| 71. |
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| 72. |
- Karikari, Thomas, et al.
(författare)
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Blood phosphorylated tau 181 as a biomarker for Alzheimer's disease: a diagnostic performance and prediction modelling study using data from four prospective cohorts.
- 2020
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Ingår i: The Lancet. Neurology. - 1474-4465 .- 1474-4422. ; 19:5, s. 422-433
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Tidskriftsartikel (refereegranskat)abstract
- CSF and PET biomarkers of amyloid β and tau accurately detect Alzheimer's disease pathology, but the invasiveness, high cost, and poor availability of these detection methods restrict their widespread use as clinical diagnostic tools. CSF tau phosphorylated at threonine 181 (p-tau181) is a highly specific biomarker for Alzheimer's disease pathology. We aimed to assess whether blood p-tau181 could be used as a biomarker for Alzheimer's disease and for prediction of cognitive decline and hippocampal atrophy.We developed and validated an ultrasensitive blood immunoassay for p-tau181. Assay performance was evaluated in four clinic-based prospective cohorts. The discovery cohort comprised patients with Alzheimer's disease and age-matched controls. Two validation cohorts (TRIAD and BioFINDER-2) included cognitively unimpaired older adults (mean age 63-69 years), participants with mild cognitive impairment (MCI), Alzheimer's disease, and frontotemporal dementia. In addition, TRIAD included healthy young adults (mean age 23 years) and BioFINDER-2 included patients with other neurodegenerative disorders. The primary care cohort, which recruited participants in Montreal, Canada, comprised control participants from the community without a diagnosis of a neurological condition and patients referred from primary care physicians of the Canadian National Health Service for specialist care. Concentrations of plasma p-tau181 were compared with established CSF and PET biomarkers and longitudinal measurements using Spearman correlation, area under the curve (AUC), and linear regression analyses.We studied 37 individuals in the discovery cohort, 226 in the first validation cohort (TRIAD), 763 in the second validation cohort (BioFINDER-2), and 105 in the primary care cohort (n=1131 individuals). In all cohorts, plasma p-tau181 showed gradual increases along the Alzheimer's disease continuum, from the lowest concentrations in amyloid β-negative young adults and cognitively unimpaired older adults, through higher concentrations in the amyloid β-positive cognitively unimpaired older adults and MCI groups, to the highest concentrations in the amyloid β-positive MCI and Alzheimer's disease groups (p<0·001, Alzheimer's disease vs all other groups). Plasma p-tau181 distinguished Alzheimer's disease dementia from amyloid β-negative young adults (AUC=99·40%) and cognitively unimpaired older adults (AUC=90·21-98·24% across cohorts), as well as other neurodegenerative disorders, including frontotemporal dementia (AUC=82·76-100% across cohorts), vascular dementia (AUC=92·13%), progressive supranuclear palsy or corticobasal syndrome (AUC=88·47%), and Parkinson's disease or multiple systems atrophy (AUC=81·90%). Plasma p-tau181 was associated with PET-measured cerebral tau (AUC=83·08-93·11% across cohorts) and amyloid β (AUC=76·14-88·09% across cohorts) pathologies, and 1-year cognitive decline (p=0·0015) and hippocampal atrophy (p=0·015). In the primary care cohort, plasma p-tau181 discriminated Alzheimer's disease from young adults (AUC=100%) and cognitively unimpaired older adults (AUC=84·44%), but not from MCI (AUC=55·00%).Blood p-tau181 can predict tau and amyloid β pathologies, differentiate Alzheimer's disease from other neurodegenerative disorders, and identify Alzheimer's disease across the clinical continuum. Blood p-tau181 could be used as a simple, accessible, and scalable test for screening and diagnosis of Alzheimer's disease.Alzheimer Drug Discovery Foundation, European Research Council, Swedish Research Council, Swedish Alzheimer Foundation, Swedish Dementia Foundation, Alzheimer Society Research Program.
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| 73. |
- Karlsson, Linda, et al.
(författare)
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Cerebrospinal fluid reference proteins increase accuracy and interpretability of biomarkers for brain diseases.
