| 1. |
- Binette, Alexa Pichet, et al.
(författare)
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Amyloid-associated increases in soluble tau is a key driver in accumulation of tau aggregates and cognitive decline in early Alzheimer
- 2022
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Ingår i: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 18:S1
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Tidskriftsartikel (refereegranskat)abstract
- Background: For optimal design of anti-amyloid-β (Aβ) and anti-tau clinical trials, it is important to understand how Aβ and soluble phosphorylated tau (p-tau) relate to the accumulation of tau aggregates assessed with positron emission tomography (PET) and subsequent cognitive decline across the Alzheimer's disease (AD) continuum. Method: We included 327 participants from the Swedish BioFINDER-2 cohort with cerebrospinal fluid (CSF) p-tau217, Aβ-PET, longitudinal tau-PET, and longitudinal cognition. The main groups of interest were Aβ-positive non-demented participants and AD dementia patients (Table 1 and Figure 1), and analyses were conducted separately in each group. First, we investigated how soluble p-tau217 and regional Aβ-PET were associated with tau-PET rate of change across the 200 brain parcels from the Schaefer atlas. We also tested the mediating effect of p-tau217 between Aβ-PET and tau-PET change. Second, we investigated how soluble p-tau217 and tau-PET change related to change in cognition, and mediation between these variables. Result: In early AD stages (non-demented participants), increased concentration of soluble p-tau217 was the main driver of accumulation of insoluble tau aggregates across the brain (measured as tau-PET rate of change), beyond the effect of regional Aβ-PET and baseline tau-PET (Figure 2A-C). Further, averaged across all regions, soluble p-tau217 mediated 54% of the association between Aβ and tau aggregation (Figure 2D). Higher soluble p-tau217 concentrations were also associated with cognitive decline, which was mediated by faster increase of tau aggregates (Figure 3). Repeating the same analyses in the AD dementia group, results were different. In late stage of AD, when Aβ fibrils and soluble p-tau levels have plateaued, soluble p-tau217 was not associated with accumulation of tau aggregates beyond baseline tau-PET (Figure 4A), and cognitive decline was driven by the accumulation rate of insoluble tau aggregates and not soluble p-tau217 (Figure 4B-C). Conclusion: Soluble p-tau is a main driver of tau aggregation and future cognitive decline in earlier stages of AD, whereas tau aggregation accumulation is more likely an important driver of disease in later stages. Overall, our data suggest that therapeutic approaches reducing soluble p-tau levels might be most favorable in early AD.
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| 2. |
- Cullen, Nicholas C., et al.
(författare)
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Test-retest variability of plasma biomarkers in Alzheimer's disease and its effects on clinical prediction models
- 2023
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Ingår i: Alzheimers & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 19:3, s. 797-806
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION The effect of random error on the performance of blood-based biomarkers for Alzheimer's disease (AD) must be determined before clinical implementation. METHODS We measured test-retest variability of plasma amyloid beta (A beta)42/A beta 40, neurofilament light (NfL), glial fibrillary acidic protein (GFAP), and phosphorylated tau (p-tau)217 and simulated effects of this variability on biomarker performance when predicting either cerebrospinal fluid (CSF) A beta status or conversion to AD dementia in 399 non-demented participants with cognitive symptoms. RESULTS Clinical performance was highest when combining all biomarkers. Among single-biomarkers, p-tau217 performed best. Test-retest variability ranged from 4.1% (A beta 42/A beta 40) to 25% (GFAP). This variability reduced the performance of the biomarkers (approximate to Delta AUC [area under the curve] -1% to -4%) with the least effects on models with p-tau217. The percent of individuals with unstable predicted outcomes was lowest for the multi-biomarker combination (14%). DISCUSSION Clinical prediction models combining plasma biomarkers-particularly p-tau217-exhibit high performance and are less effected by random error. Individuals with unstable predicted outcomes ("gray zone") should be recommended for further tests.
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| 3. |
- Groot, Colin, et al.
