Alzheimer’s disease is characterized by β‐amyloid plaques and tau tangles. Plasma levels of phospho‐tau217 (P‐tau217) accurately differentiate Alzheimer’s disease dementia from other dementias, but ...it is unclear to what degree this reflects β‐amyloid plaque accumulation, tau tangle accumulation, or both. In a cohort with post‐mortem neuropathological data (N = 88), both plaque and tangle density contributed independently to higher P‐tau217, but P‐tau217 was not elevated in patients with non‐Alzheimer’s disease tauopathies (N = 9). Several findings were replicated in a cohort with PET imaging (“BioFINDER‐2”, N = 426), where β‐amyloid and tau PET were independently associated with P‐tau217. P‐tau217 concentrations correlated with β‐amyloid PET (but not tau PET) in early disease stages and with both β‐amyloid and (more strongly) tau PET in late disease stages. Finally, P‐tau217 mediated the association between β‐amyloid and tau in both cohorts, especially for tau outside of the medial temporal lobe. These findings support the hypothesis that plasma P‐tau217 concentration is increased by both β‐amyloid plaques and tau tangles and is congruent with the hypothesis that P‐tau is involved in β‐amyloid‐dependent formation of neocortical tau tangles.
Synopsis
Plasma levels of phosphorylated tau, including P‐tau217, are elevated in Alzheimer's disease (AD). This study explores the underlying processes associated with the increased levels of plasma P‐tau217, using post‐mortem data and positron emission tomography (PET) of β‐amyloid and tau.
Plasma P‐tau217 is independently associated with higher levels of both β‐amyloid pathology and tau pathology in the brain.
The first changes in plasma P‐tau217 may reflect the early accumulation of β‐amyloid before there is widespread tau aggregation.
Once tau aggregation reaches the neocortex, there is a strong correlation between plasma P‐tau217 and the amount of aggregated tau.
Plasma P‐tau217 mediates the association between β‐amyloid accumulation and tau accumulation.
Plasma levels of phosphorylated tau, including P‐tau217, are elevated in Alzheimer's disease (AD). This study explores the underlying processes associated with the increased levels of plasma P‐tau217, using post‐mortem data and positron emission tomography (PET) of β‐amyloid and tau.
The aggregation of the 42-residue form of the amyloid-β peptide (Aβ42) is a pivotal event in Alzheimer’s disease (AD). The use of chemical kinetics has recently enabled highly accurate ...quantifications of the effects of small molecules on specific microscopic steps in Aβ42 aggregation. Here, we exploit this approach to develop a rational drug discovery strategy against Aβ42 aggregation that uses as a readout the changes in the nucleation and elongation rate constants caused by candidate small molecules. We thus identify a pool of compounds that target specific microscopic steps in Aβ42 aggregation. We then test further these small molecules in human cerebrospinal fluid and in a Caenorhabditis elegans model of AD. Our results show that this strategy represents a powerful approach to identify systematically small molecule lead compounds, thus offering an appealing opportunity to reduce the attrition problem in drug discovery.
There is an urgent need for biomarkers in plasma to identify Alzheimer's disease (AD). It has previously been shown that a signature of 18 plasma proteins can identify AD during pre-dementia and ...dementia stages (Ray et al, Nature Medicine, 2007). We quantified the same 18 proteins in plasma from 174 controls, 142 patients with AD, and 88 patients with other dementias. Only three of these proteins (EGF, PDGF-BB and MIP-1δ) differed significantly in plasma between controls and AD. The 18 proteins could classify patients with AD from controls with low diagnostic precision (area under the ROC curve was 63%). Moreover, they could not distinguish AD from other dementias. In conclusion, independent validation of results is important in explorative biomarker studies.
Introduction
Further evidence is needed to support the use of plasma amyloid β (Aβ) biomarkers as Alzheimer's disease prescreening tools. This study evaluated the clinical performance and robustness ...of plasma Aβ42/Aβ40 for amyloid positivity prescreening.
Methods
Data were collected from 333 BioFINDER and 121 Alzheimer's Disease Neuroimaging Initiative study participants. Risk and predictive values versus percentile of plasma Aβ42/Aβ40 evaluated the actionability of plasma Aβ42/Aβ40, and simulations modeled the impact of potential uncertainties and biases. Amyloid PET was the brain amyloidosis reference standard.
Results
Elecsys plasma Aβ42/Aβ40 could potentially rule out amyloid pathology in populations with low‐to‐moderate amyloid positivity prevalence. However, simulations showed small measurement or pre‐analytical errors in Aβ42 and/or Aβ40 cause misclassifications, impacting sensitivity or specificity. The minor fold change between amyloid PET positive and negative cases explains the biomarkers low robustness.
