Amyloid-β Biomarkers Research Articles

A streamlined, resource-efficient immunoprecipitation-mass spectrometry method for quantifying plasma amyloid-β biomarkers in Alzheimer's disease.

High-performance, resource-efficient methods for plasma amyloid-β (Aβ) quantification in Alzheimer's disease are lacking; existing mass spectrometry-based assays are resource- and time-intensive. We developed a streamlined mass spectrometry method with a single immunoprecipitation step, an optimized buffer system, and ≤75% less antibody requirement. Analytical and clinical performances were compared with an in-house reproduced version of a well-known two-step assay. The streamlined assay showed high dilution linearity (r2>0.99) and precision (< 10% coefficient of variation), low quantification limits (Aβ1-40: 12.5 pg/ml; Aβ1-42: 3.125 pg/ml), and high signal correlation (r2~0.7) with the two-step immunoprecipitation assay. The novel single-step assay showed more efficient recovery of Aβ peptides via fewer immunoprecipitation steps, with significantly higher signal-to-noise ratios, even at plasma sample volumes down to 50 pl. Both assays had equivalent performances in distinguishing non-elevated vs. elevated brain Aβ-PET individuals. The new method enables simplified yet robust evaluation of plasma Aβ biomarkers in Alzheimer's disease.

Self-calibrating surface-enhanced Raman scattering-lateral flow immunoassay for determination of amyloid-β biomarker of Alzheimer's disease

Rapid early diagnosis of Alzheimer's disease (AD) is critical for its effective and prompt treatment since the clinically available treatments can only relieve the symptoms or slow the disease progression. However, it is still a grand challenge to accurately diagnose AD at its early stage because of the indiscernible early symptoms and the lack of sensitive detection tools. Here, we develop a self-calibrating surface-enhanced Raman scattering (SERS)-lateral flow immunoassay (LFIA) biosensor for quantitative analysis of amyloid-β1-42 (Aβ1-42) biomarker in biofluids, enabling accurate AD diagnosis. The designed SERS-LFIA biosensor makes full use of the unique aspects of the LFIA format and the SERS technique to quantify the Aβ1-42 level in complex biofluids with high sensitivity, excellent anti-interference capability, low-cost, and operation simplicity. The key aspect of the design of this biosensor is that internal standard (IS)-SERS nanoparticles are embedded in the test line of the test strip as a self-calibration unit for correction of fluctuations of SERS signals caused by various external factors such as test parameters and sample heterogeneity. We demonstrate significant improvement of the detection performance of the SERS-LFIA biosensor for ratiometric quantification of Aβ1-42 owing to the built-in IS in the test line. We expect that the present IS-based biosensing strategy provides a promising tool for accurate AD diagnosis and longitudinal monitoring of therapeutic response with great promises for clinical translation.

MRAβ: A multimodal MRI-derived amyloid-β biomarker for Alzheimer's disease.

Florbetapir 18 F (AV45), a highly sensitive and specific positron emission tomographic (PET) molecular biomarker binding to the amyloid-β of Alzheimer's disease (AD), is constrained by radiation and cost. We sought to combat it by combining multimodal magnetic resonance imaging (MRI) images and a collaborative generative adversarial networks model (CollaGAN) to develop a multimodal MRI-derived Amyloid-β (MRAβ) biomarker. We collected multimodal MRI and PET AV45 data of 380 qualified participants from the ADNI dataset and 64 subjects from OASIS3 dataset. A five-fold cross-validation CollaGAN were applied to generate MRAβ. In the ADNI dataset, we found MRAβ could characterize the subject-level AV45 spatial variations in both AD and mild cognitive impairment (MCI). Voxel-wise two-sample t-tests demonstrated amyloid-β depositions identified by MRAβ in AD and MCI were significantly higher than healthy controls (HCs) in widespread cortices (p < .05, corrected) and were much similar to those by AV45 (r > .92, p < .001). Moreover, a 3D ResNet classifier demonstrated that MRAβ was comparable to AV45 in discriminating AD from HC in both the ADNI and OASIS3 datasets, and in discriminate MCI from HC in ADNI. Finally, we found MRAβ could mimic cortical hyper-AV45 in HCs who later converted to MCI (r = .79, p < .001) and was comparable to AV45 in discriminating them from stable HC (p > .05). In summary, our work illustrates that MRAβ synthesized by multimodal MRI could mimic the cerebral amyloid-β depositions like AV45 and lends credence to the feasibility of advancing MRI toward molecular-explainable biomarkers.