(författare)
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A biomarker profile of elevated CSF p-tau with normal tau PET is associated with increased tau accumulation rates on PET in early Alzheimer’s disease
- 2022
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Ingår i: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 18:S1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Different tau biomarkers become abnormal at different stages of Alzheimer’s disease (AD), with CSF p-tau typically being elevated at subthreshold levels of tau-PET binding. To capitalize on the temporal order of tau biomarker-abnormality and capture the earliest changes of tau accumulation, we selected a group of amyloid-β-positive (A+) individuals with elevated CSF p-tau levels but negative tau-PET scans and assessed longitudinal changes in tau-PET, cortical thickness and cognitive decline. Method: Individuals without dementia (i.e., cognitively unimpaired (CU) or mild cognitive impairment, n=231) were selected from the BioFINDER-2 study. These subjects were categorized into biomarker groups based on Gaussian mixture modelling to determine cut-offs for abnormal CSF Aβ42/40 (A; <0.078), CSF p-tau217 (P; >110 pg/ml) and [18F]RO948 tau-PET SUVR within a temporal meta-ROI (T; SUVR >1.40). Resulting groups were: A+P-T- (concordant, n=30), A+P+T- (discordant, n=48) and A+P+T+ (concordant, n=18). We additionally used 135 A- CU individuals (A- CU) as a reference group (Tables 1 and 2). Differences in annual change in regional tau-PET SUVR, cortical thickness and cognition between the A+P+T- group and the other groups were assessed using general linear models, adjusted for age, sex, clinical diagnosis and (for cognitive measures) education. Result: Longitudinal change in tau-PET was faster in the A+P+T- group than in the A- CU and A+P-T- groups across medial temporal and neocortical regions, with the medial temporal increases being more pronounced. The A+P+T- group showed slower rate of increases in tau-PET compared to the A+P+T+ group, primarily in neocortical regions (Figures 1 and 2). We did not detect differences in yearly change in cortical thickness (Figure 3) or in cognitive decline (Figure 3) between the A+P+T- and A+P-T- groups. The A+P+T+ group, however, showed faster cognitive decline compared to all other groups. Conclusion: These findings suggest that the A+P+T- biomarker profile is associated with early tau accumulation, and with relative sparing of cortical thinning and cognitive decline compared to A+P+T+ individuals. Therefore, the A+P+T- group represents an interesting target-group for early anti-tau interventions and for examining the emergence of tau aggregates in early AD.
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| 4. |
- Gustavsson, Anders, et al.
(författare)
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Health utility in preclinical and prodromal Alzheimer's disease for establishing the value of new disease-modifying treatments—EQ-5D data from the Swedish BioFINDER study
- 2021
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Ingår i: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 17:11, s. 1832-1842
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Tidskriftsartikel (refereegranskat)abstract
- Quality of life and health utility are important outcomes for patients with Alzheimer's disease (AD) and central for demonstrating the value of new treatments. Estimates in biomarker-confirmed AD populations are missing, potentially delaying payer approval of treatment. We examined whether health utility, assessed with the EuroQoL-5 3-level version (EQ-5D-3L), differed between individuals with a positive or negative amyloid beta (Aβ) biomarker in patients with mild cognitive impairment (MCI) and cognitively unimpaired (CU) participants from the Swedish BioFINDER study (n = 578). Participants with prodromal AD (Aβ-positive MCI) reported better health utility (n = 79, mean = 0.81, 95% confidence interval [CI] 0.77–0.85) than Aβ-negative MCI (mean = 0.71, 95% CI 0.64–0.78), but worse than controls (Aβ-negative CU, mean = 0.87, 95% CI 0.86–0.89). Health utility in preclinical AD (Aβ-positive CU; mean = 0.86, 95% CI 0.83–0.89) was similar to controls. This relatively good health utility in prodromal AD suggests a larger value of delaying progression to dementia than previously anticipated and a great value of delaying clinical progression in preclinical AD.
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| 5. |
- Hansson, Oskar, et al.
(författare)
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Cerebral hypoperfusion is not associated with an increase in amyloid β pathology in middle-aged or elderly people
- 2018
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Ingår i: Alzheimer's and Dementia. - : Wiley. - 1552-5279 .- 1552-5260. ; 14:1, s. 54-61
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: It is hypothesized that cerebral hypoperfusion promotes the development of Alzheimer pathology. We therefore studied whether longstanding cerebral hypoperfusion is associated with Alzheimer pathology in nondemented humans.METHODS: Cerebral blood flow and amyloid β ((18)F-Flutemetamol) positron emission tomography retention were assessed in eleven patients with unilateral occlusion of precerebral arteries resulting in chronic and uneven hypoperfusion. A subset of patients underwent tau ((18)F-AV-1451) positron emission tomography.RESULTS: The blood flow was significantly reduced on the affected side of the brain in patients with unilateral occlusion of the internal carotid artery or stenosis of the middle cerebral artery. However, the cortical uptake of (18)F-Flutemetamol or (18)F-AV-1451 was not altered.DISCUSSION: Our results suggest that longstanding cerebral hypoperfusion in humans does not result in accumulation of amyloid β fibrils or tau aggregates.
