Plasma Amyloid-β Research Articles

Association of plasma β-amyloid 40 and 42 concentration with type 2 diabetes among Chinese adults.

There is evidence for a bidirectional association between type 2 diabetes and Alzheimer's disease. Plasma β-amyloid (Aβ) is a potential biomarker for Alzheimer's disease. We aimed to investigate the association of plasma Aβ40 and Aβ42 with risk of type 2 diabetes. We performed a case-control study and a nested case-control study within a prospective cohort study. In the case-control study, we included 1063 newly diagnosed individuals with type 2 diabetes and 1063 control participants matched by age (±3years) and sex. In the nested case-control study, we included 121 individuals with incident type 2 diabetes and 242 matched control individuals. Plasma Aβ40 and Aβ42 concentrations were simultaneously measured with electrochemiluminescence immunoassay. Conditional logistic regression was used to evaluate the association of plasma Aβ40 and Aβ42 concentrations with the likelihood of type 2 diabetes. In the case-control study, the multivariable-adjusted ORs for type 2 diabetes, comparing the highest with the lowest quartile of plasma Aβ concentrations, were 1.97 (95% CI 1.46, 2.66) for plasma Aβ40 and 2.01 (95% CI 1.50, 2.69) for plasma Aβ42. Each 30ng/l increment of plasma Aβ40 was associated with 28% (95% CI 15%, 43%) higher odds of type 2 diabetes, and each 5ng/l increment of plasma Aβ42 was associated with 37% (95% CI 21%, 55%) higher odds of type 2 diabetes. Individuals in the highest tertile for both plasma Aβ40 and Aβ42 concentrations had 2.96-fold greater odds of type 2 diabetes compared with those in the lowest tertile for both plasma Aβ40 and Aβ42 concentrations. In the nested case-control study, the multivariable-adjusted ORs for type 2 diabetes for the highest vs the lowest quartile were 3.79 (95% CI 1.81, 7.94) for plasma Aβ40 and 2.88 (95% CI 1.44, 5.75) for plasma Aβ42. The multivariable-adjusted ORs for type 2 diabetes associated with each 30ng/l increment in plasma Aβ40 and each 5ng/l increment in plasma Aβ42 were 1.44 (95% CI 1.18, 1.74) and 1.47 (95% CI 1.15, 1.88), respectively. Our findings suggest positive associations of plasma Aβ40 and Aβ42 concentration with risk of type 2 diabetes. Further studies are warranted to elucidate the underlying mechanisms and explore the potential roles of plasma Aβ in linking type 2 diabetes and Alzheimer's disease.

Longitudinal evaluation of the natural history of amyloid-β in plasma and brain.

Plasma amyloid-β peptide concentration has recently been shown to have high accuracy to predict amyloid-β plaque burden in the brain. These amyloid-β plasma markers will allow wider screening of the population and simplify and reduce screening costs for therapeutic trials in Alzheimer’s disease. The aim of this study was to determine how longitudinal changes in blood amyloid-β track with changes in brain amyloid-β. Australian Imaging, Biomarker and Lifestyle study participants with a minimum of two assessments were evaluated (111 cognitively normal, 7 mild cognitively impaired, 15 participants with Alzheimer’s disease). Amyloid-β burden in the brain was evaluated through PET and was expressed in Centiloids. Total protein amyloid-β 42/40 plasma ratios were determined using ABtest® assays. We applied our method for obtaining natural history trajectories from short term data to measures of total protein amyloid-β 42/40 plasma ratios and PET amyloid-β. The natural history trajectory of total protein amyloid-β 42/40 plasma ratios appears to approximately mirror that of PET amyloid-β, with both spanning decades. Rates of change of 7.9% and 8.8%, were observed for total protein amyloid-β 42/40 plasma ratios and PET amyloid-β, respectively. The trajectory of plasma amyloid-β preceded that of brain amyloid-β by a median value of 6 years (significant at 88% confidence interval). These findings, showing the tight association between changes in plasma and brain amyloid-β, support the use of plasma total protein amyloid-β 42/40 plasma ratios as a surrogate marker of brain amyloid-β. Also, that plasma total protein amyloid-β 42/40 plasma ratios has potential utility in monitoring trial participants, and as an outcome measure.

Population-based blood screening for preclinical Alzheimer's disease in a British birth cohort at age 70.

