The Alzheimer's Association appropriate use recommendations for blood biomarkers in Alzheimer's disease

Hansson, Oskar; Edelmayer, Rebecca M.; Boxer, Adam L.; Carrillo, María C.; Mielke, Michelle M.; Rabinovici, Gil D.; Salloway, Stephen; Sperling, Reisa A.; Zetterberg, Henrik; Teunissen, Charlotte E.

doi:10.1002/alz.12756

Cited by 301 publications

(270 citation statements)

References 136 publications

Supporting

Mentioning

263

Contrasting

Order By: Relevance

“…5,11,13,14 Nonetheless, there are still important topics to be addressed to optimize their usage in clinical practice, including improved interpretation of obtained plasma biomarker results and a fair headto-head comparison, especially against gold standard neuropathological measures. 15 One of the most important knowledge voids of plasma biomarkers is the degree to which they specifically correlate with key neuropathological changes. Although previous studies have already investigated the association of some of these biomarkers with measures of neuropathology, whether these markers are primarily related to amyloid, tau, or to both pathologies is still under debate.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Specific associations between plasma biomarkers and post-mortem amyloid plaque and neurofibrillary tau tangle loads

Salvadó

Ossenkoppele

Ashton

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

Several promising plasma biomarkers have recently been developed that could serve as diagnostic and/or prognostic tools for Alzheimer's disease (AD). However, their neuropathological correlates have not yet been fully determined. Therefore, we aimed to investigate the independent associations between multiple plasma biomarkers (i.e., phosphorylated tau217 [p-tau217], p-tau181, p-tau231, the amyloid-β42/40 [Aβ42/40] ratio, glial fibrillary acidic protein [GFAP] and neurofilament light [NfL]) and core semi-quantitative measures of AD pathology (i.e., amyloid plaques and tau neurofibrillary tangles) as well as common co-pathologies (i.e., cerebral amyloid angiopathy, Lewy body disease, TAR DNA-binding protein 43, cerebral white matter rarefaction and argyrophilic grain disease). We included 105 participants from the Arizona Study of Aging and Neurodegenerative Disorders and Brain and Body Donation Program with antemortem collected plasma samples and a post-mortem neuropathological exam (mean(SD) time: 482(355) days), 48 of whom had longitudinal p-tau217 and p-tau181 (mean(SD) follow-up time: 1,378(1,357) days). Participants ranged from cognitively unimpaired to Alzheimer's and non-Alzheimer's dementia. All markers except NfL were associated with plaques (|β|≥0.37, p<0.001) and tangles (|β|≥0.27, p<0.008), in univariable analyses adjusted for age, sex and time between blood sampling and death. In multivariable models, when including both plaques and tangles as independent variables, the Aβ42/40 ratio and p-tau231 were only associated with plaques (βAβ42/40 [95%CI]=-0.59[-0.80,-0.38], R2plaques/R2=77.6%; βp-tau231[95%CI]=0.32[0.09,0.56], R2plaques/R2=45.9%, all p≤0.007), while GFAP was only associated with tangles (βGFAP[95%CI]=0.39[0.19,0.59], p<0.001, R2tangles/R2=30.4%). In contrast, p-tau217 and p-tau181 were associated with both plaques (βp-tau217[95%CI]=0.46[0.30,0.62], R2plaques/R2=40.4%; βp-tau181[95%CI]=0.41[0.22,0.60], R2plaques/R2=35.7%, both p<0.001) and tangles (βp-tau217[95%CI]=0.40[0.24,0.57], p<0.001, R2tangles/R2=30.7%; βp-tau181[95%CI]=0.30[0.10,0.49], p=0.004, R2tangles/R2=17.1%). A parsimonious model predicting plaque load included p-tau217 and Aβ42/40, while a parsimonious model for tangle burden included only p-tau217. Further, combining p-tau217 and Aβ42/40 ratio yielded the highest accuracy for predicting intermediate/high AD neuropathological change ([ADNC], AUC[95%CI]=0.90[0.84,0.96],R2=0.66). High plasma NfL levels were predictive of presence of cerebral white matter rarefaction (AUC[95%CI]=0.76[0.66,0.85],R2=0.25). Finally, p-tau217 (β[95%CI]=0.13[0.02,0.24], p=0.018), but not p-tau181 (β[95%CI]=0.12[-0.05,0.29], p=0.152), levels increased more over time in participants with intermediate/high ADNC compared with those with none/low ADNC. In this relatively large neuropathological study with multiple plasma biomarkers available, we showed that the Aβ42/40 ratio and p-tau231 were specific markers of plaque pathology, and GFAP of tangle pathology, while p-tau181 and, especially, p-tau217 were markers of both plaque and tangle pathologies. Our results suggest that high-performing assays of plasma p-tau217 and Aβ42/40 might be an optimal biomarker combination to detect ADNC in vivo.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Specific associations between plasma biomarkers and post-mortem amyloid plaque and neurofibrillary tau tangle loads