- 2024
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Ingår i: Nature Communications. - 2041-1723. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- Cerebrospinal fluid (CSF) biomarkers reflect brain pathophysiology and are used extensively in translational research as well as in clinical practice for diagnosis of neurological diseases, e.g., Alzheimer's disease (AD). However, CSF biomarker concentrations may be influenced by non-disease related inter-individual variability. Here we use a data-driven approach to demonstrate the existence of inter-individual variability in mean standardized CSF protein levels. We show that these non-disease related differences cause many commonly reported CSF biomarkers to be highly correlated, thereby producing misleading results if not accounted for. To adjust for this inter-individual variability, we identified and evaluated high-performing reference proteins which improved the diagnostic accuracy of key CSF AD biomarkers. Our reference protein method attenuates the risk for false positive findings, and improves the sensitivity and specificity of CSF biomarkers, with broad implications for both research and clinical practice.
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| 74. |
- Kumar, Atul, et al.
(författare)
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Genetic effects on longitudinal cognitive decline during the early stages of Alzheimer’s disease
- 2021
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Cognitive decline in early-stage Alzheimer’s disease (AD) may depend on genetic variability. In the Swedish BioFINDER study, we used polygenic scores (PGS) (for AD, intelligence, and educational attainment) to predict longitudinal cognitive change (measured by mini-mental state examination (MMSE) [primary outcome] and other cognitive tests) over a mean of 4.2 years. We included 260 β-amyloid (Aβ) negative cognitively unimpaired (CU) individuals, 121 Aβ-positive CU (preclinical AD), 50 Aβ-negative mild cognitive impairment (MCI) patients, and 127 Aβ-positive MCI patients (prodromal AD). Statistical significance was determined at Bonferroni corrected p value < 0.05. The PGS for intelligence (beta = 0.1, p = 2.9e−02) was protective against decline in MMSE in CU and MCI participants regardless of Aβ status. The polygenic risk score for AD (beta = − 0.12, p = 9.4e−03) was correlated with the rate of change in MMSE and was partially mediated by Aβ-pathology (mediation effect 20%). There was no effect of education PGS on cognitive measures. Genetic variants associated with intelligence mitigate cognitive decline independent of Aβ-pathology, while effects of genetic variants associated with AD are partly mediated by Aβ-pathology.
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| 75. |
- Kumar, Atul, et al.
(författare)
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Genetic influence during the early phases of Alzheimer's disease on longitudinal cognitive impairment
- 2021
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Ingår i: Alzheimer's & dementia : the journal of the Alzheimer's Association. - 1552-5279. ; 17
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The rate of cognitive decline in the early stages of Alzheimer's disease (AD) is variable, which may be partly due to genetic factors. We therefore investigated genetic predictors of longitudinal cognitive decline in AD. METHOD: In the Swedish BioFINDER study, we used polygenic scores (PGS) (of AD, intelligence and educational attainment), and genetic variants (in a genome-wide association study [GWAS]) to predict longitudinal change in cognition (measured by MMSE) over a mean of 4.2 years. We included 555 b-amyloid (Aβ) negative cognitively unimpaired (CU) individuals, 206 Aβ-positive CU (preclinical AD), 110 Aβ-negative mild cognitive impairment (MCI) patients, and 146 Aβ-positive MCI patients (prodromal AD). Mixed-effect models were fitted with longitudinal MMSE data as dependent variable. Random slopes and intercepts were extracted and were rank-based inverse normal transformed (INT) to be used as dependent variables in linear regression models. RESULT: AD polygenic risk score (PRS) and intelligence PGS (but not education PGS) were associated with rate of cognitive decline (Figure 1). The AD PRS was only associated with decline in Ab-positive individuals, but the intelligence PGS was protective irrespective of Ab-status (Figure 2). The model containing only the APOE burden (ε4 and ε2 counts) was associated with cognitive decline with a nominal level of significance, whereas this was not found for the early-stage AD cohort (Figure 1 and 2). Our GWAS identified 8 genes (out of which 3 genes independent of Aβ-status) associated with rate of cognitive decline at a p-value ≤ 5e-05 (Table 1). CONCLUSION: An a priori defined genetic risk score for AD was only associated with rate of cognitive decline in early stage AD (Aβ+ CU and Aβ+ MCI) and not in an unselected population, while a polygenic score for intelligence was protective irrespective of Aβ status. Together with novel genetic associations for rate of cognitive decline in AD, this may provide new insights into the pathophysiology of AD and new therapeutic development targets.
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| 76. |
- Kumar, Atul, et al.