Alzheimer’s disease has a preclinical stage when cerebral amyloid-β deposition occurs before symptoms emerge, and when amyloid-β-targeted therapies may have maximum benefits. Existing amyloid-β status measurement techniques, including amyloid PET and CSF testing, are difficult to deploy at scale, so blood biomarkers are increasingly considered for screening. We compared three different blood-based techniques—liquid chromatography-mass spectrometry measures of plasma amyloid-β, and single molecule array (Simoa) measures of plasma amyloid-β and phospho-tau181—to detect cortical 18F-florbetapir amyloid PET positivity (defined as a standardized uptake value ratio of >0.61 between a predefined cortical region of interest and eroded subcortical white matter) in dementia-free members of Insight 46, a substudy of the population-based British 1946 birth cohort. We used logistic regression models with blood biomarkers as predictors of amyloid PET status, with or without age, sex and APOE ε4 carrier status as covariates. We generated receiver operating characteristics curves and quantified areas under the curves to compare the concordance of the different blood tests with amyloid PET. We determined blood test cut-off points using Youden’s index, then estimated numbers needed to screen to obtain 100 amyloid PET-positive individuals. Of the 502 individuals assessed, 441 dementia-free individuals with complete data were included; 82 (18.6%) were amyloid PET-positive. The area under the curve for amyloid PET status using a base model comprising age, sex and APOE ε4 carrier status was 0.695 (95% confidence interval: 0.628–0.762). The two best-performing Simoa plasma biomarkers were amyloid-β42/40 (0.620; 0.548–0.691) and phospho-tau181 (0.707; 0.646–0.768), but neither outperformed the base model. Mass spectrometry plasma measures performed significantly better than any other measure (amyloid-β1-42/1-40: 0.817; 0.770–0.864 and amyloid-β composite: 0.820; 0.775–0.866). At a cut-off point of 0.095, mass spectrometry measures of amyloid-β1-42/1-40 detected amyloid PET positivity with 86.6% sensitivity and 71.9% specificity. Without screening, to obtain 100 PET-positive individuals from a population with similar amyloid PET positivity prevalence to Insight 46, 543 PET scans would need to be performed. Screening using age, sex and APOE ε4 status would require 940 individuals, of whom 266 would proceed to scan. Using mass spectrometry amyloid-β1-42/1-40 alone would reduce these numbers to 623 individuals and 243 individuals, respectively. Across a theoretical range of amyloid PET positivity prevalence of 10–50%, mass spectrometry measures of amyloid-β1-42/1-40 would consistently reduce the numbers proceeding to scans, with greater cost savings demonstrated at lower prevalence.

Composite Scores of Plasma Tau and β-Amyloids Correlate with Dementia in Down Syndrome.

Dementia frequently occurs in Down syndrome (DS) patients, and early intervention is important in its management. We have previously demonstrated a positive correlation of plasma β-amyloid Aβ42 levels and negative correlations of Aβ40 and tau levels with dementia in DS. In this study, we examined more cases and constructed composite scores with both tau and amyloids to correlate with dementia in DS. Plasma Aβ42, Aβ40, and tau proteins were measured by an immunomagnetic reduction assay in DS patients. Data were randomly and repeatedly split into training and validating sets, and logistic regression was applied to calculate the area under the curve (AUC) for each biomarker. A total of 73 DS patients (among them, 23 had neurodegeneration) and 77 controls were recruited. In DS patients without dementia, plasma Aβ40 and tau levels were highly elevated, but Aβ42 levels were lower than those of the healthy controls. DS patients with dementia, compared with DS patients with no dementia, had a large decline in Aβ40 and tau but a rise in Aβ42. For biomarker scores correlating with dementia, Aβ40 revealed an AUC of 0.912; the composite score of Aβ40 × tau revealed an AUC of 0.953; and a combined composite score of 0.1 for Aβ40 × Tau +0.9 Tau × Aβ40/Aβ42 achieved the highest AUC of 0.965. Therefore, composite biomarker scores including both plasma tau and β-amyloid levels correlate with dementia in DS better than using individual biomarker scores. The pattern of tau decline and Aβ42 rise in DS patients with dementia are also different from previous findings in Alzheimer's disease.

The Potential Emergence of Disease-Modifying Treatments for Alzheimer Disease: The Role of Primary Care in Managing the Patient Journey.

