Plasma phosphorylated tau181 (P-tau181) might be increased in Alzheimer's disease (AD), but its usefulness for differential diagnosis and prognosis is unclear. We studied plasma P-tau181 in three ...cohorts, with a total of 589 individuals, including cognitively unimpaired participants and patients with mild cognitive impairment (MCI), AD dementia and non-AD neurodegenerative diseases. Plasma P-tau181 was increased in preclinical AD and further increased at the MCI and dementia stages. It correlated with CSF P-tau181 and predicted positive Tau positron emission tomography (PET) scans (area under the curve (AUC) = 0.87-0.91 for different brain regions). Plasma P-tau181 differentiated AD dementia from non-AD neurodegenerative diseases with an accuracy similar to that of Tau PET and CSF P-tau181 (AUC = 0.94-0.98), and detected AD neuropathology in an autopsy-confirmed cohort. High plasma P-tau181 was associated with subsequent development of AD dementia in cognitively unimpaired and MCI subjects. In conclusion, plasma P-tau181 is a noninvasive diagnostic and prognostic biomarker of AD, which may be useful in clinical practice and trials.
Blood‐based biomarkers for Alzheimer's disease Leuzy, Antoine; Mattsson‐Carlgren, Niklas; Palmqvist, Sebastian ...
EMBO molecular medicine,
11 January 2022, Volume:
14, Issue:
1
Journal Article
Peer reviewed
Open access
Neurodegenerative disorders such as Alzheimer's disease (AD) represent a mounting public health challenge. As these diseases are difficult to diagnose clinically, biomarkers of underlying ...pathophysiology are playing an ever‐increasing role in research, clinical trials, and in the clinical work‐up of patients. Though cerebrospinal fluid (CSF) and positron emission tomography (PET)‐based measures are available, their use is not widespread due to limitations, including high costs and perceived invasiveness. As a result of rapid advances in the development of ultra‐sensitive assays, the levels of pathological brain‐ and AD‐related proteins can now be measured in blood, with recent work showing promising results. Plasma P‐tau appears to be the best candidate marker during symptomatic AD (i.e., prodromal AD and AD dementia) and preclinical AD when combined with Aβ42/Aβ40. Though not AD‐specific, blood NfL appears promising for the detection of neurodegeneration and could potentially be used to detect the effects of disease‐modifying therapies. This review provides an overview of the progress achieved thus far using AD blood‐based biomarkers, highlighting key areas of application and unmet challenges.
This Review discusses recent advances in blood‐based biomarkers for Alzheimer's disease, highlighting the key areas of application and unmet challenges.
Cerebrospinal fluid (CSF) p-tau181 (tau phosphorylated at threonine 181) is an established biomarker of Alzheimer's disease (AD), reflecting abnormal tau metabolism in the brain. Here we investigate ...the performance of CSF p-tau217 as a biomarker of AD in comparison to p-tau181. In the Swedish BioFINDER cohort (n = 194), p-tau217 shows stronger correlations with the tau positron emission tomography (PET) tracer
Fflortaucipir, and more accurately identifies individuals with abnormally increased
Fflortaucipir retention. Furthermore, longitudinal increases in p-tau217 are higher compared to p-tau181 and better correlate with
Fflortaucipir uptake. P-tau217 correlates better than p-tau181 with CSF and PET measures of neocortical amyloid-β burden and more accurately distinguishes AD dementia from non-AD neurodegenerative disorders. Higher correlations between p-tau217 and
Fflortaucipir are corroborated in an independent EXPEDITION3 trial cohort (n = 32). The main results are validated using a different p-tau217 immunoassay. These findings suggest that p-tau217 might be more useful than p-tau181 in the diagnostic work up of AD.
Plasma biomarkers of amyloid, tau, and neurodegeneration (ATN) need to be characterized in cognitively unimpaired (CU) elderly individuals. We therefore tested if plasma measurements of amyloid-β ...(Aβ)42/40, phospho-tau217 (P-tau217), and neurofilament light (NfL) together predict clinical deterioration in 435 CU individuals followed for an average of 4.8 ± 1.7 years in the BioFINDER study. A combination of all three plasma biomarkers and basic demographics best predicted change in cognition (Pre-Alzheimer's Clinical Composite; R
= 0.14, 95% CI 0.12-0.17; P < 0.0001) and subsequent AD dementia (AUC = 0.82, 95% CI 0.77-0.91, P < 0.0001). In a simulated clinical trial, a screening algorithm combining all three plasma biomarkers would reduce the required sample size by 70% (95% CI 54-81; P < 0.001) with cognition as trial endpoint, and by 63% (95% CI 53-70, P < 0.001) with subsequent AD dementia as trial endpoint. Plasma ATN biomarkers show usefulness in cognitively unimpaired populations and could make large clinical trials more feasible and cost-effective.
