Investigating reliable amyloid accumulation in Centiloids: Results from the AMYPAD Prognostic and Natural History Study

Bollack, Ariane; Collij, Lyduine E.; García, David Vállez; Shekari, Mahnaz; Altomare, Daniele; Payoux, Pierre; Dubois, Bruno; Grau‐Rivera, Oriol; Boada, Mercè; Marquié, Marta; Nordberg, Agneta; Walker, Zuzana; Scheltens, Philip; Schöll, Michael; Wolz, Robin; Schott, Jonathan M.; Gismondi, Rossella; Stephens, Andrew; Buckley, Christopher; Frisoni, Giovanni B.; Hanseeuw, Bernard; Visser, Pieter Jelle; Vandenberghe, Rik; Drzezga, Alexander; Yaqub, Maqsood; Boellaard, Ronald; Gispert, Juan Domingo; Markiewicz, Pawel; Cash, David M.; Farrar, Gill; Barkhof, Frederik; ,

doi:10.1002/alz.13761

Cited by 2 publications

(1 citation statement)

References 71 publications

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“…We also performed sensitivity analyses for 20-CL and 12-CL thresholds . To categorize study participants as Aβ accumulators or nonaccumulators, we applied a previously defined threshold of greater than 3.0 CL per year …”

Section: Methodsmentioning

confidence: 99%

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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Section: Methodsmentioning

confidence: 99%

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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Association of glial fibrillary acid protein, Alzheimer's disease pathology and cognitive decline

Peretti,

Boccalini,

Ribaldi

et al. 2024

Brain

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Increasing evidence shows that neuroinflammation is a possible modulator of tau spread effects on cognitive impairment in Alzheimer’s disease. In this context, plasma levels of the glial fibrillary acidic protein (GFAP) have been suggested to have a robust association with Alzheimer’s disease pathophysiology. This study aims to assess the correlation between plasma GFAP and Alzheimer’s disease pathology, and their synergistic effect on cognitive performance and decline. A cohort of 122 memory clinic subjects with amyloid and tau positron emission tomography, MRI scans, plasma GFAP, and Mini-Mental State Examination (MMSE) was included in the study. A subsample of 94 subjects had a follow-up MMSE score at least one year after baseline. Regional and voxel-based correlations between Alzheimer’s disease biomarkers and plasma GFAP were assessed. Mediation analyses were performed to evaluate the effects of plasma GFAP on the association between amyloid and tau PET, and tau PET and cognitive impairment and decline. GFAP was associated with increased tau PET ligand uptake in the lateral temporal and inferior temporal lobes in a strong left-sided pattern independently of age, gender, education, amyloid, and APOE status (β=0.001, p < 0.01). The annual rate of MMSE change was significantly and independently correlated with both GFAP (β=0.006, p < 0.01) and global tau SUVR (β=4.33, p < 0.01), but not with amyloid burden. Partial mediation effects of GFAP were found on the association between amyloid and tau pathology (13.7%), and between tau pathology and cognitive decline (17.4%), but not on global cognition at baseline. Neuroinflammation measured by circulating GFAP is independently associated with tau Alzheimer’s disease pathology and with cognitive decline, suggesting neuroinflammation as a potential target for future disease-modifying trials targeting tau pathology. Peretti et al. show that a circulatory marker of neuroinflammation—glial fibrillary acidic protein—is associated with tau pathology in lateral temporal and frontal regions in patients with Alzheimer's disease, independent of amyloid load. Neuroinflammation appears to modulate the association between amyloid and tau biomarkers.

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Investigating reliable amyloid accumulation in Centiloids: Results from the AMYPAD Prognostic and Natural History Study

Cited by 2 publications

References 71 publications

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

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

Association of glial fibrillary acid protein, Alzheimer's disease pathology and cognitive decline

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