Basal Forebrain Atrophy, Cortical Thinning, and Amyloid-β Status in Parkinson's disease-Related Cognitive Decline.

Degeneration of the cortically-projecting cholinergic basal forebrain (cBF) is a well-established pathologic correlate of cognitive decline in Parkinson's disease (PD). In Alzheimer's disease (AD) the effect of cBF degeneration on cognitive decline was found to be mediated by parallel atrophy of denervated cortical areas. To examine whether the association between cBF degeneration and cognitive decline in PD is mediated by parallel atrophy of cortical areas and whether these associations depend on the presence of comorbid AD pathology. We studied 162 de novo PD patients who underwent serial 3 T magnetic resonance imaging scanning (follow-up: 2.33 ± 1.46 years) within the Parkinson's Progression Markers Initiative. cBF volume and regional cortical thickness were automatically calculated using established procedures. Individual slopes of structural brain changes and cognitive decline were estimated using linear-mixed models. Associations between longitudinal cBF degeneration, regional cortical thinning, and cognitive decline were assessed using regression analyses and mediation effects were assessed using nonparametric bootstrap. Complementary analyses assessed the effect of amyloid-β biomarker positivity on these associations. After controlling for global brain atrophy, longitudinal cBF degeneration was highly correlated with faster cortical thinning (PFDR < 0.05), and thinning in cBF-associated cortical areas mediated the association between cBF degeneration and cognitive decline (rcBF-MoCA = 0.30, P < 0.001). Interestingly, both longitudinal cBF degeneration and its association with cortical thinning were largely independent of amyloid-β status. cBF degeneration in PD is linked to parallel thinning of cortical target areas, which mediate the effect on cognitive decline. These associations are independent of amyloid-β status, indicating that they reflect proper features of PD pathophysiology. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Relationship between cerebrospinal fluid neurodegeneration biomarkers and temporal brain atrophy in cognitively healthy older adults

It is unclear whether cerebrospinal fluid (CSF) biomarkers of neurodegeneration predict brain atrophy in cognitively healthy older adults, whether these associations can be explained by phosphorylated tau181 (p-tau) and the 42 amino acid form of amyloid-β (Aβ42) biomarkers, and which neural substrates may drive these associations. We addressed these questions in 2 samples of cognitively healthy older adults who underwent longitudinal structural MRI up to 7 years and had baseline CSF levels of heart-type fatty-acid binding protein (FABP3)=, total-tau, neurogranin, and neurofilament light (NFL) (n = 189, scans = 721). The results showed that NFL, total-tau, and FABP3 predicted entorhinal thinning and hippocampal atrophy. Brain atrophy was not moderated by Aβ42 and the associations between NFL and FABP3 with brain atrophy were independent of p-tau. The spatial pattern of cortical atrophy associated with the biomarkers overlapped with neurogenetic profiles associated with expression in the axonal (total-tau, NFL) and dendritic (neurogranin) components. CSF biomarkers of neurodegeneration are useful for predicting specific features of brain atrophy in older adults, independently of amyloid and tau pathology biomarkers.

