIONCognitively unimpaired adults learning elevated‐amyloid PET results reported mildly intrusive thoughts/avoidance initially following disclosure, but these symptoms decreased over time. Concern about AD dementia and AD biomarker test‐related distress remained higher in elevated‐amyloid compared to non‐elevated‐amyloid participants.Highlights Longitudinal assessment of psychosocial reactions after amyloid PET disclosure was conducted. Transient highly intrusive thoughts or avoidance after learning elevated amyloid results. Persistent test result‐related distress after receiving elevated‐amyloid results. There is increased concern about AD dementia after receiving elevated‐amyloid results. Happiness and relief are experienced after receiving non‐elevated‐amyloid results.
INTRODUCTIONInformation on the psychosocial impact of Alzheimer's disease (AD) biomarker testing in adults at risk of AD is needed to inform best practices for communicating biomarker results.METHODSNinety‐nine cognitively unimpaired older adults learned amyloid positron emission tomography (PET) results (mean age = 72.0 ± 4.8, 95% White, 28% elevated amyloid). Linear mixed‐effects regression models were used to test the main effects and interaction of PET result × time on psychosocial outcomes up to 6 months after learning results.RESULTSA significant interaction of PET result × time was observed for concern about AD (β = 0.28, p = 0.02) and intrusive thoughts and avoidance (β = ‐0.82, p < 0.001). A main effect of PET result was observed for AD test‐related distress (β = 12.09, p < 0.001).DISCUSSIONCognitively unimpaired adults learning elevated‐amyloid PET results reported mildly intrusive thoughts/avoidance initially following disclosure, but these symptoms decreased over time. Concern about AD dementia and AD biomarker test‐related distress remained higher in elevated‐amyloid compared to non‐elevated‐amyloid participants.Highlights Longitudinal assessment of psychosocial reactions after amyloid PET disclosure was conducted. Transient highly intrusive thoughts or avoidance after learning elevated amyloid results. Persistent test result‐related distress after receiving elevated‐amyloid results. There is increased concern about AD dementia after receiving elevated‐amyloid results. Happiness and relief are experienced after receiving non‐elevated‐amyloid results.
Recent longitudinal PET imaging studies have established methods to estimate the age at which amyloid becomes abnormal at the level of the individual. Here we recontextualized amyloid levels into the temporal domain to better understand the downstream Alzheimer’s disease processes of tau neurofibrillary tangle (NFT) accumulation and cognitive decline. This cohort study included a total of 601 individuals from the Wisconsin Registry for Alzheimer’s Prevention and Wisconsin Alzheimer’s Disease Research Center that underwent amyloid and tau PET, longitudinal neuropsychological assessments, and met clinical criteria for three clinical diagnosis groups: cognitively unimpaired (CU; n=537); mild cognitive impairment (MCI; n=48); or dementia (n=16)). Cortical 11C-Pittsburgh compound B (PiB) distribution volume ratio (DVR) and sampled iterative local approximation were used to estimate amyloid positive (A+; global PiB DVR>1.16 equivalent to 17.1 Centiloids) onset age and years of A+ duration at tau PET (i.e., amyloid chronicity). Tau PET burden was quantified using 18F-MK-6240 standardized uptake value ratios (SUVRs; 70-90 min, inferior cerebellar gray matter reference region). Whole-brain and region-specific approaches were used to examine tau PET binding along the amyloid timeline and across the Alzheimer’s disease clinical continuum. Voxel-wise 18F-MK-6240 analyses revealed that with each decade of A+, the spatial extent of measurable tau spread (i.e., progressed) from regions associated with early to late NFT tau stages. Regional analyses indicated that tau burden in the entorhinal cortex was detectable, on average, within ten years of A+ onset. Additionally, the entorhinal cortex was the region most sensitive to early amyloid pathology and clinical impairment in this predominantly preclinical sample. Among initially CU (n=472) individuals with longitudinal cognitive follow-up, mixed effects models showed significant linear and non-linear interactions of A+ duration and entorhinal tau on cognitive decline, suggesting a synergistic effect whereby greater A+ duration together with a higher entorhinal tau burden increases the likelihood of cognitive decline beyond their separable effects. Overall, the amyloid time framework enabled a spatiotemporal characterization of tau deposition patterns across the Alzheimer’s disease continuum. This approach, which examined cross-sectional tau PET data along the amyloid timeline to make longitudinal disease-course inferences, demonstrated that A+ duration explains a considerable amount of variability in the magnitude and topography of tau spread, which largely recapitulated NFT staging observed in human neuropathological studies. By anchoring disease progression to the onset of amyloid, this study provides a temporal disease context which may help inform disease prognosis and timing windows for anti-amyloid therapies.