(författare)
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Genetic interaction study of Alzheimer's disease quantitative biomarkers : A polygenic risk score analysis and evaluation
- 2021
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Ingår i: Alzheimer's & dementia : the journal of the Alzheimer's Association. - 1552-5279. ; 17
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Relationship between genetic factors and pathological features of Alzheimer's disease (AD) may be studied with biomarker, using both polygenic risk scores (PRSs), as well as individual genetic variants in genome-wide association studies (GWAS). METHOD: In the Swedish BioFINDER study, we used a priori PRS for AD based on findings in recent GWAS, and AD related biomarkers in cerebrospinal fluid (CSF) in cognitively unimpaired individuals (n = 751), Mild Cognitive Impairment (n = 212), and AD (n = 150) patients. AD related biomarkers were rank-based inverse normal transformed to be used as dependent variables in linear regression models adjusted for age, gender, education, APOE ε4, ε2 count and significant principal components. We also tested individual genetic variants in GWAS for each biomarker. Analyses were performed in the total sample, and after stratification on MMSE results. RESULT: The PRS was associated with higher CSF P-tau 181 (p ≤1.2e-05) and T-tau (p ≤ 8.14e-05) and lower CSF Aβ42/40 (p ≤ 0.006) and Aβ42 (p ≤ 0.04) (Figure 1, 2). Gene Enrichment of PRS 5 genes [containing 1850 genetic variants mapped to 1607 genes] for Tau biomarker showed 13 Gene Ontology (GO) Biological Process (BP) terms at p-value < e-03 ("Dendrite Morphogenesis": top hit; p-value ≤ 9.20e-06) and 16 KEGG pathway term enriched for genes of PRS 5 ("Phosphatidylinositol signaling system": top hit; p-value ≤ 5.5e-06) (Figure 3, 4). Gene enrichment of PRS 7 [containing 62 genetic variants mapped to 58 genes] for Aβ biomarker returned 12 GO terms ("Integrin-Mediated Signaling Pathway": top hit; p-value ≤1.20e-03) and 1 term enriched for KEGG pathway (Hematopoietic cell lineage). In our predefined list of genes interacting with MAPT (22 genes) and APP (69 genes) we found 3 genes from MAPT and APP set that were involved in PRS 5 and PRS 7 respectively. We also found 9 genes from APP set that was involved in PRS 5. CONCLUSION: Elevated levels of AD related biomarkers are associated with polygenic risk scores in AD. These findings further strengthens the link between genetic and biomarker disease predictors and indicate a potential role for these markers in disease prediction and patient stratification in AD.
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| 77. |
- Kumar, Atul, et al.
(författare)
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β-Amyloid-Dependent and-Independent Genetic Pathways Regulating CSF Tau Biomarkers in Alzheimer Disease
- 2022
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Ingår i: Neurology. - 0028-3878. ; 99:5, s. 476-487
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Tidskriftsartikel (refereegranskat)abstract
- Abnormal metabolism of β-amyloid (Aβ) and soluble phosphorylated tau (P-tau), as well as neurodegeneration, are key components of Alzheimer disease (AD), but it is unclear how these different processes are related to genetic risk factors for AD.MethodsIn the Swedish BioFINDER study, we tested associations between a priori defined polygenic risk scores (PRSs) for AD (excluding single-nucleotide polymorphism [SNP] within the APOE region in the main analysis) and biomarkers in CSF (total tau [T-tau] and P-tau181; Aβ1-38, Aβ1-40, Aβ1-42, and Aβ1-42/1-40; and neurofilament light [NfL]) in cognitively unimpaired (CU) individuals (n = 751), and in patients with mild cognitive impairment (MCI) (n = 212) and AD dementia (n = 150). Results were validated in the Alzheimer's Disease Neuroimaging Initiative data set with 777 individuals (AD = 119, MCI = 442, and CU = 216).ResultsPRSs with SNPs significant at p < 5e-03 (∼1,742 variants) were associated with higher CSF P-tau181 (β = 0.13, p = 5.6e-05) and T-tau (β = 0.12, p = 4.3e-04). The associations between PRS and tau measures were partly attenuated but remained significant after adjusting for Aβ status. Aβ pathology mediated 37% of the effect of this PRS on tau levels. Aβ-dependent and Aβ-independent subsets of the PRS were identified and characterized. There were also associations between PRSs and CSF Aβ biomarkers with nominal significance, but not when corrected for multiple comparisons. There were no associations between PRSs and CSF NfL.DiscussionGenetic pathways implicated in causing AD are related to altered levels of soluble tau through both Aβ-dependent and Aβ-independent mechanisms, which may have relevance for anti-tau drug development.
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| 78. |
- Lantero Rodriguez, Juan, et al.
