Plasma Aß42/40 ratio, p-tau181, GFAP, and NfL across the Alzheimer's disease continuum: A cross-sectional and longitudinal study in the AIBL cohort.

INTRODUCTION: Plasma amyloid beta (Aß)1-42/Aß1-40 ratio, phosphorylated-tau181 (p-tau181), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) are putative blood biomarkers for Alzheimer's disease (AD). However, head-to-head cross-sectional and longitudinal comparisons of the aforementioned biomarkers across the AD continuum are lacking. METHODS: Plasma Aß1-42, Aß1-40, p-tau181, GFAP, and NfL were measured utilizing the Single Molecule Array (Simoa) platform and compared cross-sectionally across the AD continuum, wherein Aß-PET (positron emission tomography)-negative cognitively unimpaired (CU Aß-, n = 81) and mild cognitive impairment (MCI Aß-, n = 26) participants were compared with Aß-PET-positive participants across the AD continuum (CU Aß+, n = 39; MCI Aß+, n = 33; AD Aß+, n = 46) from the Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing (AIBL) cohort. Longitudinal plasma biomarker changes were also assessed in MCI (n = 27) and AD (n = 29) participants compared with CU (n = 120) participants. In addition, associations between baseline plasma biomarker levels and prospective cognitive decline and Aß-PET load were assessed over a 7 to 10-year duration. RESULTS: Lower plasma Aß1-42/Aß1-40 ratio and elevated p-tau181 and GFAP were observed in CU Aß+, MCI Aß+, and AD Aß+, whereas elevated plasma NfL was observed in MCI Aß+ and AD Aß+, compared with CU Aß- and MCI Aß-. Among the aforementioned plasma biomarkers, for models with and without AD risk factors (age, sex, and apolipoprotein E (APOE) ε4 carrier status), p-tau181 performed equivalent to or better than other biomarkers in predicting a brain Aß-/+ status across the AD continuum. However, for models with and without the AD risk factors, a biomarker panel of Aß1-42/Aß1-40, p-tau181, and GFAP performed equivalent to or better than any of the biomarkers alone in predicting brain Aß-/+ status across the AD continuum. Longitudinally, plasma Aß1-42/Aß1-40, p-tau181, and GFAP were altered in MCI compared with CU, and plasma GFAP and NfL were altered in AD compared with CU. In addition, lower plasma Aß1-42/Aß1-40 and higher p-tau181, GFAP, and NfL were associated with prospective cognitive decline and lower plasma Aß1-42/Aß1-40, and higher p-tau181 and GFAP were associated with increased Aß-PET load prospectively. DISCUSSION: These findings suggest that plasma biomarkers are altered cross-sectionally and longitudinally, along the AD continuum, and are prospectively associated with cognitive decline and brain Aß-PET load. In addition, although p-tau181 performed equivalent to or better than other biomarkers in predicting an Aß-/+ status across the AD continuum, a panel of biomarkers may have superior Aß-/+ status predictive capability across the AD continuum. HIGHLIGHTS: Area under the curve (AUC) of p-tau181 ≥ AUC of Aß42/40, GFAP, NfL in predicting PET Aß-/+ status (Aß-/+).  AUC of Aß42/40+p-tau181+GFAP panel ≥ AUC of Aß42/40/p-tau181/GFAP/NfL for Aß-/+.  Longitudinally, Aß42/40, p-tau181, and GFAP were altered in MCI versus CU.  Longitudinally, GFAP and NfL were altered in AD versus CU.  Aß42/40, p-tau181, GFAP, and NfL are associated with prospective cognitive decline.  Aß42/40, p-tau181, and GFAP are associated with increased PET Aß load prospectively.

Diagnostic and prognostic plasma biomarkers for preclinical Alzheimer's disease.

INTRODUCTION: This study involved a parallel comparison of the diagnostic and longitudinal monitoring potential of plasma glial fibrillary acidic protein (GFAP), total tau (t-tau), phosphorylated tau (p-tau181 and p-tau231), and neurofilament light (NFL) in preclinical Alzheimer's disease (AD). METHODS: Plasma proteins were measured using Simoa assays in cognitively unimpaired older adults (CU), with either absence (Aß-) or presence (Aß+) of brain amyloidosis. RESULTS: Plasma GFAP, t-tau, p-tau181, and p-tau231 concentrations were higher in Aß+ CU compared with Aß- CU cross-sectionally. GFAP had the highest effect size and area under the curve (AUC) in differentiating between Aß+ and Aß- CU; however, no statistically significant differences were observed between the AUCs of GFAP, p-tau181, and p-tau231, but all were significantly higher than the AUC of NFL, and the AUC of GFAP was higher than the AUC of t-tau. The combination of a base model (BM), comprising the AD risk factors, age, sex, and apolipoprotein E gene (APOE) ε4 status with GFAP was observed to have a higher AUC (>90%) compared with the combination of BM with any of the other proteins investigated in the current study. Longitudinal analyses showed increased GFAP and p-tau181 in Aß+ CU and increased NFL in Aß- CU, over a 12-month duration. GFAP, p-tau181, p-tau231, and NFL showed significant correlations with cognition, whereas no significant correlations were observed with hippocampal volume. DISCUSSION: These findings highlight the diagnostic and longitudinal monitoring potential of GFAP and p-tau for preclinical AD.