Insulin resistance, cognition and Alzheimer's disease biomarkers: Evidence that CSF Aβ42 moderates the association between insulin resistance and increased CSF tau levels

Mounting evidence implicates insulin resistance (IR) with reduced cognition, increased dementia risk and changes in Alzheimer's disease biomarkers. It's unclear how, and at what stage IR has the greatest impact on Alzheimer's disease biomarker progression indicative of cognitive decline. Exploration of potential factors influencing this relationship continue. We have previously reported IR to be associated with cognitive function, and increased CSF tau in a cognitively unimpaired cohort. Now, we aimed to determine if CSF total (t-tau) or phosphorylated tau (p-tau) mediated the relationship between HOMA-IR and cognition, and explore sex or amyloid-β (Aβ) biomarkers as moderators of this relationship. Mediation analysis demonstrated that CSF tau does not directly influence the association between HOMA-IR and cognition. Moderation analysis revealed CSF Aβ42 moderates the relationships between HOMA-IR and CSF tau. The combination of lower CSF Aβ42 and higher HOMA-IR was associated with increases in CSF tau. The CSF Aβ42 moderation finding has potential to be considered when assessing type 2 diabetic risk for tau pathology and cognitive decline.

Empirically defining the preclinical stages of the Alzheimer's continuum in the Alzheimer's Disease Neuroimaging Initiative.

The National Institute on Aging and the Alzheimer's Association published new research criteria defining the Alzheimer's continuum (AC) by the presence of positive amyloid-β biomarkers. Symptom severity of those on the AC is staged across six levels, including two preclinical stages (stages 1 and 2). AC stage 2 is defined by the presence of at least one of the following: (i) transitional cognitive decline; (ii) subjective cognitive decline; or (iii) neurobehavioural symptoms. In contrast, AC stage 1 is defined by the absence of symptoms. Initial empirical definitions for each symptom class were developed. These empirical criteria were then applied in a sample of 285 cognitively normal, amyloid-positive individuals from the Alzheimer's Disease Neuroimaging Initiative for purposes of AC stage 1 and 2 classification. In this sample, 56.10% of participants were asymptomatic and classified as AC stage 1. In contrast, 42.46% of individuals were positive for at least one symptom class: 22.11% for transitional cognitive decline, 20.35% for subjective cognitive decline, and 14.74% for neurobehavioural symptoms. AC stage was a predictor of cognitive/functional decline over 4 years of follow up in a longitudinal growth model (B=0.33, P < 0.001). Results provide a methodology to operationalize the National Institute on Aging and the Alzheimer's Association AC stage 1 and 2 criteria and include preliminary evidence of the validity of this approach. The methods outlined in this manuscript can be used to test hypotheses regarding prodromal Alzheimer's disease, as well as implemented in clinical trial selection procedures.

Longitudinal pathways of cerebrospinal fluid and positron emission tomography biomarkers of amyloid-\u03b2 positivity

Mismatch between CSF and PET amyloid-β biomarkers occurs in up to ≈20% of preclinical/prodromal Alzheimer’s disease individuals. Factors underlying mismatching results remain unclear. In this study we hypothesized that CSF/PET discordance provides unique biological/clinical information. To test this hypothesis, we investigated non-demented and demented participants with CSF amyloid-β42 and [18F]Florbetapir PET assessments at baseline (n = 867) and at 2-year follow-up (n = 289). Longitudinal trajectories of amyloid-β positivity were tracked simultaneously for CSF and PET biomarkers. In the longitudinal cohort (n = 289), we found that participants with normal CSF/PET amyloid-β biomarkers progressed more frequently toward CSF/PET discordance than to full CSF/PET positivity (χ2(1) = 5.40; p < 0.05). Progression to CSF+/PET+ status was ten times more frequent in cases with discordant biomarkers, as compared to csf−/pet− cases (χ2(1) = 18.86; p < 0.001). Compared to the CSF+/pet− group, the csf−/PET+ group had lower APOE-ε4ε4 prevalence (χ2(6) = 197; p < 0.001; n = 867) and slower rate of brain amyloid-β accumulation (F(3,600) = 12.76; p < 0.001; n = 608). These results demonstrate that biomarker discordance is a typical stage in the natural history of amyloid-β accumulation, with CSF or PET becoming abnormal first and not concurrently. Therefore, biomarker discordance allows for identification of individuals with elevated risk of progression toward fully abnormal amyloid-β biomarkers, with subsequent risk of neurodegeneration and cognitive decline. Our results also suggest that there are two alternative pathways (“CSF-first” vs. “PET-first”) toward established amyloid-β pathology, characterized by different genetic profiles and rates of amyloid-β accumulation. In conclusion, CSF and PET amyloid-β biomarkers provide distinct information, with potential implications for their use as biomarkers in clinical trials.