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| 6. |
- Janelidze, Shorena, et al.
(författare)
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Detecting amyloid positivity in early Alzheimer's disease using combinations of plasma A beta 42/A beta 40 and p-tau
- 2022
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Ingår i: Alzheimers & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 18:2, s. 283-293
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: We studied usefulness of combining blood amyloid beta A(beta)42/A beta 40, phosphorylated tau (p-tau)217, and neurofilament light (NfL) to detect abnormal brain A beta deposition in different stages of early Alzheimer's disease (AD). Methods: Plasma biomarkers were measured using mass spectrometry (A beta 42/A beta 40) and immunoassays (p-tau217 and NfL) in cognitively unimpaired individuals (CU, N = 591) and patients with mild cognitive impairment (MCI, N = 304) from two independent cohorts (BioFINDER-1, BioFINDER-2). Results: In CU, a combination of plasma A beta 42/A beta 40 and p-tau217 detected abnormal brain A beta status with area under the curve (AUC) of 0.83 to 0.86. In MCI, the models including p-tau217 alone or A beta 42/A beta 40 and p-tau217 had similar AUCs (0.86-0.88); however, the latter showed improved model fit. The models were implemented in an online application providing individualized risk assessments (https://brainapps.shinyappas.io/PredictAAbplasma/). Discussion:A combination of plasma A beta 42/A beta 40 and p-tau217 discriminated A beta status with relatively high accuracy, whereas p-tau217 showed strongest associations with A beta pathology in MCI but not in CU.
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| 7. |
- Leuzy, Antoine, et al.
(författare)
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Robustness of CSF Aβ42/40 and Aβ42/P-tau181 measured using fully automated immunoassays to detect AD-related outcomes
- 2023
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Ingår i: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 19:7, s. 2994-3004
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: This study investigated the comparability of cerebrospinal fluid (CSF) cutoffs for Elecsys immunoassays for amyloid beta (Aβ)42/Aβ40 or Aβ42/phosphorylated tau (p-tau)181 and the effects of measurement variability when predicting Alzheimer's disease (AD)-related outcomes (i.e., Aβ-positron emission tomography [PET] visual read and AD neuropathology). Methods: We studied 750 participants (BioFINDER study, Alzheimer's Disease Neuroimaging Initiative [ADNI], and University of California San Francisco [UCSF]). Youden's index was used to identify cutoffs and to calculate accuracy (Aβ-PET visual read as outcome). Using longitudinal variability in Aβ-negative controls, we identified a gray zone around cut-points where the risk of an inconsistent predicted outcome was >5%. Results: For Aβ42/Aβ40, cutoffs across cohorts were <0.059 (BioFINDER), <0.057 (ADNI), and <0.058 (UCSF). For Aβ42/p-tau181, cutoffs were <41.90 (BioFINDER), <39.20 (ADNI), and <46.02 (UCSF). Accuracy was ≈90% for both Aβ42/Aβ40 and Aβ42/p-tau181 using these cutoffs. Using Aβ-PET as an outcome, 8.7% of participants fell within a gray zone interval for Aβ42/Aβ40, compared to 4.5% for Aβ42/p-tau181. Similar findings were observed using a measure of overall AD neuropathologic change (7.7% vs. 3.3%). In a subset with CSF and plasma Aβ42/40, the number of individuals within the gray zone was ≈1.5 to 3 times greater when using plasma Aβ42/40. Discussion: CSF Aβ42/p-tau181 was more robust to the effects of measurement variability, suggesting that it may be the preferred Elecsys-based measure in clinical practice and trials.
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| 8. |
- Ossenkoppele, Rik, et al.