Despite recent setbacks, disease-modifying treatments (DMTs) for Alzheimer disease (AD) might become available within a few years. These DMTs are likely to be used in the early stages of AD to avoid the progression to manifest dementia, which implies that a large reservoir of prevalent cases would need to be evaluated when DMTs first become available. Primary care providers (PCPs) would play a vital role in managing the patient flow to specialty care. We review the literature on diagnostic tests that could be used by PCPs and estimate the impact of different testing approaches on demand for specialty care.While many tests have been evaluated, only the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) perform acceptably for detection of early-stage cognitive decline with sensitivities and specificities of 55% to 82% and 72% to 84%, respectively, for the MMSE; and 77% to 96% and 73% to 95%, respectively, for the MoCA. However, neither test is sufficiently specific for the AD pathology and would result in 4 to 5 false positives for each true positive. Blood-based tests for AD biomarkers may soon become available for clinical use. A plasma amyloid-β (Aβ) test has been shown to have a sensitivity of up to 97% and specificity of up to 81%. Adding this test to the MMSE or MoCA could reduce false positives by approximately 80%.These findings suggest a combination of brief cognitive tests and blood-based biomarker tests will allow PCPs to identify patients with potential early stage AD efficiently and triage them for further evaluation.

Ultrasensitive Detection of Plasma Amyloid-β as a Biomarker for Cognitively Normal Elderly Individuals at Risk of Alzheimer's Disease.

Aberrant amyloid-β (Aβ) deposition in the brain occurs two decades prior to the manifestation of Alzheimer's disease (AD) clinical symptoms and therefore brain Aβ load measured using PET serves as a gold standard biomarker for the early diagnosis of AD. However, the uneconomical nature of PET makes blood markers, that reflect brain Aβ deposition, attractive candidates for investigation as surrogate markers. Investigation of plasma Aβ as a surrogate marker for brain Aβ deposition in cognitively normal elderly individuals. Plasma Aβ40 and Aβ42 concentrations were measured using the ultrasensitive Single Molecule Array (Simoa) assay in 95 cognitively normal elderly individuals, who have all undergone PET to assess brain Aβ deposition. Based on the standard uptake value ratios (SUVR) obtained from PET imaging, using the tracer 18F-Florbetaben, plasma Aβ was compared between 32 participants assessed to have low brain Aβ load (Aβ-, SUVR <1.35) and 63 assessed to have high brain Aβ load (Aβ+, SUVR ≥1.35). Plasma Aβ42/Aβ40 ratios were lower in the Aβ+ group compared to the Aβ-group. Plasma Aβ40 and Aβ42 levels were not significantly different between Aβ-and Aβ+ groups, although a trend of higher plasma Aβ40 was observed in the Aβ+ group. Additionally, plasma Aβ42/Aβ40 ratios along with the known AD risk factors, age and APOEɛ4 status, resulted in Aβ+ participants being distinguished from Aβ-participants based on an area under the receiver operating characteristic curve shown to be 78%. Plasma Aβ ratios in this study are a potential biomarker for brain Aβ deposition and therefore, for preclinical AD. However, this method to measure plasma Aβ needs further development to increase the accuracy of this promising AD blood biomarker.

The plasma level of amyloid-β is associated with cognitive decline: a two years follow-up study in Xi'an rural areas

Objective: To explore the relationship between plasma amyloid-β (Aβ) and cognitive decline during 2 year follow-up in a population-based cohort in Xi'an rural areas. Methods: The study was conducted in Qubao village in Xi'an suburbs cognitively normal residents over 40 years old were recruited from October 2014 to March 2015 and given a face-to-face standardized interview. Mini-mental state examination (MMSE) was employed to evaluate the global cognitive function, and quantification of plasma Aβ was measured by sandwich enzyme-linked immunosorbent assay (ELISA) at baseline. Two years later, MMSE was tested at the end of study. Then logistic regression was performed to analyze the relationship between baseline Aβ and cognitive change during 2 year follow-up. Results: A total of 1 020 participants completed the study, among whom 223 subjects (21.9%) presented MMSE scores decline (defined as MMSE scores decreased ≥2 points). Compared with those without decline, participants in the MMSE decline group were older (P<0.001) and had lower education level (P<0.001), while gender, hypertension, hyperlipemia, diabetes mellitus and APOE genotype were not significantly different between two groups. One-way analysis of variance (ANOVA) showed that the MMSE score decline was slighter in the lower tertile of baseline Aβ(1)-40 compared with middle tertile (P=0.012), while MMSE decline were similar between different Aβ(1)-42 level groups and Aβ(1-42)/Aβ(1-40) ratio groups (P=0.758, P=0.671, respectively). Multivariable logistic regression analysis showed that MMSE scores in the lower baseline plasma Aβ(1-40) level declined more slowly (OR=0.565, 95%CI 0.379-0.845, P=0.005). However, the MMSE decline were also similar among different baseline plasma Aβ(1-42) levels groups and Aβ(1-42)/Aβ(1-40) ratio groups. Conclusion: Population with lower level of baseline plasma Aβ(1-40) manifests lower cognitive decline during 2 years, however further investigation on dynamics of plasma Aβ and long term follow up are needed.