Linguistic profiles, brain metabolic patterns and rates of amyloid-β biomarker positivity in patients with mixed primary progressive aphasia

We aimed to detail language profiles, brain metabolic patterns and proportion of Alzheimer's disease biomarkers in a cohort of patients with mixed primary progressive aphasia (mPPA). We considered 58 patients with PPA: 10 with non-fluent/agrammatic variant (nfvPPA), 16 with semantic variant (svPPA), 21 with logopenic variant (lvPPA) and 9 with mPPA. Patients with mPPA were further classified as 4 nf/lvPPA (with prevailing features for nfvPPA and lvPPA) and 5 s/lvPPA (with prevailing features for svPPA and lvPPA). Nf/lvPPA patients were characterized by higher proportion of Naming impairment compared to nfvPPA and more frequent Grammatical Errors and Phonologic Errors than lvPPA. S/lvPPA had higher proportion of impairment in Sentences Repetition compared to svPPA and in Single-word Comprehension compared to lvPPA. 100% of nf/lvPPA and 40% of s/lvPPA had Aβ positive biomarkers. Brain hypometabolic pattern in Nf/lvPPA was consistent with lvPPA, while s/lvPPA had a brain metabolism resembling svPPA. We concluded that nf/lvPPA patients might be considered as PPA variant due to Alzheimer's disease and s/lvPPA group mainly included patients with svPPA.

Plasma Amyloid-β Biomarker Associated with Cognitive Decline in Preclinical Alzheimer's Disease.

Using immunoprecipitation-mass spectrometry, we recently developed and validated a plasma composite biomarker for the assessment of amyloid-β (Aβ) levels. However, as yet, its relationship with clinical outcomes remains unclear. We aimed to examine the relationship between this plasma Aβ composite biomarker and cognitive function in cognitively normal older adults in two independent cohorts. Participants enrolled in the Australian Imaging, Biomarkers and Lifestyle (AIBL) study and the National Centre for Geriatrics and Gerontology (NCGG) study had undergone Aβ neuroimaging using positron emission tomography (PET), cognitive assessments and provided blood samples. We derived a high-performance plasma Aβ composite biomarker by immunoprecipitation with mass-spectrometry. Both continuous and categorical measures of the plasma Aβ composite biomarker were significantly related to decline in episodic memory and executive function. The magnitude of effects of the plasma Aβ composite on episodic memory and executive function were comparable to that observed for the effects of PET Aβ levels on these same outcome measures. Several plasma Aβ biomarkers have been developed, but none have yet been applied to investigate their relationship with cognitive outcomes. Our results have important implications for the use of this biomarker in the detection of at-risk individuals.

Homocysteic Acid in Blood Can Detect Mild Cognitive Impairment: A Preliminary Study.

