| 1. |
- Erickson, Pontus, et al.
(författare)
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Prevalence and Clinical Implications of a β-Amyloid-Negative, Tau-Positive Cerebrospinal Fluid Biomarker Profile in Alzheimer Disease.
- 2023
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Ingår i: JAMA neurology. - 2168-6157. ; 80:9, s. 969-979
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Tidskriftsartikel (refereegranskat)abstract
- Knowledge is lacking on the prevalence and prognosis of individuals with a β-amyloid-negative, tau-positive (A-T+) cerebrospinal fluid (CSF) biomarker profile.To estimate the prevalence of a CSF A-T+ biomarker profile and investigate its clinical implications.This was a retrospective cohort study of the cross-sectional multicenter University of Gothenburg (UGOT) cohort (November 2019-January 2021), the longitudinal multicenter Alzheimer Disease Neuroimaging Initiative (ADNI) cohort (individuals with mild cognitive impairment [MCI] and no cognitive impairment; September 2005-May 2022), and 2 Wisconsin cohorts, Wisconsin Alzheimer Disease Research Center and Wisconsin Registry for Alzheimer Prevention (WISC; individuals without cognitive impairment; February 2007-November 2020). This was a multicenter study, with data collected from referral centers in clinical routine (UGOT) and research settings (ADNI and WISC). Eligible individuals had 1 lumbar puncture (all cohorts), 2 or more cognitive assessments (ADNI and WISC), and imaging (ADNI only) performed on 2 separate occasions. Data were analyzed on August 2022 to April 2023.Baseline CSF Aβ42/40 and phosphorylated tau (p-tau)181; cognitive tests (ADNI: modified preclinical Alzheimer cognitive composite [mPACC]; WISC: modified 3-test PACC [PACC-3]). Exposures in the ADNI cohort included [18F]-florbetapir amyloid positron emission tomography (PET), magnetic resonance imaging (MRI), [18F]-fluorodeoxyglucose PET (FDG-PET), and cross-sectional tau-PET (ADNI: [18F]-flortaucipir, WISC: [18F]-MK6240).Primary outcomes were the prevalence of CSF AT biomarker profiles and continuous longitudinal global cognitive outcome and imaging biomarker trajectories in A-T+ vs A-T- groups. Secondary outcomes included cross-sectional tau-PET.A total of 7679 individuals (mean [SD] age, 71.0 [8.4] years; 4101 male [53%]) were included in the UGOT cohort, 970 individuals (mean [SD] age, 73 [7.0] years; 526 male [54%]) were included in the ADNI cohort, and 519 individuals (mean [SD] age, 60 [7.3] years; 346 female [67%]) were included in the WISC cohort. The prevalence of an A-T+ profile in the UGOT cohort was 4.1% (95% CI, 3.7%-4.6%), being less common than the other patterns. Longitudinally, no significant differences in rates of worsening were observed between A-T+ and A-T- profiles for cognition or imaging biomarkers. Cross-sectionally, A-T+ had similar tau-PET uptake to individuals with an A-T- biomarker profile.Results suggest that the CSF A-T+ biomarker profile was found inapproximately5% of lumbar punctures and was not associated with a higher rate of cognitive decline or biomarker signs of disease progression compared with biomarker-negative individuals.
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| 2. |
- Allison, Samantha L, et al.
(författare)
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Neurodegeneration, Alzheimer's disease biomarkers, and longitudinal verbal learning and memory performance in late middle age.