Discussion
Implementing plasma Aβ42/Aβ40 for routine clinical use may pose significant challenges, with misclassification risks.
Highlights
Plasma Aβ42/Aβ40 ruled out amyloid PET positivity in a setting of low amyloid‐positive prevalence.
Including (pre‐) analytical errors or measurement biases caused misclassifications.
Plasma Aβ42/Aβ40 had a low inherent dynamic range, independent of analytical method.
Other blood biomarkers may be easier to implement as robust prescreening tools.
To elucidate the relationship between cerebrospinal fluid (CSF) total‐tau (T‐tau) and phosphorylated tau (P‐tau) with the tau PET ligand 18F‐AV‐1451 in Alzheimer's disease (AD), we examined 30 ...cognitively healthy elderly (15 with preclinical AD), 14 prodromal AD, and 39 AD dementia patients. CSF T‐tau and P‐tau were highly correlated (R = 0.92, P < 0.001), but they were only moderately associated with retention of 18F‐AV‐1451, and mainly in demented AD patients. 18F‐AV‐1451, but not CSF T‐tau or P‐tau, was strongly associated with atrophy and cognitive impairment. CSF tau was increased in preclinical AD, despite normal 18F‐AV‐1451 retention. However, not all dementia AD patients exhibited increased CSF tau, even though 18F‐AV‐1451 retention was always increased at this disease stage. We conclude that CSF T‐tau and P‐tau mainly behave as biomarkers of “disease state”, since they appear to be increased in many cases of AD at all disease stages, already before the emergence of tau aggregates. In contrast, 18F‐AV‐1451 is a biomarker of “disease stage”, since it is increased in clinical stages of the disease, and is associated with brain atrophy and cognitive decline.
Synopsis
Tau pathology is a key feature of Alzheimer's disease (AD) but the relationship between cerebrospinal fluid tau, the tau PET tracer 18F‐AV‐1451 and other hallmarks of AD is unclear. This is now studied in a cohort of cognitively healthy controls and patients with prodromal and dementia stages of AD.
Cerebrospinal fluid total‐tau and phosphorylated‐tau levels are moderately correlated with 18F‐AV‐1451 tau PET retention.
Correlations between cerebrospinal fluid tau and 18F‐AV‐1451 tau PET are seen primarily in the dementia stage of Alzheimer's disease.
Cerebrospinal fluid tau levels are increased already in preclinical AD.
18F‐AV‐1451 tau PET is more strongly related to neurodegeneration and cognitive decline than cerebrospinal fluid tau levels are.
Cerebrospinal fluid tau levels may be useful primarily to identify the presence of Alzheimer's disease, while 18F‐AV‐1451 tau PET may be useful also to track the progression of the disease.
Tau pathology is a key feature of Alzheimer's disease (AD) but the relationship between cerebrospinal fluid tau, the tau PET tracer 18F‐AV‐1451 and other hallmarks of AD is unclear. This is now studied in a cohort of cognitively healthy controls and patients with prodromal and dementia stages of AD.
To determine how fully automated Elecsys CSF immunoassays for β-amyloid (Aβ) and tau biomarkers and an ultrasensitive Simoa assay for neurofilament light chain (NFL) correlate with neuropathologic ...changes of Alzheimer disease (AD) and frontotemporal lobar degeneration (FTLD).
We studied 101 patients with antemortem CSF and neuropathology data. CSF samples were collected a mean of 2.9 years before death (range 0.2-7.5 years). CSF was analyzed for Aβ
, Aβ
, total tau (T-tau), tau phosphorylated at amino acid residue 181 (P-tau), P-tau/Aβ
and Aβ
/Aβ
ratios, and NFL. Neuropathology measures included Thal phases, Braak stages, Consortium to Establish a Registry for Alzheimer's Disease (CERAD) scores, AD neuropathologic change (ADNC), and primary and contributory pathologic diagnoses. Associations between CSF biomarkers and neuropathologic features were tested in regression models adjusted for age, sex, and time from sampling to death.
CSF biomarkers were associated with neuropathologic measures of Aβ (Thal, CERAD score), tau (Braak stage), and overall ADNC. The CSF P-tau/Aβ
and Aβ
/Aβ
ratios had high sensitivity, specificity, and overall diagnostic performance for intermediate-high ADNC (area under the curve range 0.95-0.96). Distinct biomarker patterns were seen in different FTLD subtypes, with increased NFL and reduced P-tau/T-tau in FTLD-TAR DNA-binding protein 43 and reduced T-tau in progressive supranuclear palsy compared to other FTLD variants.