Background:In the treatment of Alzheimer’s disease (AD), it is thought to be most effective to intervene at the earliest and mildest stages. For diagnosis at the earliest and mildest stages, it is desirable to use a biomarker that can be detected by a minimally invasive, cost-effective technique. Recent research indicates the potential clinical usefulness of plasma amyloid-β (Aβ) biomarkers in predicting brain Aβ burden at an individual level. However, it is as yet unproven that accumulation of Aβ necessarily leads to the development of AD.Objective:Homocysteic acid (HCA) is useful as an early diagnostic marker for mild cognitive impairment (MCI), a pre-stage of AD.Methods:We measured the concentration of HCA, tumor necrosis factor alpha, cortisol, tau, and phosphorylated tau (p-tau) in patients’ plasma of 22 AD, 23 MCI, and 9 negative control (NC) cases.Results:Plasma HCA was shown to be very high in areas under the receiver operating characteristic curves (AUC), distinguished between MCI and NC; when 0.116μM was chosen as the analyte concentration cut-off, the sensitivity was 95.7% and the specificity was 70%.Conclusion:Our results suggest that plasma HCA may be a useful indicator as an early diagnostic marker for MCI. HCA seems to be upstream from neurodegeneration in the AD pathology because it is known that an overactive NMDA receptor promotes amyloid polymerization and tau phosphorylation in AD.

Soluble TREM2 is elevated in Parkinson's disease subgroups with increased CSF tau.

Parkinson's disease is the second most common neurodegenerative disease after Alzheimer's disease and affects 1% of the population above 60 years old. Although Parkinson's disease commonly manifests with motor symptoms, a majority of patients with Parkinson's disease subsequently develop cognitive impairment, which often progresses to dementia, a major cause of morbidity and disability. Parkinson's disease is characterized by α-synuclein accumulation that frequently associates with amyloid-β and tau fibrils, the hallmarks of Alzheimer's disease neuropathological changes; this co-occurrence suggests that onset of cognitive decline in Parkinson's disease may be associated with appearance of pathological amyloid-β and/or tau. Recent studies have highlighted the appearance of the soluble form of the triggering receptor expressed on myeloid cells 2 (sTREM2) receptor in CSF during development of Alzheimer's disease. Given the known association of microglial activation with advancing Parkinson's disease, we investigated whether CSF and/or plasma sTREM2 differed between CSF biomarker-defined Parkinson's disease participant subgroups. In this cross-sectional study, we examined 165 participants consisting of 17 cognitively normal elderly subjects, 45 patients with Parkinson's disease with no cognitive impairment, 86 with mild cognitive impairment, and 17 with dementia. Stratification of subjects by CSF amyloid-β and tau levels revealed that CSF sTREM2 concentrations were elevated in Parkinson's disease subgroups with a positive tau CSF biomarker signature, but not in Parkinson's disease subgroups with a positive CSF amyloid-β biomarker signature. These findings indicate that CSF sTREM2 could serve as a surrogate immune biomarker of neuronal injury in Parkinson's disease.

Comparison between amyloid-PET and CSF amyloid-β biomarkers in a clinical cohort with memory deficits

With increasing prevalence of Alzheimer's disease (AD) and advances in research of therapeutic approaches, an early and accurate in-vivo diagnosis is crucial. Different biomarkers that are able to identify AD are currently in focus. However, whether and to which extend results of cerebrospinal fluid (CSF) and imaging biomarkers are comparable, is unclear. This study aims to correlate CSF and amyloid imaging biomarkers comparing them to cognitive measurements in order to determine whether these methods provide identical or complementary information.The study comprises 33 consecutive patients with suspected cognitive decline that underwent lumbar puncture for CSF biomarker analysis and Amyloid-PET/CT within the diagnostic evaluation of memory impairment. Amyloid PET/CTs were evaluated visually and quantitatively. CSF and imaging data were retrospectively evaluated and results were compared to cognition tests, age, gender, and ApoE status.Global cortex SUVr levels correlated highly with CSF Aβ42/40 and moderately with Aβ42 but not with Aβ40. Global cortex SUVr and Aβ42/40 correlated with mini mental status examination.This study indicates that Amyloid-PET and CSF biomarkers might not reflect identical clinical information and a combination of both seems to be the most accurate way to characterize clinically unclear cognitive decline.

Prevalence of amyloid-β pathology in distinct variants of primary progressive aphasia.

