Blood-based Biomarker For Alzheimer's Disease Research Articles

From Practice to Public Health: Broadening Neuropsychology's Reach & Value-An Introduction to the National Academy of Neuropsychology's 2022 Annual Conference Special Issue.

This special issue is centered around presentations from the National Academy of Neuropsychology 2022 Annual Conference. The theme of the conference, "From Practice to Public Health: Broadening Neuropsychology's Reach & Value" is pivotal for the field's future. With an ever-shifting technological landscape and recent changes in clinical practice post-COVID, we are left wondering how neuropsychology will develop. How will we use biomedical and technological advances, such as blood-based Alzheimer's disease biomarkers or passive digital recordings, to improve clinical care and further expand our understanding of disease mechanisms? As neuropsychologists, how can we use our expertise to empirically inform public health policy? The diagnosis and treatment of post-acute sequelae of COVID-19, the identification and characterization of post-pandemic educational setbacks, and the adaptation of new technological and diagnostic advances into clinical practice workflows represent a vital set of new challenges and opportunities poised to disrupt traditional modes of practice. The articles in this special issue convey the role of neuropsychology in addressing these emerging issues and illustrate how and why neuropsychology is well positioned to be at the forefront of clinical practice and scientific advancements.

Plasma p-tau181 as an outcome and predictor of multidomain intervention effects: a secondary analysis of a randomised, controlled, dementia prevention trial.

It is unknown whether multidomain interventions, which might preserve late-life cognition, affect Alzheimer's disease pathology. Previous studies measured cerebrospinal fluid and imaging Alzheimer's disease biomarkers in small subsamples of multidomain trial participants. Newly developed assays enable the measurement of blood-based Alzheimer's disease biomarkers in larger samples. We aimed to assess whether plasma tau phosphorylated at threonine 181 (p-tau181) was able to detect or predict 3-year multidomain intervention effects. This is a secondary analysis of the randomised, controlled, Multidomain Alzheimer Prevention Trial (MAPT) testing a 3-year multidomain intervention, omega-3 fatty acid supplementation, or both versus placebo, in individuals aged 70 years and older in 13 memory centres in France and Monaco. Plasma p-tau181 was measured in stored blood samples in a subsample of 527 participants on an intention-to-treat basis. Changes in cognitive score were calculated as a composite measure using the average of Z scores for the following tests: Mini Mental State Examination orientation items, Free and Cued Selective Reminding Test (sum of free and total recall scores), category fluency, and Digit Symbol Substitution Test. Intervention effects on 3-year change in p-tau181 concentration were estimated by use of a linear mixed model with centre-specific random intercepts. Recruitment took place between May 30, 2008, and Feb 24, 2011. Median baseline plasma p-tau181 was 8·8 pg/mL (IQR 6·7-11·9) in the total sample, and significantly higher in older individuals, men, APOE ε4 carriers, and participants with renal dysfunction or a positive PET amyloid scan. During 3-year follow-up, individuals with raised baseline p-tau181 underwent greater cognitive decline (eg, mean difference in 3-year change on the composite cognitive score between control group participants with normal and abnormal baseline levels of p-tau was -0·34 [effect size -0·52; 95% CI -0·61 to 0·07] in the fully adjusted model using a 12·4 pg/mL cutoff for abnormal baseline p-tau181), but there were no intervention effects on change in p-tau181 either in this subgroup or the total population, and no effect on cognitive change in individuals with raised baseline p-tau181 (eg, in the fully adjusted model using the 12·4 pg/mL cutoff for p-tau181 abnormality, the mean difference [95% CI] in this subgroup in 3-year decline on the composite cognitive score between the control group and the multidomain + omega-3 group, the omega-3 group, and the multidomain intervention group, was, respectively: 0·13 [-0·21 to 0·47], 0·03 [-0·30 to 0·36], and 0·10 [-0·26 to 0·46]). Surprisingly, individuals with raised baseline p-tau181 showed a decrease in p-tau181 during follow-up (eg, unadjusted mean [95% CI] 3-year change was -3·01 pg/mL (-4·45 to -1·56) in control group subjects with abnormal baseline p-tau181 [using the 12·4 pg/mL abnormal p-tau cutoff]). Our results support the utility of p-tau181 as a prognostic biomarker, but it did not predict or detect intervention effects in this study. Further investigation of its usefulness as a prevention trial outcome measure is required. Toulouse Gérontopôle, French Ministry of Health and Pierre Fabre Research Institute.

Interaction Between Arteriosclerosis and Amyloid-β on Cognitive Function.

Dementia is a multifactorial disease, with Alzheimer's disease (AD) and vascular pathology often co-occurring in many individuals with dementia. Yet, the interplay between AD and vascular pathology in cognitive decline is largely undetermined. The aim of the present study was to examine the joint effect of arteriosclerosis and AD pathology on cognition in the general population without dementia. We determined the interaction between blood-based AD biomarkers and CT-defined arteriosclerosis on cognition in 2,229 dementia-free participants of the population-based Rotterdam Study (mean age: 68.9 years, 52% women) cross-sectionally. Amyloid-β (Aβ)42 and arterial calcification were associated with cognitive performance. After further adjustment for confounders in a model that combined all biomarkers, only arterial calcification remained independently associated with cognition. There was a significant interaction between arterial calcification and Aβ42 and between arterial calcification and the ratio of Aβ42/40. Yet, estimates attenuated, and interactions were no longer statistically significant after adjustment for cardio metabolic risk factors. Arteriosclerosis and AD display additive interaction-effects on cognition in the general population, that are due in part to cardio metabolic risk factors. These findings suggest that joint assessment of arteriosclerosis and AD pathology is important for understanding of disease etiology in individuals with cognitive impairment.