Salvadó

Ossenkoppele

Ashton

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Different technical approaches have been used to look for neurodegeneration-related specific blood biomarkers, such as those of proteomics [ 11 , 12 ] or miRNomics [ 13 , 14 ] or metabolomics [ 15 , 16 ], attempting to detect specific brain molecules —amyloid-beta (A

), tau and glial fibrillary acidic protein neurofilaments light chains [ 17 , 18 ]. On the other hand, fewer studies have been performed to assay non-specific blood analytes in patients with neurodegenerative illnesses [ 19 , 20 ], and more specifically AD [ 11 , 21 , 22 ] to find out novel interesting and useful correlations to brain biomarkers. Levels of blood biomarkers have been recently proposed to predict brain (A

) deposition [ 21 ] and, consequently, a cognitive impairment.…”

Section: Introductionmentioning

confidence: 99%

Blood Analytes as Biomarkers of Mechanisms Involved in Alzheimer’s Disease Progression

Baldini

Greco

Lomi

et al. 2022

IJMS

View full text Add to dashboard Cite

Alzheimer’s disease (AD) is the leading cause of dementia, but the pathogenetic factors are not yet well known, and the relationships between brain and systemic biochemical derangements and disease onset and progression are unclear. We aim to focus on blood biomarkers for an accurate prognosis of the disease. We used a dataset characterized by longitudinal findings collected over the past 10 years from 90 AD patients. The dataset included 277 observations (both clinical and biochemical ones, encompassing blood analytes encompassing routine profiles for different organs, together with immunoinflammatory and oxidative markers). Subjects were grouped into four severity classes according to the Clinical Dementia Rating (CDR) Scale: mild (CDR = 0.5 and CDR = 1), moderate (CDR = 2), severe (CDR = 3) and very severe (CDR = 4 and CDR = 5). Statistical models were used for the identification of potential blood markers of AD progression. Moreover, we employed the Pathfinder tool of the Reactome database to investigate the biological pathways in which the analytes of interest could be involved. Statistical results reveal an inverse significant relation between four analytes (high-density cholesterol, total cholesterol, iron and ferritin) with AD severity. In addition, the Reactome database suggests that such analytes could be involved in pathways that are altered in AD progression. Indeed, the identified blood markers include molecules that reflect the heterogeneous pathogenetic mechanisms of AD. The combination of such blood analytes might be an early indicator of AD progression and constitute useful therapeutic targets.

show abstract

“… 3 , 4 Nonetheless, before widespread implementation, more evidence is needed to address different aspects relating to clinical use. 5 , 6 Few studies had explored the influence of non‐neurologic factors on plasma levels of neurofilament light chain (NfL) and recently for other biomarkers. 7 , 8 , 9 , 10 They consistently identified the association of chronic kidney disease and elevation of most biomarkers.…”

Section: Introductionmentioning

confidence: 99%

Elevation of plasma phosphorylated tau181 during neurological illnesses affecting consciousness and kidney dysfunction

Thanapornsangsuth

Ongphichetmetha

Luechaipanit

et al. 2022

Alz & Dem Diag Ass & Dis Mo

View full text Add to dashboard Cite

Introduction Phosphorylated tau (p‐tau)181 has become a promising blood‐based Alzheimer's disease (AD) biomarker. We studied the agreement of plasma p‐tau181 and cerebrospinal fluid (CSF) markers in patients with alteration of consciousness (AOC). Methods Plasma and CSF were simultaneously collected in participants presenting with AOC. Plasma p‐tau181 was measured using the single‐molecule array. CSF biomarkers were classified according to the amyloid/tau/neurodegeneration (AT[N]) framework. Results Among participants enrolled, the median (interquartile range) age was 57 (28.5–75) years and 5.8% had AD. Plasma p‐tau181 yielded area under the curve of 0.85 and showed moderate correlation with CSF p‐tau181 (Rho = 0.42, P < .001). Using the historical cut‐point, many non‐AD participants had elevated plasma p‐tau181 resulting in a specificity of 0.57. Plasma p‐tau181 correlated with the glomerular filtration rate (Rho = –0.52, P < .001). Among A− participants with elevated plasma p‐tau181, 42% had kidney dysfunction. Discussion Plasma p‐tau181 showed inadequate specificity in patients with AOC partially attributable to concomitant kidney dysfunction.

show abstract

The Alzheimer's Association appropriate use recommendations for blood biomarkers in Alzheimer's disease

Cited by 301 publications

References 136 publications

Specific associations between plasma biomarkers and post-mortem amyloid plaque and neurofibrillary tau tangle loads

Specific associations between plasma biomarkers and post-mortem amyloid plaque and neurofibrillary tau tangle loads

Blood Analytes as Biomarkers of Mechanisms Involved in Alzheimer’s Disease Progression

Elevation of plasma phosphorylated tau181 during neurological illnesses affecting consciousness and kidney dysfunction

Contact Info

Product

Resources

About