(författare)
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Plasma N-terminal containing tau fragments (NTA-tau): a biomarker of tau deposition in Alzheimer's Disease
- 2024
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Ingår i: MOLECULAR NEURODEGENERATION. - 1750-1326. ; 19:1
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Tidskriftsartikel (refereegranskat)abstract
- Background Novel phosphorylated-tau (p-tau) blood biomarkers (e.g., p-tau181, p-tau217 or p-tau231), are highly specific for Alzheimer's disease (AD), and can track amyloid-beta (A beta) and tau pathology. However, because these biomarkers are strongly associated with the emergence of A beta pathology, it is difficult to determine the contribution of insoluble tau aggregates to the plasma p-tau signal in blood. Therefore, there remains a need for a biomarker capable of specifically tracking insoluble tau accumulation in brain. Methods NTA is a novel ultrasensitive assay targeting N-terminal containing tau fragments (NTA-tau) in cerebrospinal fluid (CSF) and plasma, which is elevated in AD. Using two well-characterized research cohorts (BioFINDER-2, n = 1,294, and BioFINDER-1, n = 932), we investigated the association between plasma NTA-tau levels and disease progression in AD, including tau accumulation, brain atrophy and cognitive decline. Results We demonstrate that plasma NTA-tau increases across the AD continuum, especially during late stages, and displays a moderate-to-strong association with tau-PET (beta = 0.54, p < 0.001) in A beta-positive participants, while weak with A beta-PET (beta = 0.28, p < 0.001). Unlike plasma p-tau181, GFAP, NfL and t-tau, tau pathology determined with tau-PET is the most prominent contributor to NTA-tau variance (52.5% of total R-2), while having very low contribution from A beta pathology measured with CSF A beta 42/40 (4.3%). High baseline NTA-tau levels are predictive of tau-PET accumulation (R-2 = 0.27), steeper atrophy (R-2 >= 0.18) and steeper cognitive decline (R-2 >= 0.27) in participants within the AD continuum. Plasma NTA-tau levels significantly increase over time in A beta positive cognitively unimpaired (beta(std) = 0.16) and impaired (beta(std) = 0.18) at baseline compared to their A beta negative counterparts. Finally, longitudinal increases in plasma NTA-tau levels were associated with steeper longitudinal decreases in cortical thickness (R-2 = 0.21) and cognition (R-2 = 0.20). Conclusion Our results indicate that plasma NTA-tau levels increase across the AD continuum, especially during mid-to-late AD stages, and it is closely associated with in vivo tau tangle deposition in AD and its downstream effects. Moreover, this novel biomarker has potential as a cost-effective and easily accessible tool for monitoring disease progression and cognitive decline in clinical settings, and as an outcome measure in clinical trials which also need to assess the downstream effects of successful A beta removal.
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| 79. |
- Lerch, Ondrej, et al.
(författare)
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Predicting progression from subjective cognitive decline to mild cognitive impairment or dementia based on brain atrophy patterns
- 2024
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Ingår i: Alzheimer's Research and Therapy. - 1758-9193. ; 16:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder where pathophysiological changes begin decades before the onset of clinical symptoms. Analysis of brain atrophy patterns using structural MRI and multivariate data analysis are an effective tool in identifying patients with subjective cognitive decline (SCD) at higher risk of progression to AD dementia. Atrophy patterns obtained from models trained to classify advanced AD versus normal subjects, may not be optimal for subjects at an early stage, like SCD. In this study, we compared the accuracy of the SCD progression prediction using the ‘severity index’ generated using a standard classification model trained on patients with AD dementia versus a new model trained on β-amyloid (Aβ) positive patients with amnestic mild cognitive impairment (aMCI). Methods: We used structural MRI data of 504 patients from the Swedish BioFINDER-1 study cohort (cognitively normal (CN), Aβ-negative = 220; SCD, Aβ positive and negative = 139; aMCI, Aβ-positive = 106; AD dementia = 39). We applied multivariate data analysis to create two predictive models trained to discriminate CN individuals from either individuals with Aβ positive aMCI or AD dementia. Models were applied to individuals with SCD to classify their atrophy patterns as either high-risk “disease-like” or low-risk “CN-like”. Clinical trajectory and model accuracy were evaluated using 8 years of longitudinal data. Results: In predicting progression from SCD to MCI or dementia, the standard, dementia-based model, reached 100% specificity but only 10.6% sensitivity, while the new, aMCI-based model, reached 72.3% sensitivity and 60.9% specificity. The aMCI-based model was superior in predicting progression from SCD to MCI or dementia, reaching a higher receiver operating characteristic area under curve (AUC = 0.72; P = 0.037) in comparison with the dementia-based model (AUC = 0.57). Conclusion: When predicting conversion from SCD to MCI or dementia using structural MRI data, prediction models based on individuals with milder levels of atrophy (i.e. aMCI) may offer superior clinical value compared to standard dementia-based models.
