LITERATURE UPDATE
study for association of disease risk genes with these biomarkers. The prediction accuracy of Alzheimer’s disease clinical diagnosis by the combination of all biomarkers, APOE and polygenic risk score reached area under receiver operating characteristic curve (AUC) = 0.81, with the most significant contributors being ε4, Aβ40 or Aβ42, GFAP and NfL. All biomarkers were significantly associated with age in cases and controls (P<4.3 × 10–5
).
Concentrations of the Aβ-related biomarkers in plasma were significantly lower in cases compared with controls, whereas other biomarker levels were significantly higher in cases. In the case-control genome-wide analyses, APOE-ε4 was associated with all biomarkers (P=0.011-4.78 × 10–8
), except
NfL. No novel genome-wide significant single nucleotide polymorphisms were found in the case-control design; however, in a case-only analysis, the authors found two independent genome- wide significant associations between the Aβ42/Aβ40 ratio and WWOX and COPG2 genes. Disease prediction modelling by the combination of all biomarkers indicates that the variance attributed to P-tau181 is mostly captured by APOE-ε4, whereas Aβ40, Aβ42, GFAP and NfL biomarkers explain additional variation over and above APOE.
The authors identified novel plausible genome wide-significant genes associated with Aβ42/Aβ40 ratio in a sample which is 50 times smaller than current genome-wide association studies in Alzheimer’s disease.
Head-to-head comparison of 10 plasma phospho-tau assays in prodromal Alzheimer’s disease. Janelidze S, Bali D, Ashton NJ et al. Brain. 2023 Apr 19; 146 (4): 1592–601. doi: 10.1093/brain/awac333.
Plasma phospho-tau (p-tau) species have emerged as the most promising blood- based biomarkers of Alzheimer’s disease. In this study, the authors performed a head-to-head comparison of p-tau181, p-tau217 and p-tau231 measured using 10 assays to detect abnormal brain amyloid-β (Aβ) status and predict future progression to Alzheimer’s dementia. The study included 135 patients with baseline diagnosis of mild cognitive impairment (mean age 72.4 years; 60.7% women) who were followed for an average of 4.9 years. Seventy-one participants had abnormal Aβ-status (ie abnormal CSF Aβ42/40) at baseline; and 45 of these Aβ-positive participants progressed to Alzheimer’s dementia during follow-up.
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Neurons stained green with antibody to ubiquitin C-terminal hydrolase L1 (UCH-L1), and astrocytes stained red with antibody to glial fibrillary acidic protein (GFAP) found in cytoplasmic filaments.
P-tau concentrations were determined in baseline plasma and CSF. P-tau217 and p-tau181 were both measured using immunoassays developed by Lilly Research Laboratories (Lilly) and mass spectrometry assays developed at Washington University (WashU). P-tau217 was also analysed using Simoa immunoassay developed by Janssen Research and Development (Janss). P-tau181 was measured using Simoa immunoassay from ADxNeurosciences (ADx), Lumipulse immunoassay from Fujirebio (Fuji) and Splex immunoassay from Mesoscale Discovery (Splex). Both p-tau181 and p-tau231 were quantified using Simoa immunoassay developed at the University of Gothenburg (UGOT). The authors found that the mass
spectrometry-based p-tau217 (p-tau217WashU) exhibited significantly better performance than all other plasma p-tau biomarkers when detecting abnormal Aβ status {area under curve [AUC] = 0.947; P<0.015) or progression to Alzheimer’s dementia (AUC = 0.932; P<0.027). Among immunoassays, p-tau217Lilly had the highest AUCs (0.886–0.889), which was not significantly different from the AUCs of p-tau217Janss, p-tau181ADx and p-tau181WashU (AUC range 0.835–0.872; P>0.09), but higher compared with AUC of p-tau231UGOT, p-tau181Lilly, p-tau181UGOT, p-tau181Fuji and p-tau181Splex (AUC range 0.642–0.813; P≤0.029). Correlations between plasma and CSF values were strongest for p-tau217WashU (r=0.891) followed by p-tau217Lilly (r=0.755; P=0.003 versus p-tau217WashU) and weak to moderate for the rest of the
p-tau biomarkers (r range 0.320–0.669). In conclusion, these findings suggest that among all tested plasma p-tau assays, mass spectrometry-based measures of p-tau217 perform best when identifying mild cognitive impairment patients with abnormal brain Aβ or those who will subsequently progress to Alzheimer’s dementia. Several other assays (p-tau217Lilly, p-tau217Janss, p-tau181ADx and p-tau181WashU) showed relatively high and consistent accuracy across both outcomes. The results further indicate that the highest performing assays have performance metrics that rival the gold standards of Aβ-PET and CSF. If further validated, the authors’ findings will have significant impacts in diagnosis, screening and treatment for Alzheimer’s dementia in the future.
GFAP as a Potential Biomarker for Alzheimer’s Disease: A Systematic Review and Meta-Analysis Kim KY, Shin KY, Chang KA. Cells. 2023 May 4; 12 (9): 1309. doi: 10.3390/ cells12091309.
Blood biomarkers have been considered tools for the diagnosis, prognosis and monitoring of Alzheimer’s disease (AD). Although amyloid-β peptide (Aβ) and tau are primarily blood biomarkers, recent studies have identified other reliable candidates that can serve as measurable indicators of pathological conditions. One such candidate is the glial fibrillary acidic protein (GFAP), an astrocytic cytoskeletal protein that can be detected in blood samples. Increasing evidence
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