Plasma neurofilament light chain and amyloid-ß are associated with the kynurenine pathway metabolites in preclinical Alzheimer's disease.

BACKGROUND: Blood markers indicative of neurodegeneration (neurofilament light chain; NFL), Alzheimer's disease amyloid pathology (amyloid-ß; Aß), and neuroinflammation (kynurenine pathway; KP metabolites) have been investigated independently in neurodegenerative diseases. However, the association of these markers of neurodegeneration and AD pathology with neuroinflammation has not been investigated previously. Therefore, the current study examined whether NFL and Aß correlate with KP metabolites in elderly individuals to provide insight on the association between blood indicators of neurodegeneration and neuroinflammation. METHODS: Correlations between KP metabolites, measured using liquid chromatography and gas chromatography coupled with mass spectrometry, and plasma NFL and Aß concentrations, measured using single molecule array (Simoa) assays, were investigated in elderly individuals aged 65-90 years, with normal global cognition (Mini-Mental State Examination Score ≥ 26) from the Kerr Anglican Retirement Village Initiative in Ageing Health cohort. RESULTS: A positive correlation between NFL and the kynurenine to tryptophan ratio (K/T) reflecting indoleamine 2,3-dioxygenase activity was observed (r = .451, p < .0001). Positive correlations were also observed between NFL and kynurenine (r = .364, p < .0005), kynurenic acid (r = .384, p < .0001), 3-hydroxykynurenine (r = .246, p = .014), anthranilic acid (r = .311, p = .002), and quinolinic acid (r = .296, p = .003). Further, significant associations were observed between plasma Aß40 and the K/T (r = .375, p < .0005), kynurenine (r = .374, p < .0005), kynurenic acid (r = .352, p < .0005), anthranilic acid (r = .381, p < .0005), and quinolinic acid (r = .352, p < .0005). Significant associations were also observed between plasma Aß42 and the K/T ratio (r = .215, p = .034), kynurenic acid (r = .214, p = .035), anthranilic acid (r = .278, p = .006), and quinolinic acid (r = .224, p = .027) in the cohort. On stratifying participants based on their neocortical Aß load (NAL) status, NFL correlated with KP metabolites irrespective of NAL status; however, associations between plasma Aß and KP metabolites were only pronounced in individuals with high NAL while associations in individuals with low NAL were nearly absent. CONCLUSIONS: The current study shows that KP metabolite changes are associated with biomarker evidence of neurodegeneration. Additionally, the association between KP metabolites and plasma Aß seems to be NAL status dependent. Finally, the current study suggests that an association between neurodegeneration and neuroinflammation manifests in the periphery, suggesting that preventing cytoskeleton cytotoxicity by KP metabolites may have therapeutic potential.

Plasma apolipoprotein J as a potential biomarker for Alzheimer's disease: Australian Imaging, Biomarkers and Lifestyle study of aging.

INTRODUCTION: For early detection of Alzheimer's disease (AD), the field needs biomarkers that can be used to detect disease status with high sensitivity and specificity. Apolipoprotein J (ApoJ, also known as clusterin) has long been associated with AD pathogenesis through various pathways. The aim of this study was to investigate the potential of plasma apoJ as a blood biomarker for AD. METHODS: Using the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging, the present study assayed plasma apoJ levels over baseline and 18 months in 833 individuals. Plasma ApoJ levels were analyzed with respect to clinical classification, age, gender, apolipoprotein E (APOE) ε4 allele status, mini-mental state examination score, plasma amyloid beta (Aß), neocortical Aß burden (as measured by Pittsburgh compound B-positron emission tomography), and total adjusted hippocampus volume. RESULTS: ApoJ was significantly higher in both mild cognitive impairment (MCI) and AD groups as compared with healthy controls (HC; P < .0001). ApoJ significantly correlated with both "standardized uptake value ratio" (SUVR) and hippocampus volume and weakly correlated with the plasma Aß1-42/Aß1-40 ratio. Plasma apoJ predicted both MCI and AD from HC with greater than 80% accuracy for AD and greater than 75% accuracy for MCI at both baseline and 18-month time points. DISCUSSION: Mean apoJ levels were significantly higher in both MCI and AD groups. ApoJ was able to differentiate between HC with high SUVR and HC with low SUVR via APOE ε4 allele status, indicating that it may be included in a biomarker panel to identify AD before the onset of clinical symptoms.