To estimate the prevalence of amyloid positivity, defined by positron emission tomography (PET)/cerebrospinal fluid (CSF) biomarkers and/or neuropathological examination, in primary progressive aphasia (PPA) variants. We conducted a meta-analysis with individual participant data from 1,251 patients diagnosed with PPA (including logopenic [lvPPA, n = 443], nonfluent [nfvPPA, n = 333], semantic [svPPA, n = 401], and mixed/unclassifiable [n = 74] variants of PPA) from 36 centers, with a measure of amyloid-β pathology (CSF [n = 600], PET [n = 366], and/or autopsy [n = 378]) available. The estimated prevalence of amyloid positivity according to PPA variant, age, and apolipoprotein E (ApoE) ε4 status was determined using generalized estimating equation models. Amyloid-β positivity was more prevalent in lvPPA (86%) than in nfvPPA (20%) or svPPA (16%; p < 0.001). Prevalence of amyloid-β positivity increased with age in nfvPPA (from 10% at age 50 years to 27% at age 80 years, p < 0.01) and svPPA (from 6% at age 50 years to 32% at age 80 years, p < 0.001), but not in lvPPA (p = 0.94). Across PPA variants, ApoE ε4 carriers were more often amyloid-β positive (58.0%) than noncarriers (35.0%, p < 0.001). Autopsy data revealed Alzheimer disease pathology as the most common pathologic diagnosis in lvPPA (76%), frontotemporal lobar degeneration-TDP-43 in svPPA (80%), and frontotemporal lobar degeneration-TDP-43/tau in nfvPPA (64%). This study shows that the current PPA classification system helps to predict underlying pathology across different cohorts and clinical settings, and suggests that age and ApoE genotype should be considered when interpreting amyloid-β biomarkers in PPA patients. Ann Neurol 2018;84:737-748.

Application of Bézier Curves for Calculating Likelihood Ratios for Plasma Amyloid-β Biomarkers for Alzheimer's Disease.

Introduction: Alzheimer's disease, being the most frequent cause of dementia in elderly people, still is difficult to diagnose and to predict its occurrence. The clinical application of biomarkers for diagnosis of Alzheimer's disease has been restricted so far to the analysis of proteins in the cerebrospinal fluid like amyloid β1−42 and p-tau. However, in a recently published nature letter it has been shown that the high-performance measurement of amyloid-β in plasma alone could provide a method well suited for a broad clinical application. The study uses ROC analysis to evaluate the clinical significance of the method but it does not provide likelihood ratios (LR) of the measured results.Methods: In this article, a newly developed method is used to calculate LRs for any measurement result of a study by approximation of the ROC curves using Bézier curves. Such LRs provide an estimation of the clinical significance of any particular test result by applying Bayes' theorem: Pretest odds for disease multiplied by the LR of the test result give the posttest odds.Results: The application of the Bézier curve approximation to the data of the plasma amyloid-β study is demonstrated. To generalize the calculation of LRs for all test results, a relation between the test results and the points on the Bézier curve with their LRs is established.Discussion: The application of Bézier curves in ROC analysis allows calculating LRs for all individual test results when measuring amyloid-β biomarkers for Alzheimer's disease.

Interrelationship between the Levels of C9orf72 and Amyloid-β Protein Precursor and Amyloid-β in Human Cellsand Brain Samples.

A subset of C9orf72 repeat expansion-carrying frontotemporal dementia patients display an Alzheimer-like decrease in cerebrospinal fluid amyloid-β (Aβ) biomarker levels. We report that downregulation of C9orf72 in non-neuronal human cells overexpressing amyloid-β protein precursor (AβPP) resulted in increased levels of secreted AβPP fragments and Aβ, while levels of AβPP or its C-terminal fragments (CTFs) remained unchanged. In neuronal cells, AβPP and C83 CTF levels were decreased upon C9orf72 knockdown, but those of secreted AβPP fragments or Aβ remained unchanged. C9orf72 protein levels significantly increased in human brain with advancing neurofibrillary pathology and positively correlated with brain Aβ42 levels. Our data suggest that altered C9orf72 levels may lead to cell-type specific alterations in AβPP processing, but warrant further studies to clarify the underlying mechanisms.