(författare)
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Distinct tau PET patterns in atrophy-defined subtypes of Alzheimer's disease
- 2020
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Ingår i: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 16:2, s. 335-344
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Differential patterns of brain atrophy on structural magnetic resonance imaging (MRI) revealed four reproducible subtypes of Alzheimer's disease (AD): (1) “typical”, (2) “limbic-predominant”, (3) “hippocampal-sparing”, and (4) “mild atrophy”. We examined the neurobiological characteristics and clinical progression of these atrophy-defined subtypes. Methods: The four subtypes were replicated using a clustering method on MRI data in 260 amyloid-β–positive patients with mild cognitive impairment or AD dementia, and we subsequently tested whether the subtypes differed on [18F]flortaucipir (tau) positron emission tomography, white matter hyperintensity burden, and rate of global cognitive decline. Results: Voxel-wise and region-of-interest analyses revealed the greatest neocortical tau load in hippocampal-sparing (frontoparietal-predominant) and typical (temporal-predominant) patients, while limbic-predominant patients showed particularly high entorhinal tau. Typical patients with AD had the most pronounced white matter hyperintensity load, and hippocampal-sparing patients showed the most rapid global cognitive decline. Discussion: Our data suggest that structural MRI can be used to identify biologically and clinically meaningful subtypes of AD.
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| 9. |
- Palmqvist, Sebastian, et al.
(författare)
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Accurate risk estimation of β-amyloid positivity to identify prodromal Alzheimer's disease : Cross-validation study of practical algorithms
- 2019
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Ingår i: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 15:2, s. 194-204
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: The aim was to create readily available algorithms that estimate the individual risk of β-amyloid (Aβ) positivity. Methods: The algorithms were tested in BioFINDER (n = 391, subjective cognitive decline or mild cognitive impairment) and validated in Alzheimer's Disease Neuroimaging Initiative (n = 661, subjective cognitive decline or mild cognitive impairment). The examined predictors of Aβ status were demographics; cognitive tests; white matter lesions; apolipoprotein E (APOE); and plasma Aβ42/Aβ40, tau, and neurofilament light. Results: Aβ status was accurately estimated in BioFINDER using age, 10-word delayed recall or Mini–Mental State Examination, and APOE (area under the receiver operating characteristics curve = 0.81 [0.77–0.85] to 0.83 [0.79–0.87]). When validated, the models performed almost identical in Alzheimer's Disease Neuroimaging Initiative (area under the receiver operating characteristics curve = 0.80–0.82) and within different age, subjective cognitive decline, and mild cognitive impairment populations. Plasma Aβ42/Aβ40 improved the models slightly. Discussion: The algorithms are implemented on http://amyloidrisk.com where the individual probability of being Aβ positive can be calculated. This is useful in the workup of prodromal Alzheimer's disease and can reduce the number needed to screen in Alzheimer's disease trials.
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| 10. |
- Palmqvist, Sebastian, et al.
(författare)
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An accurate fully automated panel of plasma biomarkers for Alzheimer's disease
- 2023
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Ingår i: Alzheimers & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 19:4, s. 1204-1215
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Tidskriftsartikel (refereegranskat)abstract
- Introduction There is a great need for fully automated plasma assays that can measure amyloid beta (A beta) pathology and predict future Alzheimer's disease (AD) dementia. Methods Two cohorts (n = 920) were examined: Panel A+ (n = 32 cognitively unimpaired [CU], n = 106 mild cognitive impairment [MCI], and n = 89 AD) and BioFINDER-1 (n = 461 CU, n = 232 MCI). Plasma A beta 42/A beta 40, phosphorylated tau (p-tau)181, two p-tau217 variants, ApoE4 protein, neurofilament light, and GFAP were measured using Elecsys prototype immunoassays. Results The best biomarker for discriminating A beta-positive versus A beta-negative participants was A beta 42/A beta 40 (are under the curve [AUC] 0.83-0.87). Combining A beta 42/A beta 40, p-tau181, and ApoE4 improved the AUCs significantly (0.90 to 0.93; P< 0.01). Adding additional biomarkers had marginal effects (Delta AUC <= 0.01). In BioFINDER, p-tau181, p-tau217, and ApoE4 predicted AD dementia within 6 years in CU (AUC 0.88) and p-tau181, p-tau217, and A beta 42/A beta 40 in MCI (AUC 0.87). Discussion The high accuracies for A beta pathology and future AD dementia using fully automated instruments are promising for implementing plasma biomarkers in clinical trials and clinical routine.
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