- 2021
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Ingår i: Neurobiology of aging. - : Elsevier BV. - 1558-1497 .- 0197-4580. ; 102, s. 151-160
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Tidskriftsartikel (refereegranskat)abstract
- This study examined the effect of neurodegeneration, and its interaction with Alzheimer's disease (AD) cerebrospinal fluid biomarkers, on longitudinal verbal learning and memory performance in cognitively unimpaired (CU) late middle-aged adults. Three hundred and forty-two CU adults (cognitive baseline mean age=58.4), with cerebrospinal fluid and structural MRI, completed 2-10 (median=5) cognitive assessments. Learning and memory were assessed using the Rey Auditory Verbal Learning Test (RAVLT). We used sequential comparison of nested linear mixed effects models to analyze the data. Model selection preserved a significant ptau181/Aβ42×global atrophy×age interaction; individuals with less global atrophy and lower ptau181/Aβ42 levels had less learning and delayed recall decline than individuals with more global atrophy and/or higher levels of ptau181/Aβ42. The hippocampal volume×age×ptau181/Aβ42 interaction was not significant. Findings suggest that in a sample of CU late middle-aged adults, individuals with AD biomarkers, global atrophy, or both evidence greater verbal learning and memory decline than individuals without either risk factor.
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| 3. |
- Hale, Madeline R, et al.
(författare)
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Associations between recall of proper names in story recall and CSF amyloid and tau in adults without cognitive impairment.
- 2024
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Ingår i: Neurobiology of aging. - 1558-1497. ; 133, s. 87-98
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Tidskriftsartikel (refereegranskat)abstract
- Neuropsychological measures sensitive to decline in the preclinical phase of Alzheimer's diseaseare needed. We previously demonstrated that higher amyloid-beta (Aβ) assessed by positron emission tomography in adults without cognitive impairment was associated with recall of fewer proper names in Logical Memory story recall. The current study investigated the association between proper names and cerebrospinal fluidbiomarkers (Aβ42/40, phosphorylated tau181 [pTau181], neurofilament light) in 223 participants from the Wisconsin Registry for Alzheimer's Prevention. We assessed associations between biomarkers and delayed Logical Memory total score and proper names using binary logistic regressions. Sensitivity analyses used multinomial logistic regression and stratified biomarker groups. Lower Logical Memory total score and proper names scores from themost recent visit were associated with biomarker positivity. Relatedly, there was a 27% decreased risk of being classified Aβ42/40+/pTau181+for each additional proper name recalled. A linear mixed effects model found that longitudinal change in proper names recall was predicted by biomarker status. These results demonstrate a novel relationship between proper names and Alzheimer's disease-cerebrospinal fluid pathology.
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| 4. |
- Jonaitis, Erin M, et al.
(författare)
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Measuring longitudinal cognition: Individual tests versus composites.
- 2019
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Ingår i: Alzheimer's & dementia (Amsterdam, Netherlands). - : Wiley. - 2352-8729. ; 11, s. 74-84
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Tidskriftsartikel (refereegranskat)abstract
- Longitudinal cohort studies of cognitive aging must confront several sources of within-person variability in scores. In this article, we compare several neuropsychological measures in terms of longitudinal error variance and relationships with biomarker-assessed brain amyloidosis (Aβ).Analyses used data from the Wisconsin Registry for Alzheimer's Prevention. We quantified within-person longitudinal variability and age-related trajectories for several global and domain-specific composites and their constituent scores. For a subset with cerebrospinal fluid or amyloid positron emission tomography measures, we examined how Aβ modified cognitive trajectories.Global and theoretically derived composites exhibited lower intraindividual variability and stronger age × Aβ interactions than did empirically derived composites or raw scores from single tests. For example, the theoretical executive function outperformed other executive function scores on both metrics.These results reinforce the need for careful selection of cognitive outcomes in study design, and support the emerging consensus favoring composites over single-test measures.
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| 5. |
- Van Hulle, Carol, et al.
(författare)
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An examination of a novel multipanel of CSF biomarkers in the Alzheimer's disease clinical and pathological continuum.