High-precision plasma β-amyloid 42/40 predicts current and future brain amyloidosis.

We examined whether plasma β-amyloid (Aβ)42/Aβ40, as measured by a high-precision assay, accurately diagnosed brain amyloidosis using amyloid PET or CSF p-tau181/Aβ42 as reference standards. Using an immunoprecipitation and liquid chromatography-mass spectrometry assay, we measured Aβ42/Aβ40 in plasma and CSF samples from 158 mostly cognitively normal individuals that were collected within 18 months of an amyloid PET scan. Plasma Aβ42/Aβ40 had a high correspondence with amyloid PET status (receiver operating characteristic area under the curve [AUC] 0.88, 95% confidence interval [CI] 0.82-0.93) and CSF p-tau181/Aβ42 (AUC 0.85, 95% CI 0.79-0.92). The combination of plasma Aβ42/Aβ40, age, and APOE ε4 status had a very high correspondence with amyloid PET (AUC 0.94, 95% CI 0.90-0.97). Individuals with a negative amyloid PET scan at baseline and a positive plasma Aβ42/Aβ40 (<0.1218) had a 15-fold greater risk of conversion to amyloid PET-positive compared to individuals with a negative plasma Aβ42/Aβ40 (p = 0.01). Plasma Aβ42/Aβ40, especially when combined with age and APOE ε4 status, accurately diagnoses brain amyloidosis and can be used to screen cognitively normal individuals for brain amyloidosis. Individuals with a negative amyloid PET scan and positive plasma Aβ42/Aβ40 are at increased risk for converting to amyloid PET-positive. Plasma Aβ42/Aβ40 could be used in prevention trials to screen for individuals likely to be amyloid PET-positive and at risk for Alzheimer disease dementia. This study provides Class II evidence that plasma Aβ42/Aβ40 levels accurately determine amyloid PET status in cognitively normal research participants.

LONGITUDINAL EVALUATION OF THE NATURAL HISTORY OF Aβ IN PLASMA AND BRAIN

Plasma amyloid-β (Aβ) peptides have recently been shown to have high accuracy to predict Aβ burden in the brain. These Aβ plasma markers will allow a wider screening of the population but also simplify and reduce screening costs for therapeutic trials by identifying individuals at-risk of developing Alzheimer's disease (AD) at the preclinical/prodromal stages. While several studies reported the relationship between plasma and brain Aβ they have not evaluated how they change over time in relation to each other. The aim of this study was to determine how changes in blood Aβ track with changes in brain Aβ. We evaluated data from AIBL individuals that had a minimum of three assessments and deemed Aβ accumulators (N=133; Table 1) from the Australian Imaging, Biomarker and Lifestyle (AIBL) study of aging. Total protein Aβ42/40 plasma ratios (TP42/40) were determined using ABtest® assays in cognitively normal (NC, n=111), mild cognitively impaired (MCI, n=7) and AD (n=15) participants. PET-Aβ was quantified using CapAIBL1 and expressed in Centiloids2. We applied our method for obtaining natural history trajectories from short term data3,4 to measures of TP42/40 and PET-Aβ. This resulted in two curves detailing the natural history of the Aβ changes. To allow comparison between the curves, they were each aligned at the median values exhibited by the AD participants. Cross-sectional analysis showed a robust inverse association between TP42/40 and PET-Aβ. The natural history trajectory of TP42/40 appears to approximately mirror that of PET-Aβ, with both spanning decades (Figure 1). Both of the measures of Aβ have similar rates of change in the linear, dynamic stage of their trajectory. These rates of change are 7.9% and 8.8%, for TP42/40 and PET-Aβ, respectively. This fast-moving part of the curves appear to start ∼19 years before typical mild-AD for PET-Aβ but ∼23 years before typical mild-AD for TP42/40.

