Modeling the temporal evolution of plasma p‐tau in relation to amyloid beta and tau PET

Cogswell, Petrice M.; Lundt, Emily S.; Therneau, Terry M.; Wiste, Heather J.; Graff‐Radford, Jonathan; Algeciras‐Schimnich, Alicia; Lowe, Val J.; Mielke, Michelle M.; Schwarz, Christopher G.; Senjem, Matthew L.; Gunter, Jeffrey L.; Knopman, David S.; Vemuri, Prashanthi; Petersen, Ronald C.; Jack Jr, Clifford R.

doi:10.1002/alz.13539

Cited by 10 publications

(10 citation statements)

References 79 publications

(147 reference statements)

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“…It is also important to consider the potential contribution of early tau pathology on microstructural decline in the plasma+/PET‐ group. Although group‐level p‐tau181 in plasma‐/PET‐ and plasma+/PET‐ groups did not significantly differ, several participants in both groups had p‐tau181 measures that exceeded the positivity cut‐point according to healthy normative data in a recent study 60 …”

Section: Discussionmentioning

confidence: 88%

“…Although group-level p-tau181 in plasma-/PET-and plasma+/PET-groups did not significantly differ, several participants in both groups had p-tau181 measures that exceeded the positivity cut-point according to healthy normative data in a recent study. 60 FW imaging has emerged as a clinically relevant tool for tracking progression of neurodegenerative disease. For example, FW is reliably increased in substantia nigra over a 1-year period in patients with Parkinson's disease and predicts subsequent progression of motor and cognitive impairment.…”

Section: Discussionmentioning

confidence: 99%

“…Although group‐level p‐tau181 in plasma‐/PET‐ and plasma+/PET‐ groups did not significantly differ, several participants in both groups had p‐tau181 measures that exceeded the positivity cut‐point according to healthy normative data in a recent study. 60 …”

Section: Discussionmentioning

confidence: 99%

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Diffusion MRI relates to plasma Aβ42/40 in PET negative participants without dementia

DeSimone,

Wang,

Loewenstein

et al. 2024

Alzheimer's & Dementia

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INTRODUCTIONMagnetic resonance imaging (MRI) biomarkers are needed for indexing early biological stages of Alzheimer's disease (AD), such as plasma amyloid‐β (Aβ42/40) positivity in Aβ positron emission tomography (PET) negative individuals.METHODSDiffusion free‐water (FW) MRI was acquired in individuals with normal cognition (NC) and mild cognitive impairment (MCI) with Aβ plasma‐/PET‐ (NC = 22, MCI = 60), plasma+/PET‐ (NC = 5, MCI = 20), and plasma+/PET+ (AD dementia = 21) biomarker status. Gray and white matter FW and fractional anisotropy (FAt) were compared cross‐sectionally and the relationships between imaging, plasma and PET biomarkers were assessed.RESULTSPlasma+/PET‐ demonstrated increased FW (24 regions) and decreased FAt (66 regions) compared to plasma‐/PET‐. FW (16 regions) and FAt (51 regions) were increased in plasma+/PET+ compared to plasma+/PET‐. Composite brain FW correlated with plasma Aβ42/40 and p‐tau181.DISCUSSIONFW imaging changes distinguish plasma Aβ42/40 positive and negative groups, independent of group differences in cognitive status, Aβ PET status, and other plasma biomarkers (i.e., t‐tau, p‐tau181, glial fibrillary acidic protein, neurofilament light).Highlights Plasma Aβ42/40 positivity is associated with brain microstructure decline. Plasma+/PET‐ demonstrated increased FW in 24 total GM and WM regions. Plasma+/PET‐ demonstrated decreased FAt in 66 total GM and WM regions. Whole‐brain FW correlated with plasma Aβ42/40 and p‐tau181 measures. Plasma+/PET‐ demonstrated decreased cortical volume and thickness.

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Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

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Diffusion MRI relates to plasma Aβ42/40 in PET negative participants without dementia

DeSimone,

Wang,

Loewenstein

et al. 2024

Alzheimer's & Dementia

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“…for amyloid PET, 27,32 2.76 pg/mL for Quanterix Simoa p-tau181, and 0.21 pg/mL for Lilly MSD p-tau217. 33 As illustrated in Supplemental Figure 1, the overall percent agreement was 76% for p-tau217 and p-tau181, 80% for amyloid PET and p-tau217, and 69% for amyloid PET and p-tau181. The results above prompted us to assess whether individual prediction of memory decline rate was feasible with very extreme biomarker values.…”

Section: Plasma Plus Pet Biomarker Modelsmentioning

confidence: 85%

“…Figure 3 illustrates that the rank correlations with amyloid PET are larger for p‐tau217 (ρ = 0.49) compared with p‐tau181 (ρ = 0.35), but both would be considered modest. To assess how interchangeable either p‐tau217 or p‐tau181 might be with amyloid PET for studies at the population level, we applied cut points of Centiloid 22 (1.48 SUVR) for amyloid PET, 27,32 2.76 pg/mL for Quanterix Simoa p‐tau181, and 0.21 pg/mL for Lilly MSD p‐tau217 33 . As illustrated in Supplemental Figure 1, the overall percent agreement was 76% for p‐tau217 and p‐tau181, 80% for amyloid PET and p‐tau217, and 69% for amyloid PET and p‐tau181.…”

Section: Resultsmentioning

confidence: 99%

Comparison of plasma biomarkers and amyloid PET for predicting memory decline in cognitively unimpaired individuals