- 2021
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Ingår i: Alzheimer's & dementia : the journal of the Alzheimer's Association. - : Wiley. - 1552-5279. ; 17:3, s. 431-445
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Tidskriftsartikel (refereegranskat)abstract
- This study examines the utility of a multipanel of cerebrospinal fluid (CSF) biomarkers complementing Alzheimer's disease (AD) biomarkers in a clinical research sample. We compared biomarkers across groups defined by clinical diagnosis and pTau181 /Aβ42 status (+/-) and explored their value in predicting cognition.CSF biomarkers amyloid beta (Aβ)42 , pTau181 , tTau, Aβ40 , neurogranin, neurofilament light (NfL), α-synuclein, glial fibrillary acidic protein (GFAP), chitinase-3-like protein 1 (YKL-40), soluble triggering receptor expressed on myeloid cells 2 (sTREM2), S100 calcium binding protein B (S100B), and interleukin 6 (IL6), were measured with the NeuroToolKit (NTK) for 720 adults ages 40 to 93 years (mean age=63.9 years, standard deviation [SD]=9.0; 50 with dementia; 54 with mild cognitive impairment [MCI], 616 unimpaired).Neurodegeneration and glial activation biomarkers were elevated in pTau181 /Aβ42 + MCI/dementia participants relative to all pTau181 /Aβ42 - participants. Neurodegeneration biomarkers increased with clinical severity among pTau181 /Aβ42 + participants and predicted worse cognitive performance. Glial activation biomarkers were unrelated to cognitive performance.The NTK contains promising markers that improve the pathophysiological characterization of AD. Neurodegeneration biomarkers beyond tTau improved statistical prediction of cognition and disease stages.
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| 6. |
- Xu, Yuexuan, et al.
(författare)
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Effect of Pathway-Specific Polygenic Risk Scores for Alzheimer's Disease (AD) on Rate of Change in Cognitive Function and AD-Related Biomarkers Among Asymptomatic Individuals.
- 2023
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Ingår i: Journal of Alzheimer's disease : JAD. - 1875-8908. ; 94:4, s. 1587-1605
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Tidskriftsartikel (refereegranskat)abstract
- Genetic scores for late-onset Alzheimer's disease (LOAD) have been associated with preclinical cognitive decline and biomarker variations. Compared with an overall polygenic risk score (PRS), a pathway-specific PRS (p-PRS) may be more appropriate in predicting a specific biomarker or cognitive component underlying LOAD pathology earlier in the lifespan.In this study, we leveraged longitudinal data from the Wisconsin Registry for Alzheimer's Prevention and explored changing patterns in cognition and biomarkers at various age points along six biological pathways.PRS and p-PRSs with and without APOE were constructed separately based on the significant SNPs associated with LOAD in a recent genome-wide association study meta-analysis and compared to APOE alone. We used a linear mixed-effects model to assess the association between PRS/p-PRSs and cognitive trajectories among 1,175 individuals. We also applied the model to the outcomes of cerebrospinal fluid biomarkers in a subset. Replication analyses were performed in an independent sample.We found p-PRSs and the overall PRS can predict preclinical changes in cognition and biomarkers. The effects of PRS/p-PRSs on rate of change in cognition, amyloid-β, and tau outcomes are dependent on age and appear earlier in the lifespan when APOE is included in these risk scores compared to when APOE is excluded.In addition to APOE, the p-PRSs can predict age-dependent changes in amyloid-β, tau, and cognition. Once validated, they could be used to identify individuals with an elevated genetic risk of accumulating amyloid-β and tau, long before the onset of clinical symptoms.
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| 7. |
- Xu, Yuexuan, et al.
(författare)
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Effect of Pathway-specific Polygenic Risk Scores for Alzheimer's Disease (AD) on Rate of Change in Cognitive Function and AD-related Biomarkers among Asymptomatic Individuals.
- 2023
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Ingår i: medRxiv : the preprint server for health sciences. - : Cold Spring Harbor Laboratory.