Blood amyloid levels and risk of dementia in the Ginkgo Evaluation of Memory Study (GEMS): A longitudinal analysis

IntroductionBoth high or low plasma amyloid levels have been associated with risk of dementia in nondemented subjects. MethodsWe examined baseline plasma β-amyloid (Aβ) levels in relationship to incident dementia during a period of 8.5 years in 2840 subjects age >75 years; 2381 were cognitively normal (CN) and 450 mild cognitive impairment. ResultsIncreased plasma Aβ1-40 and Aβ1-42 levels were associated with gender (women), age, low education, creatinine levels, history of stroke, and hypertension. CN participants who developed dementia had lower levels of Aβ1-42 and Aβ1-42/Aβ1-40 ratio compared with those who did not. Aβ levels did not predict dementia in mild cognitive impairment participants. DiscussionThere was an inverse association between Aβ1-42 and Aβ1-42/Aβ1-40 ratio to risk of dementia in CN participants. Cerebral and cardiovascular disease and renal function are important determinants of increased Aβ levels and must be considered in evaluations of relationship of plasma Aβ and subsequent risk of dementia.

Performance of Fully Automated Plasma Assays as Screening Tests for Alzheimer Disease–Related β-Amyloid Status

Accurate blood-based biomarkers for Alzheimer disease (AD) might improve the diagnostic accuracy in primary care, referrals to memory clinics, and screenings for AD trials. To examine the accuracy of plasma β-amyloid (Aβ) and tau measured using fully automated assays together with other blood-based biomarkers to detect cerebral Aβ. Two prospective, cross-sectional, multicenter studies. Study participants were consecutively enrolled between July 6, 2009, and February 11, 2015 (cohort 1), and between January 29, 2000, and October 11, 2006 (cohort 2). Data were analyzed in 2018. The first cohort comprised 842 participants (513 cognitively unimpaired [CU], 265 with mild cognitive impairment [MCI], and 64 with AD dementia) from the Swedish BioFINDER study. The validation cohort comprised 237 participants (34 CU, 109 MCI, and 94 AD dementia) from a German biomarker study. The cerebrospinal fluid (CSF) Aβ42/Aβ40 ratio was used as the reference standard for brain Aβ status. Plasma Aβ42, Aβ40 and tau were measured using Elecsys immunoassays (Roche Diagnostics) and examined as predictors of Aβ status in logistic regression models in cohort 1 and replicated in cohort 2. Plasma neurofilament light chain (NFL) and heavy chain (NFH) and APOE genotype were also examined in cohort 1. The mean (SD) age of the 842 participants in cohort 1 was 72 (5.6) years, with a range of 59 to 88 years, and 446 (52.5%) were female. For the 237 in cohort 2, mean (SD) age was 66 (10) years with a range of 23 to 85 years, and 120 (50.6%) were female. In cohort 1, plasma Aβ42 and Aβ40 predicted Aβ status with an area under the receiver operating characteristic curve (AUC) of 0.80 (95% CI, 0.77-0.83). When adding APOE, the AUC increased significantly to 0.85 (95% CI, 0.82-0.88). Slight improvements were seen when adding plasma tau (AUC, 0.86; 95% CI, 0.83-0.88) or tau and NFL (AUC, 0.87; 95% CI, 0.84-0.89) to Aβ42, Aβ40 and APOE. The results were similar in CU and cognitively impaired participants, and in younger and older participants. Applying the plasma Aβ42 and Aβ40 model from cohort 1 in cohort 2 resulted in slightly higher AUC (0.86; 95% CI, 0.81-0.91), but plasma tau did not contribute. Using plasma Aβ42, Aβ40, and APOE in an AD trial screening scenario reduced positron emission tomography costs up to 30% to 50% depending on cutoff. Plasma Aβ42 and Aβ40 measured using Elecsys immunoassays predict Aβ status in all stages of AD with similar accuracy in a validation cohort. Their accuracy can be further increased by analyzing APOE genotype. Potential future applications of these blood tests include prescreening of Aβ positivity in clinical AD trials to lower the costs and number of positron emission tomography scans or lumbar punctures.

Potential Value of Plasma Amyloid-β, Total Tau, and Neurofilament Light for Identification of Early Alzheimer's Disease.