CSF biomarkers, including P-tau, T-tau, Aβ
, Aβ
, and NFL, support in vivo identification of AD neuropathology and correlate with FTLD neuropathology.
This study provides Class II evidence that distinct CSF biomarker patterns, including for P-tau, T-tau, Aβ
, Aβ
, and NFL, are associated with AD and FTLD neuropathology.
Several promising plasma biomarkers for Alzheimer's disease have been recently developed, but their neuropathological correlates have not yet been fully determined. To investigate and compare ...independent associations between multiple plasma biomarkers (p‐tau181, p‐tau217, p‐tau231, Aβ42/40, GFAP, and NfL) and neuropathologic measures of amyloid and tau, we included 105 participants from the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND) with antemortem plasma samples and a postmortem neuropathological exam, 48 of whom had longitudinal p‐tau217 and p‐tau181. When simultaneously including plaque and tangle loads, the Aβ42/40 ratio and p‐tau231 were only associated with plaques (ρAβ42/4095%CI = −0.53−0.65, −0.35, ρp‐tau23195%CI = 0.280.10, 0.43), GFAP was only associated with tangles (ρGFAP95%CI = 0.390.17, 0.57), and p‐tau217 and p‐tau181 were associated with both plaques (ρp‐tau21795%CI = 0.400.21, 0.56, ρp‐tau18195%CI = 0.360.15, 0.50) and tangles (ρp‐tau21795%CI = 0.520.34, 0.66; ρp‐tau18195%CI = 0.360.17, 0.52). A model combining p‐tau217 and the Aβ42/40 ratio showed the highest accuracy for predicting the presence of Alzheimer's disease neuropathological change (ADNC, AUC95%CI = 0.890.82, 0.96) and plaque load (R2 = 0.55), while p‐tau217 alone was optimal for predicting tangle load (R2 = 0.45). Our results suggest that high‐performing assays of plasma p‐tau217 and Aβ42/40 might be an optimal combination to assess Alzheimer's‐related pathology in vivo.
Synopsis
This study conducted a head‐to‐head comparison between multiple plasma biomarkers and neuropathological measures of amyloid plaques and neurofibrillary tangles.
Plasma p‐tau217 and p‐tau181 are independently associated with both amyloid plaques and tau neurofibrillary tangles, the main pathological hallmarks of Alzheimer's disease.
Plasma p‐tau217 may be a better Alzheimer's biomarker than p‐tau181 as it shows stronger associations with Alzheimer's pathology and is more sensitive to early pathological changes.
Plasma p‐tau217 longitudinal changes may help in predicting the presence of Alzheimer's pathology.
Plasma Aβ42/40 and plasma p‐tau231 are specifically associated with amyloid pathology, whereas plasma glial fibrillary acidic protein (GFAP) is specifically associated with tau pathology.
Plasma neurofilament light (NfL) is increased in participants with cerebral white matter rarefaction even after accounting for the presence of Alzheimer's disease pathology.
This study conducted a head‐to‐head comparison between multiple plasma biomarkers and neuropathological measures of amyloid plaques and neurofibrillary tangles.
The Scale for Outcomes in Parkinson's disease for Autonomic symptoms (SCOPA-AUT) is an instrument intended to assess overall and domain-specific autonomic symptom burden. In this study the SCOPA-AUT ...is translated into Swedish and its measurement properties are assessed.
Following translation the SCOPA-AUT was field-tested regarding comprehensibility, relevance, and respondent burden (n = 20). It was then tested according to Rasch measurement theory using data from 242 persons with PD, of whom 162 completed SCOPA-AUT at baseline and 1-2 years later, giving a total of 404 data points for analysis.
The Swedish SCOPA-AUT took a mean of 6 min to complete and was considered easy to use and relevant by respondents. SCOPA-AUT exhibited acceptable Rasch model fit, represents more severe levels of dysautonomia than that reported by the sample, and response categories were not working as expected for 17 items. Local dependency was identified and followed a pattern resembling the suggested subscales. Accounting for the subscale structure eliminated local dependency and reduced the initially inflated reliability from 0.81 to 0.68.
The SCOPA-AUT is useful as a clinical check-list but requires further developmental work in order to meet more rigorous standards as an outcome measurement instrument.