Jack,

Wiste,

Algeciras‐Schimnich

et al. 2024

Alzheimer's & Dementia

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BACKGROUNDWe compared the ability of several plasma biomarkers versus amyloid positron emission tomography (PET) to predict rates of memory decline among cognitively unimpaired individuals.METHODSWe studied 645 Mayo Clinic Study of Aging participants. Predictor variables were age, sex, education, apolipoprotein E (APOE) ε4 genotype, amyloid PET, and plasma amyloid beta (Aβ)42/40, phosphorylated tau (p‐tau)181, neurofilament light (NfL), glial fibrillary acidic protein (GFAP), and p‐tau217. The outcome was a change in a memory composite measure.RESULTSAll plasma biomarkers, except NfL, were associated with mean memory decline in models with individual biomarkers. However, amyloid PET and plasma p‐tau217, along with age, were key variables independently associated with mean memory decline in models combining all predictors. Confidence intervals were narrow for estimates of population mean prediction, but person‐level prediction intervals were wide.DISCUSSIONPlasma p‐tau217 and amyloid PET provide useful information about predicting rates of future cognitive decline in cognitively unimpaired individuals at the population mean level, but not at the individual person level.

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Plasma Phosphorylated Tau 217 and Aβ42/40 to Predict Early Brain Aβ Accumulation in People Without Cognitive Impairment

Janelidze,

Barthélemy,

Salvadó

et al. 2024

JAMA Neurol

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ImportancePhase 3 trials of successful antiamyloid therapies in Alzheimer disease (AD) have demonstrated improved clinical efficacy in people with less severe disease. Plasma biomarkers will be essential for efficient screening of participants in future primary prevention clinical trials testing antiamyloid therapies in cognitively unimpaired (CU) individuals with initially low brain β-amyloid (Aβ) levels who are at high risk of accumulating Aβ.ObjectiveTo investigate if combining plasma biomarkers could be useful in predicting subsequent development of Aβ pathology in CU individuals with subthreshold brain Aβ levels (defined as Aβ levels &lt;40 Centiloids) at baseline.Design, Setting, and ParticipantsThis was a longitudinal study including Swedish BioFINDER-2 (enrollment 2017-2022) and replication in 2 independent cohorts, the Knight Alzheimer Disease Research Center (Knight ADRC; enrollment 1988 and 2019) and Swedish BioFINDER-1 (enrollment 2009-2015). Included for analysis was a convenience sample of CU individuals with baseline plasma phosphorylated tau 217 (p-tau217) and Aβ42/40 assessments and Aβ assessments with positron emission tomography (Aβ-PET) or cerebrospinal fluid (CSF) Aβ42/40. Data were analyzed between April 2023 and May 2024.ExposuresBaseline plasma levels of Aβ42/40, p-tau217, the ratio of p-tau217 to nonphosphorylated tau (%p-tau217), p-tau231, and glial fibrillary acidic protein (GFAP).Main Outcomes and MeasuresCross-sectional and longitudinal PET and CSF measures of brain Aβ pathology.ResultsThis study included 495 (BioFINDER-2), 283 (Knight ADRC), and 205 (BioFINDER-1) CU participants. In BioFINDER-2, the mean (SD) age was 65.7 (14.4) with 261 females (52.7%). When detecting abnormal CSF Aβ-status, a combination of plasma %p-tau217 and Aβ42/40 showed better performance (area under the curve = 0.949; 95% CI, 0.929-0.970; P &lt;.02) than individual biomarkers. In CU participants with subthreshold baseline Aβ-PET, baseline plasma %p-tau217 and Aβ42/40 levels were significantly associated with baseline Aβ-PET (n = 384) and increases in Aβ-PET over time (n = 224). Associations of plasma %p-tau217 and Aβ42/40 and their interaction with baseline Aβ-PET (%p-tau217: β = 2.77; 95% CI, 1.84-3.70; Aβ42/40: β = −1.64; 95% CI, −2.53 to −0.75; %p-tau217 × Aβ42/40: β = −2.14; 95% CI, −2.79 to −1.49; P &lt; .001) and longitudinal Aβ-PET (%p-tau217: β = 0.67; 95% CI, 0.48-0.87; Aβ42/40: β = −0.33; 95% CI, −0.51 to −0.15; %p-tau217 × Aβ42/40: β = −0.31; 95% CI, −0.44 to −0.18; P &lt; .001) were also significant in the models combining the 2 baseline biomarkers as predictors. Similarly, baseline plasma p-tau217 and Aβ42/40 were independently associated with longitudinal Aβ-PET in Knight ADRC (%p-tau217: β = 0.71; 95% CI, 0.26-1.16; P = .002; Aβ42/40: β = −0.74; 95% CI, −1.26 to −0.22; P = .006) and longitudinal CSF Aβ42/40 in BioFINDER-1 (p-tau217: β = −0.0003; 95% CI, −0.0004 to −0.0001; P = .01; Aβ42/40: β = 0.0004; 95% CI, 0.0002-0.0006; P &lt; .001) in CU participants with subthreshold Aβ levels at baseline. Plasma p-tau231 and GFAP did not provide any clear independent value.Conclusions and RelevanceResults of this cohort study suggest that combining plasma p-tau217and Aβ42/40 levels could be useful for predicting development of Aβ pathology in people with early stages of subthreshold Aβ accumulation. These biomarkers might thus facilitate screening of participants for future primary prevention trials.

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Modeling the temporal evolution of plasma p‐tau in relation to amyloid beta and tau PET

Cited by 10 publications

References 79 publications

Diffusion MRI relates to plasma Aβ42/40 in PET negative participants without dementia

Diffusion MRI relates to plasma Aβ42/40 in PET negative participants without dementia

Comparison of plasma biomarkers and amyloid PET for predicting memory decline in cognitively unimpaired individuals

Plasma Phosphorylated Tau 217 and Aβ42/40 to Predict Early Brain Aβ Accumulation in People Without Cognitive Impairment

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