High performance plasma amyloid-β biomarkers for Alzheimer's disease.

To facilitate clinical trials of disease-modifying therapies for Alzheimer's disease, which are expected to be most efficacious at the earliest and mildest stages of the disease, supportive biomarker information is necessary. The only validated methods for identifying amyloid-β deposition in the brain-the earliest pathological signature of Alzheimer's disease-are amyloid-β positron-emission tomography (PET) imaging or measurement of amyloid-β in cerebrospinal fluid. Therefore, a minimally invasive, cost-effective blood-based biomarker is desirable. Despite much effort, to our knowledge, no study has validated the clinical utility of blood-based amyloid-β markers. Here we demonstrate the measurement of high-performance plasma amyloid-β biomarkers by immunoprecipitation coupled with mass spectrometry. The ability of amyloid-β precursor protein (APP)669-711/amyloid-β (Aβ)1-42 and Aβ1-40/Aβ1-42 ratios, and their composites, to predict individual brain amyloid-β-positive or -negative status was determined by amyloid-β-PET imaging and tested using two independent data sets: a discovery data set (Japan, n = 121) and a validation data set (Australia, n = 252 including 111 individuals diagnosed using 11C-labelled Pittsburgh compound-B (PIB)-PET and 141 using other ligands). Both data sets included cognitively normal individuals, individuals with mild cognitive impairment and individuals with Alzheimer's disease. All test biomarkers showed high performance when predicting brain amyloid-β burden. In particular, the composite biomarker showed very high areas under the receiver operating characteristic curves (AUCs) in both data sets (discovery, 96.7%, n = 121 and validation, 94.1%, n = 111) with an accuracy approximately equal to 90% when using PIB-PET as a standard of truth. Furthermore, test biomarkers were correlated with amyloid-β-PET burden and levels of Aβ1-42 in cerebrospinal fluid. These results demonstrate the potential clinical utility of plasma biomarkers in predicting brain amyloid-β burden at an individual level. These plasma biomarkers also have cost-benefit and scalability advantages over current techniques, potentially enabling broader clinical access and efficient population screening.

Amyloid biomarkers: pushing the limits of early detection.

This scientific commentary refers to ‘Cerebrospinal fluid analysis detects cerebral amyloid-β accumulation earlier than positron emission tomography’, by Palmqvist et al. (doi:10.1093/brain/aww015). One of the major advances in Alzheimer’s disease clinical research over the past two decades has been the development and validation of biomarkers for amyloid plaques and neurofibrillary tangles, the core neuropathological lesions that define the disease. Amyloid plaque deposition can be detected in vivo based on reductions in CSF levels of the amyloid-beta 1-42 amino acid polypeptide (amyloid-β1-42), or by PET imaging with radiotracers that bind selectively to the fibrillar aggregates of amyloid-β that form plaques (Blennow et al. , 2015). Collectively, amyloid-β biomarkers provide strong evidence for a prolonged ‘preclinical’ or ‘asymptomatic at-risk’ stage of Alzheimer’s disease, in which amyloid pathology is present in situ decades prior to the onset of clinical dementia (Sperling et al. , 2011). Even in the absence of overt cognitive deficits, normal individuals who have positive amyloid-β biomarkers show accelerated neurodegeneration and declining performance on neuropsychological tests compared to their amyloid-β-negative counterparts, and are at increased risk for developing incident cognitive impairment (Jagust, 2016). These observations have shifted the landscape of Alzheimer’s disease clinical research towards preclinical, biomarker-based detection of amyloid, and the implementation of early therapeutic interventions aimed at lowering amyloid and thus delaying or ultimately preventing the onset of clinical dementia (Sperling et al. , 2011). In this issue of Brain , Palmqvist and colleagues provide compelling evidence that CSF amyloid-β1-42 may be more sensitive than amyloid PET to the early stages of amyloid deposition (Palmqvist et al. , 2016), a finding that has important ramifications for our understanding of preclinical Alzheimer’s disease and for the design of prevention trials. Though they measure very different elements of amyloid biology, CSF amyloid-β1-42 and amyloid PET …

Suspected non-Alzheimer disease pathophysiology--concept and controversy.