To date, the development of disease-modifying therapies for Alzheimer's disease (AD) has largely focused on the removal of amyloid beta Aβ fragments from the CNS. Proteomic profiling of patient ...fluids may help identify novel therapeutic targets and biomarkers associated with AD pathology. Here, we applied the Olink™ ProSeek immunoassay to measure 270 CSF and plasma proteins across 415 Aβ- negative cognitively normal individuals (Aβ- CN), 142 Aβ-positive CN (Aβ+ CN), 50 Aβ- mild cognitive impairment (MCI) patients, 75 Aβ+ MCI patients, and 161 Aβ+ AD patients from the Swedish BioFINDER study. A validation cohort included 59 Aβ- CN, 23 Aβ- + CN, 44 Aβ- MCI and 53 Aβ+ MCI. To compare protein concentrations in patients versus controls, we applied multiple linear regressions adjusting for age, gender, medications, smoking and mean subject-level protein concentration, and corrected findings for false discovery rate (FDR, q < 0.05). We identified, and replicated, altered levels of ten CSF proteins in Aβ+ individuals, including CHIT1, SMOC2, MMP-10, LDLR, CD200, EIF4EBP1, ALCAM, RGMB, tPA and STAMBP (- 0.14 < d < 1.16; q < 0.05). We also identified and replicated alterations of six plasma proteins in Aβ+ individuals OSM, MMP-9, HAGH, CD200, AXIN1, and uPA (- 0.77 < d < 1.28; q < 0.05). Multiple analytes associated with cognitive performance and cortical thickness (q < 0.05). Plasma biomarkers could distinguish AD dementia (AUC = 0.94, 95% CI = 0.87-0.98) and prodromal AD (AUC = 0.78, 95% CI = 0.68-0.87) from CN. These findings reemphasize the contributions of immune markers, phospholipids, angiogenic proteins and other biomarkers downstream of, and potentially orthogonal to, Aβ- and tau in AD, and identify candidate biomarkers for earlier detection of neurodegeneration.
Pre-analytical factors can cause substantial variability in the measurements of cerebrospinal fluid (CSF) and plasma biomarkers of Alzheimer's disease (AD). However, their effects on the performance ...of one of the most promising plasma AD biomarkers, phosphorylated tau (p-tau)217, are not known.
We included 50 amyloid-β positive (Aβ
) and 50 Aβ
participants from the Swedish BioFINDER-1 study. Plasma and CSF p-tau217 were measured using an immunoassay developed by Lilly Research Laboratories. We examined the effect of four plasma handling conditions, i.e., (1) thawing at room temperature (RT) with no centrifugation, (2) thawing at RT followed by centrifugation, (3) thawing on ice with no centrifugation, and (4) thawing on ice followed by centrifugation. In addition, we also tested the effects of up to 3 freeze-thaw cycles on the associations of plasma p-tau217 with AD-related pathologies measured with CSF p-tau217 and CSF Aβ42/Aβ40.
In the whole cohort (combining Aβ
and Aβ
participants), we found significant correlations between plasma p-tau217 and both CSF p-tau217 (R
0.614-0.717, p < 0.001) and CSF Aβ42/Aβ40 (Spearman R
, - 0.515 to - 0.652, p < 0.001) for each of the four tested conditions. Correlations between plasma and CSF p-tau217 were also significant for all conditions in the Aβ
group (R
, 0.506-0.579, p < 0.001). However, in this Aβ
subgroup, correlations with CSF Aβ42/Aβ40 were only significant for centrifuged samples (thawed at RT, R = - 0.394, p = 0.010; thawed on ice, R = - 0.406; p = 0.007). In Aβ
participants, correlations between plasma and CSF p-tau217 were again significant only for centrifuged samples (thawed at RT, R = 0.394, p = 0.007; thawed on ice, R = 0.334; p = 0.022), with no correlations seen between plasma p-tau217 and CSF Aβ42/Aβ40 for any of the conditions. While the accuracy of plasma p-tau217 to identify individuals with abnormal CSF Aβ42/Aβ40 or CSF p-tau217 status was high, the AUCs for samples thawed at RT and analyzed without centrifugation were numerically lower than the AUCs of other conditions (CSF Aβ42/Aβ40 = 0.845 vs 0.872-0.884; CSF p-tau217 = 0.866 vs 0.908-0.924, p
> 0.11). P-tau217 concentration was consistently higher in non-centrifuged samples than in centrifuged samples (p ≤ 0.021). There were no differences between samples freeze-thawed once, twice, or three times.
Centrifugation improved the performance of plasma p-tau217, but thawing temperatures and up to three freeze-thaw cycles did not have a significant impact. These results may inform the future development of standardized sample-handling protocols for AD biomarkers.
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