Plasma Aβ42/40 ratio, p‐tau181, GFAP, and NfL across the Alzheimer's disease continuum: A cross‐sectional and longitudinal study in the AIBL cohort

Chatterjee, Pratishtha; Pedrini, Steve; Doecke, James D.; Thota, Rohith N.; Villemagne, Victor L.; Doré, Vincent; Singh, Abhay Kumar; Wang, Penghao; Rainey‐Smith, Stephanie R.; Fowler, Christopher; Taddei, Kevin; Sohrabi, Hamid R.; Molloy, Mark P.; Ames, David; Maruff, Paul; Rowe, Christopher C.; Masters, Colin L.; Martins, Ralph N.

doi:10.1002/alz.12724

Cited by 110 publications

(84 citation statements)

References 55 publications

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“…Additionally, MAO-B PET signal has also been reported to be significantly higher at 6 months than at 8–15 months or 18–24 months in APPswe mice [ 65 ]. In contrast, plasma GFAP has been observed to increase along the AD continuum [ 12, 13 ]. Together, these observations suggest that the low to moderate strength associations observed between plasma GFAP and 18 F-SMBT-1 PET signal within the current study could also be attributed to the study participant status within the AD continuum.…”

Section: Discussionmentioning

confidence: 99%

“…It has been suggested that reactive astrocytes release GFAP into blood via astrocyte end-feet encompassing brain capillaries [ 13 ]. Indeed, plasma GFAP levels are elevated in individuals with high Aβ in the brain (Aβ+) compared to those with low Aβ in the brain (Aβ–) [ 6, 7, 14, 15 ]; and have demonstrated high accuracy in differentiating Aβ+ from Aβ–participants, as assessed by PET, along the AD continuum [ 12 ]. Furthermore, plasma GFAP has a higher accuracy than CSF GFAP in distinguishing Aβ+ from Aβ–participants [ 8 ] and can predict progression from the mild cognitive impaired stage (MCI; prodromal AD) to AD [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

“…GFAP, an astrocyte cytoskeletal protein, is upregulated in reactive astrocytes [9]. Reactive astrocytes surround A␤ plaques, and GFAP upregulation in brain tissue is associated with A␤ plaque density [10][11][12]. It has been suggested that reactive astrocytes release GFAP into blood via astrocyte end-feet encompassing brain capillaries [13].…”

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confidence: 99%

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Plasma Glial Fibrillary Acidic Protein Is Associated with 18F-SMBT-1 PET: Two Putative Astrocyte Reactivity Biomarkers for Alzheimer’s Disease

Chatterjee

Doré

Pedrini

et al. 2023

JAD

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Background: Astrocyte reactivity is an early event along the Alzheimer’s disease (AD) continuum. Plasma glial fibrillary acidic protein (GFAP), posited to reflect astrocyte reactivity, is elevated across the AD continuum from preclinical to dementia stages. Monoamine oxidase-B (MAO-B) is also elevated in reactive astrocytes observed using 18F-SMBT-1 PET in AD. Objective: The objective of this study was to evaluate the association between the abovementioned astrocyte reactivity biomarkers. Methods: Plasma GFAP and Aβ were measured using the Simoa ® platform in participants who underwent brain 18F-SMBT-1 and Aβ–PET imaging, comprising 54 healthy control (13 Aβ–PET+ and 41 Aβ–PET–), 11 mild cognitively impaired (3 Aβ–PET+ and 8 Aβ–PET–) and 6 probable AD (5 Aβ–PET+ and 1 Aβ–PET–) individuals. Linear regressions were used to assess associations of interest. Results: Plasma GFAP was associated with 18F-SMBT-1 signal in brain regions prone to early Aβ deposition in AD, such as the supramarginal gyrus (SG), posterior cingulate (PC), lateral temporal (LT) and lateral occipital cortex (LO). After adjusting for age, sex, APOE ɛ4 genotype, and soluble Aβ (plasma Aβ 42/40 ratio), plasma GFAP was associated with 18F-SMBT-1 signal in the SG, PC, LT, LO, and superior parietal cortex (SP). On adjusting for age, sex, APOE ɛ4 genotype and insoluble Aβ (Aβ–PET), plasma GFAP was associated with 18F-SMBT-1 signal in the SG. Conclusion: There is an association between plasma GFAP and regional 18F-SMBT-1 PET, and this association appears to be dependent on brain Aβ load.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Plasma Glial Fibrillary Acidic Protein Is Associated with 18F-SMBT-1 PET: Two Putative Astrocyte Reactivity Biomarkers for Alzheimer’s Disease

Chatterjee

Doré

Pedrini

et al. 2023

JAD

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“…Despite the rapidly developing research on plasma biomarkers, studies investigating longitudinal change remain limited. Chatterjee et al reported that plasma measures of Aβ 42 /Aβ 40 , tau phosphorylated at threonine 181 (p-tau181), and glial fibrillary acidic protein (GFAP) change more rapidly among individuals with mild cognitive impairment (MCI) compared to cognitively normal individuals [8]. O’Connor et al found that longitudinal trajectories of plasma neurofilament light chain (NfL) and p-tau181 among autosomal dominant AD mutation carriers started diverging from trajectories observed for non-carriers at about 16–17 years prior to estimated symptom onset [9].…”