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| 80. |
- Leuzy, Antoine, et al.
(författare)
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Biomarker-Based Prediction of Longitudinal Tau Positron Emission Tomography in Alzheimer Disease
- 2022
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Ingår i: JAMA Neurology. - : American Medical Association (AMA). - 2168-6149. ; 79:2, s. 149-158
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Tidskriftsartikel (refereegranskat)abstract
- Importance: There is currently no consensus as to which biomarkers best predict longitudinal tau accumulation at different clinical stages of Alzheimer disease (AD). Objective: To describe longitudinal [18F]RO948 tau positron emission tomography (PET) findings across the clinical continuum of AD and determine which biomarker combinations showed the strongest associations with longitudinal tau PET and best optimized clinical trial enrichment. Design, Setting, and Participants: This longitudinal cohort study consecutively enrolled amyloid-β (Aβ)-negative cognitively unimpaired (CU) participants, Aβ-positive CU individuals, Aβ-positive individuals with mild cognitive impairment (MCI), and individuals with AD dementia between September 2017 and November 2020 from the Swedish BioFINDER-2 (discovery cohort) and BioFINDER-1 (validation cohort) studies. Exposures: Baseline plasma and cerebrospinal fluid Aβ42/Aβ40, tau phosphorylated at threonine-217 (p-tau217), p-tau181 and neurofilament light, magnetic resonance imaging, amyloid PET ([18F]flutemetamol), and tau PET ([18F]RO948 in the BioFINDER-2 study; [18F]flortaucipir in the BioFINDER-1 study). Main Outcomes and Measures: Baseline tau PET standardized uptake value ratio (SUVR) and annual percent change in tau PET SUVR across regions of interest derived using a data-driven approach combining clustering and event-based modeling. Regression models were used to examine associations between individual biomarkers and longitudinal tau PET and to identify which combinations best predicted longitudinal tau PET. These combinations were then entered in a power analysis to examine how their use as an enrichment strategy would affect sample size in a simulated clinical trial. Results: Of 343 participants, the mean (SD) age was 72.56 (7.24) years, and 157 (51.1%) were female. The clustering/event-based modeling-based approach identified 5 regions of interest (stages). In Aβ-positive CU individuals, the largest annual increase in tau PET SUVR was seen in stage I (entorhinal cortex, hippocampus, and amygdala; 4.04% [95% CI, 2.67%-5.32%]). In Aβ-positive individuals with MCI and with AD dementia, the greatest increases were seen in stages II (temporal cortical regions; 4.45% [95% CI, 3.41%-5.49%]) and IV (certain frontal regions; 5.22% [95% CI, 3.95%-6.49%]), respectively. In Aβ-negative CU individuals and those with MCI, modest change was seen in stage I (1.38% [95% CI, 0.78%-1.99%] and 1.80% [95% CI, 0.76%-2.84%], respectively). When looking at individual predictors and longitudinal tau PET in the stages that showed most change, plasma p-tau217 (R2= 0.27, P <.005), tau PET (stage I baseline SUVR; R2= 0.13, P <.05) and amyloid PET (R2= 0.10, P <.05) were significantly associated with longitudinal tau PET in stage I in Aβ-positive CU individuals. In Aβ-positive individuals with MCI, plasma p-tau217 (R2= 0.24, P <.005) and tau PET (stage II baseline SUVR; R2= 0.44, P <.001) were significantly associated with longitudinal tau PET in stage II. Findings were replicated in BioFINDER-1 using longitudinal [18F]flortaucipir. For the power analysis component, plasma p-tau217 with tau PET resulted in sample size reductions of 43% (95% CI, 34%-46%; P <.005) in Aβ-positive CU individuals and of 68% (95% CI, 61%-73%; P <.001) in Aβ-positive individuals with MCI. Conclusions and Relevance: In trials using tau PET as the outcome, plasma p-tau217 with tau PET may prove optimal for enrichment in preclinical and prodromal AD. However, plasma p-tau217 was most important in preclinical AD, while tau PET was more important in prodromal AD..
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