BackgroundAdults with Down syndrome (DS) are at risk for Alzheimer’s disease (AD). Recent natural history cohort studies have characterized AD biomarkers, with a focus on PET amyloid-beta (Aβ) and PET tau. Leveraging these well-characterized biomarkers, the present study examined the timeline to symptomatic AD based on estimated years since reaching Aβ+, referred to as “amyloid age”, and in relation to tau in a large cohort of individuals with DS.MethodsIn this multicenter cohort study, 25 – 57-year-old adults with DS (n = 167) were assessed twice from 2017 to 2022, with approximately 32 months between visits as part of the Alzheimer Biomarker Consortium - Down Syndrome. Adults with DS completed amyloid and tau PET scans, and were administered the modified Cued Recall Test and the Down Syndrome Mental Status Examination. Study partners completed the National Task Group-Early Detection Screen for Dementia.FindingsMixed linear regressions showed significant quadratic associations between amyloid age and cognitive performance and cubic associations between amyloid age and tau, both at baseline and across 32 months. Using broken stick regression models, differences in mCRT scores were detected beginning 2.7 years following Aβ+ in cross-sectional models, with an estimated decline of 1.3 points per year. Increases in tau began, on average, 2.7 – 6.1 years following Aβ+. On average, participants with mild cognitive impairment were 7.4 years post Aβ+ and those with dementia were 12.7 years post Aβ+.InterpretationThere is a short timeline to initial cognitive decline and dementia from Aβ+ (Centiloid = 18) and tau deposition in DS relative to late onset AD. The established timeline based on amyloid age (or equivalent Centiloid values) is important for clinical practice and informing AD clinical trials, and avoids limitations of timelines based on chronological age.Funding.National Institute on Aging and the National Institute for Child Health and Human Development.Research in ContextEvidence before this studyWe searched PubMed for articles published involving the progression of Aβ and tau deposition in adults with Down syndrome from database inception to March 1, 2024. Terms included “amyloid”, “Down syndrome”, “tau”, “Alzheimer’s disease”, “cognitive decline”, and “amyloid chronicity,” with no language restrictions. One previous study outlined the progression of tau in adults with Down syndrome without consideration of cognitive decline or clinical status. Other studies reported cognitive decline associated with Aβ burden and estimated years to AD symptom onset in Down syndrome. Amyloid age estimates have also been created for older neurotypical adults and compared to cognitive performance, but this has not been investigated in Down syndrome.Added value of this studyThe timeline to symptomatic Alzheimer’s disease in relation to amyloid, expressed as duration of Aβ+, and tau has yet to be described in adults with Down syndrome. Our longitudinal study is the first to provide a timeline of cognitive decline and transition to mild cognitive impairment and dementia in relation to Aβ+.Implications of all the available evidenceIn a cohort study of 167 adults with Down syndrome, cognitive decline began 2.7 – 5.4 years and tau deposition began 2.7 – 6.1 years following Aβ+ (Centiloid = 18). Adults with Down syndrome converted to MCI after ~7 years and dementia after ~12-13 years of Aβ+. This shortened timeline to AD symptomology from Aβ+ and tau deposition in DS based on amyloid age (or corresponding Centiloid values) can inform clinical AD intervention trials and is of use in clinical settings.
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