The objective of the study was to explore the potential value of plasma indicators for identifying amnesic mild cognitive impairment (aMCI) and determine whether levels of plasma indicators are related to the performance of cognitive function and brain tissue volumes. In total, 155 participants (68 aMCI patients and 87 health controls) were recruited in the present cross-sectional study. The levels of plasma amyloid-β (Aβ) 40, Aβ42, total tau (t-tau), and neurofilament light (NFL) were measured using an ultrasensitive quantitative method. Machine learning algorithms were performed for establishing an optimal model of identifying aMCI. Compared with healthy controls, Aβ40 and Aβ42 levels were lower and NFL levels were higher in plasma of aMCI patients with an exception of t-tau levels. In aMCI patients, the higher plasma Aβ40 levels were correlated with the impaired episodic memory and negative correlations were observed between plasma t-tau levels and global cognitive function and gray matter (GM) volume. In addition, the higher plasma NFL levels were correlated with reduced hippocampus volume and total GM volume of the left inferior and middle temporal gyrus. An integrated model included clinical features, hippocampus volume, and plasma Aβ42 and NFL and had the highest accuracy for detecting aMCI patients (accuracy, 74.2%). We demonstrated that plasma Aβ40, Aβ42, t-tau, and NFL may be useful to identify aMCI and correlate with cognitive decline and brain atrophy. Among these plasma indicators, Aβ42 and NFL are more valuable as key members of a peripheral biomarker panel to detect aMCI.

Abstract 59: Relation of Plasma B-amyloid, Tau and Clusterin and Cerebral Microbleeds: Framingham Heart Study

Introduction: Plasma β-amyloid (Aβ), Tau and Clusterin have been considered biomarkers of vascular and dementia pathology, and as candidate biomarkers to identify persons at high risk of dementia. Cerebral microbleeds (CMBs) are subclinical MRI markers representing the most common forms of cerebral small vessel disease: hypertensive for deep CMB and cerebral amyloid angiopathy for lobar CMB. CMB are associated with higher risk of stroke and dementia, predating clinical diagnosis by several years. We studied the association of circulating Aβ, Tau and Clusterin levels with CMB to elucidate their role as biomarkers for the angiopathies represented by CMB, and further understand the early pathophysiology of cerebrovascular disease predating diagnosis of clinical dementia and stroke. Methods: We included dementia and stroke-free Framingham Heart Study participants (mean age 57years, 54% women) with available brain MRI T2*gradient-echo sequences and Aβ (N=1711), Tau (N=3680) and Clusterin (N=3129) measurements. We used multivariable logistic regression analyses to relate circulating biomarker levels to CMB presence overall and stratified by brain topography (OR per SD increase in biomarker level). Models were adjusted for age, sex, time between biomarker measurement and MRI, APOE-e4 genotype, hypertension, statin and antiplatelet use, and C-reactive protein levels. Results: CMB were observed in 208 (5.7%) participants (any lobar 174 (4.7%), any deep (56, 1.5%). After multivariable adjustment we observed a borderline association of Aβ-40 with any CMB (OR (95%CI) 1.21(0.99, 1.46) p-value=0.058), a strong association with lobar CMB (OR (95%CI) 1.37 (1.10, 1.71) p-value=0.005), and no significant association with deep CMB. Tau levels were associated with any CMB (OR (95%CI) 1.22 (1.06, 1.40) p-value=0.006), lobar CMB (OR (95%CI) 1.17 (1.01, 1.36) p-value=0.036), and no significant association with deep CMB. No significant association of CMB with clusterin or Aβ-42 levels was found. Conclusions: Our results suggest that Plasma Aβ-40 and Tau may serve as biomarkers of cerebral amyloid angiopathy (represented by lobar CMB) and support the role of CMB as markers of neuronal injury.

Effects of Meditation and Music-Listening on Blood Biomarkers of Cellular Aging and Alzheimer's Disease in Adults with Subjective Cognitive Decline: An Exploratory Randomized Clinical Trial.

Telomere length (TL), telomerase activity (TA), and plasma amyloid-β (Aβ) levels have emerged as possible predictors of cognitive decline and dementia. To assess the: 1) effects of two 12-week relaxation programs on TL, TA, and Aβ levels in adults with subjective cognitive decline; and 2) relationship of biomarker changes to those in cognitive function, psychosocial status, and quality of life (QOL). Participants were randomized to a 12-week Kirtan Kriya meditation (KK) or music listening (ML) program and asked to practice 12 minutes/day. Plasma Aβ(38/40/42) and peripheral blood mononuclear cell TL and TA were measured at baseline and 3 months. Cognition, stress, sleep, mood, and QOL were assessed at baseline, 3 months, and 6 months. Baseline blood samples were available for 53 participants (25 KK, 28 ML). The KK group showed significantly greater increases in Aβ40 than the ML group. TA rose in both groups, although increases were significant only among those with higher practice adherence and lower baseline TA. Changes in both TL and TA varied by their baseline values, with greater increases among participants with values ≤50th percentile (ps-interaction <0.006). Both groups improved in cognitive and psychosocial status (ps ≤0.05), with improvements in stress, mood, and QOL greater in the KK group. Rising Aβ levels were correlated with gains in cognitive function, mood, sleep, and QOL at both 3 and 6 months, associations that were particularly pronounced in the KK group. Increases in TL and TA were also correlated with improvements in certain cognitive and psychosocial measures. Practice of simple mind-body therapies may alter plasma Aβ levels, TL, and TA. Biomarker increases were associated with improvements in cognitive function, sleep, mood, and QOL, suggesting potential functional relationships.