Section: Introductionmentioning

confidence: 99%

Longitudinal changes in Alzheimer’s-related plasma biomarkers and brain amyloid

Bilgel

Walker

et al. 2023

Preprint

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IntroductionUnderstanding longitudinal plasma biomarker trajectories relative to brain amyloid changes can help devise disease progression assessment strategies for Alzheimer’s disease.MethodsWe examined the temporal order of changes in plasma amyloid-×βratio (Aβ42/Aβ40), glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), and two phosphorylated tau ratios (p-tau181/Aβ42and p-tau231/Aβ42) relative to11C-Pittsburgh compound B (PiB) positron emission tomography (PET) cortical amyloid burden (PiB−/+). Participants (n = 199, Baltimore Longitudinal Study of Aging) were cognitively normal at index visit with a median 6.1-year follow-up.ResultsPiB− individuals exhibited longitudinal decline in Aβ42/Aβ40(β= ×−3.85 ×10−5, SE = 9.77 × 10−4,p= 1.96 × 10−4), whereas PiB+ did not exhibit change. Change in brain amyloid was correlated with change in GFAP (r= 0.5, 95% CI = [0.26, 0.68]) and NfL (r = 0.4 [0.13, 0.62]). Greatest relative decline in Aβ42/Aβ40(−1% per year) preceded brain amyloid positivity onset by 41 years (95% CI = [32, 53]).DiscussionPlasma Aβ42/Aβ40may begin declining decades prior to brain amyloid, whereas p-tau ratio, GFAP, and NfL increase closer in time to, and in parallel with, brain amyloid accumulation.HighlightsPlasma Aβ42/Aβ40declines over time among PiB− but does not change among PiB+p-tau to Aβ42ratios increase over time among PiB+ but do not change among PiB−Rate of change in brain amyloid is correlated with change in GFAP and NfLGreatest decline in Aβ42/Aβ40may precede brain amyloid positivity by decades

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“…Only NfL levels were found to be affected by renal function in A + , but not for p-tau181. A possible explanation is that p-tau181 is a more specific biomarker for AD pathology compared with NfL ( Chatterjee et al, 2022 ; Sarto et al, 2022 ), the impact of renal function on p-tau181 levels may be weaker in A + . This was consistent with our findings that the AUC and sensitivity of p-tau181 were higher than NfL.…”

Section: Discussionmentioning

confidence: 99%

Effect of renal function on the diagnostic performance of plasma biomarkers for Alzheimer’s disease

Zhang

Zhang²,

Wang³

et al. 2023

Front. Aging Neurosci.

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BackgroundSeveral blood-based biomarkers are promising to be used in the diagnosis of Alzheimer’s disease (AD) including Aβ42/40, p-tau181, and neurofilament light (NfL). The kidney is associated with the clearance of proteins. It is crucial to evaluate the effect of renal function on the diagnostic performance of these biomarkers before clinical implementation, which is important for the establishment of reference ranges and the interpretation of results.MethodsThis study is a cross-sectional analysis based on ADNI cohort. Renal function was determined by the estimated glomerular filtration rate (eGFR). Plasma Aβ42/40 was measured by liquid chromatography–tandem mass spectrometry (LC–MS/MS). Plasma p-tau181 and NfL were analyzed by Single Molecule array (Simoa) technique. [18F] florbetapir-PET (Aβ-PET) was used as a reference standard to estimate the brain amyloid load. The cutoff of Aβ-PET positivity was defined as ≥1.11. Linear regression models were used to investigate the associations of continuous eGFR with each plasma biomarker separately. The diagnostic accuracies of plasma biomarkers for positive brain amyloid across different renal function groups were analyzed by Receiver operating characteristic (ROC) curve. Youden-Index was used to determine the cutoff levels.ResultsA total of 645 participants were included in this study. The levels and diagnostic performance of Aβ42/40 were not affected by renal function. eGFR was only found negatively associated with p-tau181 levels in Aβ-PET negetive sample (β = −0.09, p = 0.039). eGFR was found negatively associated with NfL levels both in whole sample and Aβ-PET stratified groups (β = −0.27, p < 0.001 in whole sample; β = −0.28, p = 0.004 in A−; β = −0.27, p < 0.001 in A+). The diagnostic accuracies of p-tau181 and NfL were not affected by renal function. But the cutoff values of p-tau181 and NfL changed in participants with mild to moderate eGFR decline compared to participants with normal eGFR.ConclusionPlasma Aβ42/40 was a robust biomarker for AD which was not affected by renal function. Plasma p-tau181 and NfL levels were affected by renal function, specific reference values of them should be considered in populations with different renal function stages.

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Plasma Aβ42/40 ratio, p‐tau181, GFAP, and NfL across the Alzheimer's disease continuum: A cross‐sectional and longitudinal study in the AIBL cohort

Cited by 110 publications

References 55 publications

Plasma Glial Fibrillary Acidic Protein Is Associated with 18F-SMBT-1 PET: Two Putative Astrocyte Reactivity Biomarkers for Alzheimer’s Disease

Plasma Glial Fibrillary Acidic Protein Is Associated with 18F-SMBT-1 PET: Two Putative Astrocyte Reactivity Biomarkers for Alzheimer’s Disease

Longitudinal changes in Alzheimer’s-related plasma biomarkers and brain amyloid

Effect of renal function on the diagnostic performance of plasma biomarkers for Alzheimer’s disease

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