Suspected non-Alzheimer disease pathophysiology (SNAP) is a biomarker-based concept that applies to individuals with normal levels of amyloid-β biomarkers in the brain, but in whom biomarkers of neurodegeneration are abnormal. The term SNAP has been applied to clinically normal individuals (who do not meet criteria for either mild cognitive impairment or dementia) and to individuals with mild cognitive impairment, but is applicable to any amyloid-negative, neurodegeneration-positive individual regardless of clinical status, except when the pathology underlying neurodegeneration can be reliably inferred from the clinical presentation. SNAP is present in ∼23% of clinically normal individuals aged >65 years and in ∼25% of mildly cognitively impaired individuals. APOE*ε4 is underrepresented in individuals with SNAP compared with amyloid-positive individuals. Clinically normal and mildly impaired individuals with SNAP have worse clinical and/or cognitive outcomes than individuals with normal levels of neurodegeneration and amyloid-β biomarkers. In this Perspectives article, we describe the available data on SNAP and address topical controversies in the field.

Independent information from cerebrospinal fluid amyloid-β and florbetapir imaging in Alzheimer's disease.

Reduced cerebrospinal fluid amyloid-β42 and increased retention of florbetapir positron emission tomography are biomarkers reflecting cortical amyloid load in Alzheimer's disease. However, these measurements do not always agree and may represent partly different aspects of the underlying Alzheimer's disease pathology. The goal of this study was therefore to test if cerebrospinal fluid and positron emission tomography amyloid-β biomarkers are independently related to other Alzheimer's disease markers, and to examine individuals who are discordantly classified by these two biomarker modalities. Cerebrospinal fluid and positron emission tomography amyloid-β were measured at baseline in 769 persons [161 healthy controls, 68 subjective memory complaints, 419 mild cognitive impairment and 121 Alzheimer's disease dementia, mean age 72 years (standard deviation 7 years), 47% females] and used to predict diagnosis, APOE ε4 carriage status, cerebral blood flow, cerebrospinal fluid total-tau and phosphorylated-tau levels (cross-sectionally); and hippocampal volume, fluorodeoxyglucose positron emission tomography results and Alzheimer's Disease Assessment Scale-cognitive subscale scores (longitudinally). Cerebrospinal fluid and positron emission tomography amyloid-β were highly correlated, but adjusting one of these predictors for the other revealed that they both provided partially independent information when predicting diagnosis, APOE ε4, hippocampal volume, metabolism, cognition, total-tau and phosphorylated-tau (the 95% confidence intervals of the adjusted effects did not include zero). Cerebrospinal fluid amyloid-β was more strongly related to APOE ε4 whereas positron emission tomography amyloid-β was more strongly related to tau levels (P < 0.05). Discordance (mainly isolated cerebrospinal fluid amyloid-β positivity) differed by diagnostic group (P < 0.001) and was seen in 21% of cognitively healthy people but only 6% in dementia patients. The finding that cerebrospinal fluid and positron emission tomography amyloid-β provide partially independent information about a wide range of Alzheimer's measures supports the theory that these modalities represent partly different aspects of Alzheimer's pathology. The fact that mismatch, with positive cerebrospinal fluid amyloid-β but normal positron emission tomography amyloid-β, is relatively common in cognitively healthy people may be considered when using these biomarkers to identify early stage Alzheimer's disease. Reduced cerebrospinal fluid amyloid-β may be more strongly related to early stage Alzheimer's disease, whereas increased positron emission tomography amyloid-β may be more strongly related to disease progression.