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Genetic scores for late-onset Alzheimer's disease (LOAD) have been associated with preclinical cognitive decline and biomarker variations. Compared with an overall polygenic risk score (PRS), a pathway-specific PRS (p-PRS) may be more appropriate in predicting a specific biomarker or cognitive component underlying LOAD pathology earlier in the lifespan.In this study, we leveraged 10 years of longitudinal data from initially cognitively unimpaired individuals in the Wisconsin Registry for Alzheimer's Prevention and explored changing patterns in cognition and biomarkers at various age points along six biological pathways.PRS and p-PRSs with and without apolipoprotein E ( APOE ) were constructed separately based on the significant SNPs associated with LOAD in a recent genome-wide association study meta-analysis and compared to APOE alone. We used a linear mixed-effects model to assess the association between PRS/p-PRSs and global/domain-specific cognitive trajectories among 1,175 individuals. We also applied the model to the outcomes of cerebrospinal fluid biomarkers for beta-amyloid 42 (Aβ42), Aβ42/40 ratio, total tau, and phosphorylated tau in a subset. Replication analyses were performed in an independent sample.We found p-PRSs and the overall PRS can predict preclinical changes in cognition and biomarkers. The effects of p-PRSs/PRS on rate of change in cognition, beta-amyloid, and tau outcomes are dependent on age and appear earlier in the lifespan when APOE is included in these risk scores compared to when APOE is excluded.In addition to APOE , the p-PRSs can predict age-dependent changes in beta-amyloid, tau, and cognition. Once validated, they could be used to identify individuals with an elevated genetic risk of accumulating beta-amyloid and tau, long before the onset of clinical symptoms.
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| 8. |
- Ashton, Nicholas J., et al.
(författare)
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Diagnostic Accuracy of a Plasma Phosphorylated Tau 217 Immunoassay for Alzheimer Disease Pathology
- 2024
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Ingår i: JAMA NEUROLOGY. - 2168-6149 .- 2168-6157.
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Tidskriftsartikel (refereegranskat)abstract
- ImportancePhosphorylated tau (p-tau) is a specific blood biomarker for Alzheimer disease (AD) pathology, with p-tau217 considered to have the most utility. However, availability of p-tau217 tests for research and clinical use has been limited. Expanding access to this highly accurate AD biomarker is crucial for wider evaluation and implementation of AD blood tests. ObjectiveTo determine the utility of a novel and commercially available immunoassay for plasma p-tau217 to detect AD pathology and evaluate reference ranges for abnormal amyloid beta (A beta) and longitudinal change across 3 selected cohorts. Design, Setting, and ParticipantsThis cohort study examined data from 3 single-center observational cohorts: cross-sectional and longitudinal data from the Translational Biomarkers in Aging and Dementia (TRIAD) cohort (visits October 2017-August 2021) and Wisconsin Registry for Alzheimer's Prevention (WRAP) cohort (visits February 2007-November 2020) and cross-sectional data from the Sant Pau Initiative on Neurodegeneration (SPIN) cohort (baseline visits March 2009-November 2021). Participants included individuals with and without cognitive impairment grouped by amyloid and tau (AT) status using PET or CSF biomarkers. Data were analyzed from February to June 2023. ExposuresMagnetic resonance imaging, A beta positron emission tomography (PET), tau PET, cerebrospinal fluid (CSF) biomarkers (A beta 42/40 and p-tau immunoassays), and plasma p-tau217 (ALZpath pTau217 assay). Main Outcomes and MeasuresAccuracy of plasma p-tau217 in detecting abnormal amyloid and tau pathology, longitudinal p-tau217 change according to baseline pathology status. ResultsThe study included 786 participants (mean [SD] age, 66.3 [9.7] years; 504 females [64.1%] and 282 males [35.9%]). High accuracy was observed in identifying elevated A beta (area under the curve [AUC], 0.92-0.96; 95% CI, 0.89-0.99) and tau pathology (AUC, 0.93-0.97; 95% CI, 0.84-0.99) across all cohorts. These accuracies were comparable with CSF biomarkers in determining abnormal PET signal. The detection of abnormal A beta pathology using a 3-range reference yielded reproducible results and reduced confirmatory testing by approximately 80%. Longitudinally, plasma p-tau217 values showed an annual increase only in A beta-positive individuals, with the highest increase observed in those with tau positivity. Conclusions and RelevanceThis study found that a commercially available plasma p-tau217 immunoassay accurately identified biological AD, comparable with results using CSF biomarkers, with reproducible cut-offs across cohorts. It detected longitudinal changes, including at the preclinical stage.