C-Reactive Protein, Plasma Amyloid-β Levels, and Their Interaction With Magnetic Resonance Imaging Markers

Background and Purpose- Inflammation is involved in the pathogenesis of large artery atherosclerosis, ischemic stroke, and Alzheimer dementia. However, the role of inflammation in cerebral small vessel disease and neurodegeneration remains poorly understood. We hypothesize that CRP (C-reactive protein) is associated with brain structural changes and may interact with amyloid to produce vascular and degenerative damage. We examined the association of CRP levels with imaging markers of cerebral small vessel disease and neurodegeneration. Furthermore, we studied the association of CRP with plasma Aβ (amyloid-β) levels and their joint effects with imaging markers. Methods- We included 2814 persons (mean age, 56.9 years; 44.8% women) from the Rotterdam Study with complete data on CRP and 1.5 T brain magnetic resonance imaging scans. Aβ levels were measured in a subsample (n=736). Markers of cerebral small vessel disease included lacunes, white matter hyperintensities, microbleeds, and enlarged perivascular spaces. Neurodegeneration was assessed by smaller volumes of gray matter, white matter, and hippocampus. Plasma levels of Aβ1-38, Aβ1-40, and Aβ1-42 were assessed using ELISA. Results- Higher CRP levels were associated with larger white matter hyperintensities volume (β=0.07; 95% CI, 0.00-0.13), increasing lacunar (rate ratios, 1.61; 95% CI, 1.19-2.19), enlarged perivascular spaces (rate ratios, 1.01; 95% CI, 1.00-1.03), and deep/infratentorial microbleeds (rate ratios, 1.30; 95% CI, 1.00-1.69) counts. People with high CRP levels had small gray matter volume. We also found significant interaction between CRP and Aβ such that among persons in higher tertiles of Aβ1-42, a strong association was observed between CRP and lacunar ( P interaction, 0.004), enlarged perivascular spaces ( P interaction, 0.002), and microbleed counts ( P interaction, <0.001). Similarly, among persons in higher tertile of Aβ1-38, a strong association was observed between CRP and microbleed counts ( P interaction, 0.004). Conclusions- Higher CRP levels were associated with subclinical markers of cerebral small vessel disease and neurodegeneration. This effect was augmented by an interaction between CRP and Aβ levels. Future longitudinal studies focusing on joint effects of CRP and Aβ on progression of magnetic resonance imaging markers and cognitive decline are warranted.

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.

The Level of Plasma Amyloid-β40 Is Correlated with Peripheral Transport Proteins in Cognitively Normal Adults: A Population-Based Cross-Sectional Study.

Transport proteins, soluble low-density lipoprotein receptor-related protein-1 (sLRP1), and soluble receptor of advanced glycation end products (sRAGE), play an important role in the clearance of plasma amyloid-β (Aβ). However, their relationship is not clear. The aim was to explore the relationship between plasma levels of sLRP1, sRAGE, and Aβ in a cross-sectional study. A total of 1,185 cognitively normal participants (age above 40) from a village in the suburbs of Xi'an, China were enrolled from October 8, 2014 to March 30, 2015. Plasma Aβ40, Aβ42, sLRP1, and sRAGE were tested using a commercial ELISA. Apolipoprotein E (APOE) genotyping was conducted using PCR and sequencing. The relationship between plasma levels of sLRP1, sRAGE, and Aβ was analyzed using Pearson's correlation analysis and multiple linear regression. In the total population, Log sLRP1 and Log sRAGE were positively correlated with plasma Aβ40 (r= 0.103, p < 0.001; r= 0.064, p = 0.027, respectively), but neither were associated with plasma Aβ42. After multivariable adjustment in the regression model, Log sLRP1 and Log sRAGE were still positively related with plasma Aβ40 (β= 2.969, p < 0.001; β= 1.936, p = 0.017, respectively) but not Aβ42. Furthermore, the positive correlations between transport proteins and plasma Aβ40 remained significant only in APOEɛ4 non-carriers after Pearson's analysis and multiple regression analysis after stratification by gene status. The concentrations of plasma sLRP1 and sRAGE had a significant impact on the level of plasma Aβ40 in cognitively normal adults, especially in APOEɛ4 non-carriers. However, the mechanism by which the transport proteins are involved in peripheral Aβ clearance and the relationship between transporters and amyloid burden in the brain needs further validation.