Biomarkers have revolutionized scientific research on neurodegenerative diseases, in particular Alzheimer's disease, transformed drug trial design, and are also increasingly improving patient ...management in clinical practice. A few key cerebrospinal fluid biomarkers have been robustly associated with neurodegenerative diseases. Several novel biomarkers are very promising, especially blood-based markers. However, many biomarker findings have had low reproducibility despite initial promising results. In this perspective, we identify possible sources for low reproducibility of studies on fluid biomarkers for neurodegenerative diseases, with a focus on Alzheimer's disease. We suggest guidelines for researchers and journal editors, with the aim to improve reproducibility of findings.
Axonal white matter injury is believed to be a major determinant of adverse outcomes following traumatic brain injury (TBI). We hypothesized that measurement of neurofilament light protein (NF-L), a ...protein found in long white-matter axons, in blood samples, may serve as a suitable biomarker for neuronal damage in TBI patients. To test our hypotheses, we designed a study in two parts: i) we developed an immunoassay based on Single molecule array technology for quantification of NF-L in blood, and ii) in a proof-of-concept study, we tested our newly developed method on serial serum samples from severe TBI (sTBI) patients (n = 72) and controls (n = 35). We also compared the diagnostic and prognostic utility of NF-L with the established blood biomarker S100B. NF-L levels were markedly increased in sTBI patients compared with controls. NF-L at admission yielded an AUC of 0.99 to detect TBI versus controls (AUC 0.96 for S100B), and increased to 1.00 at day 12 (0.65 for S100B). Importantly, initial NF-L levels predicted poor 12-month clinical outcome. In contrast, S100B was not related to outcome. Taken together, our data suggests that measurement of serum NF-L may be useful to assess the severity of neuronal injury following sTBI.
It is not known exactly where amyloid-β (Aβ) fibrils begin to accumulate in individuals with Alzheimer's disease (AD). Recently, we showed that abnormal levels of Aβ42 in cerebrospinal fluid (CSF) ...can be detected before abnormal amyloid can be detected using PET in individuals with preclinical AD. Using these approaches, here we identify the earliest preclinical AD stage in subjects from the ADNI and BioFINDER cohorts. We show that Aβ accumulation preferentially starts in the precuneus, medial orbitofrontal, and posterior cingulate cortices, i.e., several of the core regions of the default mode network (DMN). This early pattern of Aβ accumulation is already evident in individuals with normal Aβ42 in the CSF and normal amyloid PET who subsequently convert to having abnormal CSF Aβ42. The earliest Aβ accumulation is further associated with hypoconnectivity within the DMN and between the DMN and the frontoparietal network, but not with brain atrophy or glucose hypometabolism. Our results suggest that Aβ fibrils start to accumulate predominantly within certain parts of the DMN in preclinical AD and already then affect brain connectivity.
Introduction
This study investigated the diagnostic and disease‐monitoring potential of plasma biomarkers in mild cognitive impairment (MCI) and Alzheimer's disease (AD) dementia and cognitively ...unimpaired (CU) individuals.
Methods
Plasma was analyzed using Simoa assays from 99 CU, 107 MCI, and 103 AD dementia participants.
Results
Phosphorylated‐tau181 (P‐tau181), neurofilament light, amyloid‐β (Aβ42/40), Total‐tau and Glial fibrillary acidic protein were altered in AD dementia but P‐tau181 significantly outperformed all biomarkers in differentiating AD dementia from CU (area under the curve AUC = 0.91). P‐tau181 was increased in MCI converters compared to non‐converters. Higher P‐tau181 was associated with steeper cognitive decline and gray matter loss in temporal regions. Longitudinal change of P‐tau181 was strongly associated with gray matter loss in the full sample and with Aβ measures in CU individuals.
Discussion
P‐tau181 detected AD at MCI and dementia stages and was strongly associated with cognitive decline and gray matter loss. These findings highlight the potential value of plasma P‐tau181 as a non‐invasive and cost‐effective diagnostic and prognostic biomarker in AD.
Cigarette smoking has been linked with both increased and decreased risk for Alzheimer's disease (AD). This is relevant for the US military because the prevalence of smoking in the military is ...approximately 11% higher than in civilians.
A systematic review of published studies on the association between smoking and increased risk for AD and preclinical and human literature on the relationships between smoking, nicotine exposure, and AD-related neuropathology was conducted. Original data from comparisons of smoking and never-smoking cognitively normal elders on in vivo amyloid imaging are also presented.
Overall, literature indicates that former/active smoking is related to a significantly increased risk for AD. Cigarette smoke/smoking is associated with AD neuropathology in preclinical models and humans. Smoking-related cerebral oxidative stress is a potential mechanism promoting AD pathology and increased risk for AD.
A reduction in the incidence of smoking will likely reduce the future prevalence of AD.
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.
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