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| 9. |
- Ashton, Nicholas J., et al.
(författare)
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Differential roles of Aβ42/40, p-tau231 and p-tau217 for Alzheimer's trial selection and disease monitoring.
- 2022
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Ingår i: Nature medicine. - : Springer Science and Business Media LLC. - 1546-170X .- 1078-8956. ; 28:12, s. 2555-2562
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Tidskriftsartikel (refereegranskat)abstract
- Blood biomarkers indicative of Alzheimer's disease (AD) pathology are altered in both preclinical and symptomatic stages of the disease. Distinctive biomarkers may be optimal for the identification of AD pathology or monitoring of disease progression. Blood biomarkers that correlate with changes in cognition and atrophy during the course of the disease could be used in clinical trials to identify successful interventions and thereby accelerate the development of efficient therapies. When disease-modifying treatments become approved for use, efficient blood-based biomarkers might also inform on treatment implementation and management in clinical practice. In the BioFINDER-1 cohort, plasma phosphorylated (p)-tau231 and amyloid-β42/40 ratio were more changed at lower thresholds of amyloid pathology. Longitudinally, however, only p-tau217 demonstrated marked amyloid-dependent changes over 4-6years in both preclinical and symptomatic stages of the disease, with no such changes observed in p-tau231, p-tau181, amyloid-β42/40, glial acidic fibrillary protein or neurofilament light. Only longitudinal increases of p-tau217 were also associated with clinical deterioration and brain atrophy in preclinical AD. The selective longitudinal increase of p-tau217 and its associations with cognitive decline and atrophy was confirmed in an independent cohort (Wisconsin Registry for Alzheimer's Prevention). These findings support the differential association of plasma biomarkers with disease development and strongly highlight p-tau217 as a surrogate marker of disease progression in preclinical and prodromal AD, with impact for the development of new disease-modifying treatments.
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| 10. |
- Clark, Lindsay R, et al.
(författare)
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Age-accelerated cognitive decline in asymptomatic adults with CSF β-amyloid.
- 2018
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Ingår i: Neurology. - 1526-632X. ; 90:15
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Tidskriftsartikel (refereegranskat)abstract
- Compare cognitive and hippocampal volume trajectories in asymptomatic middle-aged and older adults with positive CSF markers of β-amyloid (Aβ) or tau to adults without an Alzheimer disease (AD)-associated biomarker profile.Three hundred ninety-two adults enrolled in a longitudinal cohort study (Wisconsin Registry for Alzheimer's Prevention or Wisconsin Alzheimer's Disease Research Center) completed a lumbar puncture and at least 2 biennial or annual neuropsychological evaluations. Cutoffs for Aβ42, total tau, and phosphorylated tau were developed via receiver operating characteristic curve analyses on a sample of 78 participants (38 dementia, 40 controls). These cutoffs were applied to a separate sample of 314 cognitively healthy adults (mean age at CSF collection = 61.5 years), and mixed-effects regression analyses tested linear and quadratic interactions of biomarker group × age at each visit on cognitive and hippocampal volume outcomes.Two hundred fifteen participants (69%) were biomarker negative (preclinical AD stage 0), 46 (15%) were Aβ+ only (preclinical AD stage 1), 25 (8%) were Aβ+ and tau+ (preclinical AD stage 2), and 28 (9%) were tau+ only. Both stage 1 and stage 2 groups exhibited greater rates of linear decline on story memory and processing speed measures, and nonlinear decline on list-learning and set-shifting measures compared to stage 0. The tau+ only group did not significantly differ from stage 0 in rates of cognitive decline.In an asymptomatic at-risk cohort, elevated CSF Aβ (with or without elevated tau) was associated with greater rates of cognitive decline, with the specific pattern of decline varying across cognitive measures.
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