Elevation of Plasma Amyloid-β Level is More Significant in Early Stage of Cognitive Impairment: A Population-Based Cross-Sectional Study.

Aggregation and deposition of amyloid-β (Aβ) in the brain is the main pathological change of Alzheimer's disease (AD). Decreased Aβ42 in the cerebrospinal fluid has been confirmed as a biomarker of AD; however, the relationship between plasma Aβ and cognitive impairment is currently unclear. The aim was to explore the relationship between plasma Aβ and cognitive impairment in a cross-sectional study. A total of 1,314 subjects (age above 40) from a village in the suburbs of Xi'an, China were enrolled between October 8, 2014 and March 30, 2015. A validated Chinese version of the Mini-Mental State Examination and neuropsychological battery were used to assess cognition. Levels of plasma Aβ42 and Aβ40 were tested using commercial enzyme-linked immunosorbent assay. Relationship of plasma Aβ and cognitive impairment was analyzed using logistic regression analysis. Of the enrolled subjects, 1,180 (89.80%) had normal cognition, 85 (6.47%) had possible cognitive impairment and 49 (3.73%) had probable cognitive impairment. Logistic regression analysis showed that the Aβ42/Aβ40 ratio (OR = 4.042, 95% CI: 1.248-11.098, p = 0.012) and plasma Aβ42 (OR = 1.036, 95% CI: 1.003-1.071, p = 0.031) was higher in the possible cognitive impairment than that in the normal cognition group. Furthermore, the plasma Aβ42/Aβ40 ratio was higher in the possible cognitive impairment group than that in the probable cognitive impairment group (OR = 0.029, 95% CI: 0.002-0.450, p = 0.011). Levels of plasma Aβ42 and Aβ42/Aβ40 ratio were elevated in patients with possible cognitive impairment, indicating that plasma Aβ42 and Aβ42/Aβ40 ratio increases may be more pronounced in early stage of cognitive impairment.

Generation of a human induced pluripotent stem cell line from a patient with a rare A673T variant in amyloid precursor protein gene that reduces the risk for Alzheimer's disease

An amyloid precursor protein (APP) A673T mutation was found to be protective against Alzheimer's disease (AD) and cognitive decline in the Icelandic population and to associate with decreased levels of plasma β-amyloid in a Finnish population-based cohort. Human fibroblasts from a Finnish male individual carrying the protective mutation were used to generate integration-free induced pluripotent stem cell (iPSCs) line by Sendai virus technology. The iPSC line retained the mutation and expressed pluripotency markers, had a normal karyotype and differentiated into all three germ layers.

Pulse pressure is associated with plasma amyloid-β transport dysfunction.

Increased pulse pressure (PP) has been implicated in the development and progression of Alzheimer's disease in middle-aged and elderly adults. Considering the close relationship between peripheral amyloid-β clearance and brain amyloid-β deposition, we investigated the potential association between PP and plasma amyloid-β transport function. In this cross-sectional study, a total of 1118 participants underwent a health assessment and quantification of plasma amyloid-β and amyloid-β transporter expression. Relationships between plasma levels of amyloid-β1-40, amyloid-β1-42, soluble low-density lipoprotein receptor-related protein-1 (sLRP1), soluble receptor for advanced glycation end products (sRAGE), and PP were determined using multiple linear regressions. PP was a significant determinant of amyloid-β1-40 level (β = 0.059, P = 0.036) and log-transformed sRAGE (β = -0.002, P = 0.029) independent of age, sex, body mass index, pulse rate, mean arterial pressure, blood glucose, blood lipids, lifestyle, and medical history. Additionally, log-transformed soluble low-density lipoprotein receptor-related protein-1 and log-transformed sRAGE were positively associated with plasma amyloid-β1-40 level (β = 3.610, P < 0.001; β = 2.573, P = 0.001). Similar associations were observed between log-transformed sRAGE and plasma amyloid-β1-42 level (β = 1.350, P = 0.022). An elevation in PP is associated with increased plasma amyloid-β1-40 and decreased log-transformed sRAGE among individuals not taking antihypertensive medication. The underlying mechanism of this effect may be relevant to peripheral amyloid-β clearance.