Plasma Aβ42/Aβ40 and phospho-tau217 concentration ratios increase the accuracy of amyloid PET classification in preclinical Alzheimer's disease.

Incorporating blood-based Alzheimer's disease biomarkers such as tau and amyloid beta (Aβ) into screening algorithms may improve screening efficiency. Plasma Aβ, phosphorylated tau (p-tau)181, and p-tau217 concentration levels from AHEAD 3-45 study participants were measured using mass spectrometry. Tau concentration ratios for each proteoform were calculated to normalize for inter-individual differences. Receiver operating characteristic (ROC) curve analysis was performed for each biomarker against amyloid positivity, defined by>20 Centiloids. Mixture of experts analysis assessed the value of including tau concentration ratios into the existing predictive algorithm for amyloid positron emission tomography status. The area under the receiver operating curve (AUC) was 0.87 for Aβ42/Aβ40, 0.74 for phosphorylated variant p-tau181 ratio (p-tau181/np-tau181), and 0.92 for phosphorylated variant p-tau217 ratio (p-tau217/np-tau217). The Plasma Predicted Centiloid (PPC), a predictive model including p-tau217/np-tau217, Aβ42/Aβ40, age, and apolipoprotein E improved AUC to 0.95. Including plasma p-tau217/np-tau217 along with Aβ42/Aβ40 in predictive algorithms may streamline screening preclinical individuals into anti-amyloid clinical trials. gov Identifier: NCT04468659 HIGHLIGHTS: The addition of plasma phosphorylated variant p-tau217 ratio (p-tau217/np-tau217) significantly improved plasma biomarker algorithms for identifying preclinical amyloid positron emission tomography positivity. Prediction performance at higher NAV Centiloid levels was improved with p-tau217/np-tau217. All models generated for this study are incorporated into the Plasma Predicted Centiloid (PPC) app for public use.

Alzheimer Disease Biomarkers: Moving from CSF to Plasma for Reliable Detection of Amyloid and tau Pathology.

Development of validated biomarkers to detect early Alzheimer disease (AD) neuropathology is needed for therapeutic AD trials. Abnormal concentrations of "core" AD biomarkers, cerebrospinal fluid (CSF) amyloid beta1-42, total tau, and phosphorylated tau correlate well with neuroimaging biomarkers and autopsy findings. Nevertheless, given the limitations of established CSF and neuroimaging biomarkers, accelerated development of blood-based AD biomarkers is underway. Here we describe the clinical significance of CSF and plasma AD biomarkers to detect disease pathology throughout the Alzheimer continuum and correlate with imaging biomarkers. Use of the AT(N) classification by CSF and imaging biomarkers provides a more objective biologically based diagnosis of AD than clinical diagnosis alone. Significant progress in measuring CSF AD biomarkers using extensively validated highly automated assay systems has facilitated their transition from research use only to approved in vitro diagnostics tests for clinical use. We summarize development of plasma AD biomarkers as screening tools for enrollment and monitoring participants in therapeutic trials and ultimately in clinical care. Finally, we discuss the challenges for AD biomarkers use in clinical trials and precision medicine, emphasizing the possible ethnocultural differences in the levels of AD biomarkers. CSF AD biomarker measurements using fully automated analytical platforms is possible. Building on this experience, validated blood-based biomarker tests are being implemented on highly automated immunoassay and mass spectrometry platforms. The progress made developing analytically and clinically validated plasma AD biomarkers within the AT(N) classification scheme can accelerate use of AD biomarkers in therapeutic trials and routine clinical practice.

Association of Plasma Biomarkers of Alzheimer Disease With Cognition and Medical Comorbidities in a Biracial Cohort.

Recent advances in blood-based biomarkers offer the potential to revolutionize the diagnosis and management of Alzheimer disease (AD), but additional research in diverse populations is critical. We assessed the profiles of blood-based AD biomarkers and their relationships to cognition and common medical comorbidities in a biracial cohort. Participants were evaluated through the Mayo Clinic Jacksonville Alzheimer Disease Research Center and matched on age, sex, and cognitive status. Plasma AD biomarkers (β-amyloid peptide 1-42 [Aβ42/40], plasma tau phosphorylated at position 181 [p-tau181], glial fibrillary acidic protein [GFAP], and neurofilament light) were measured using the Quanterix SiMoA HD-X analyzer. Cognition was assessed with the Mini-Mental State Examination. Wilcoxon rank sum tests were used to assess for differences in plasma biomarker levels by sex. Linear models tested for associations of self-reported race, chronic kidney disease (CKD), and vascular risk factors with plasma AD biomarker levels. Additional models assessed for interactions between race and plasma biomarkers in predicting cognition. The sample comprised African American (AA; N = 267) and non-Hispanic White (NHW; N = 268) participants, including 69% female participants and age range 43-100 (median 80.2) years. Education was higher in NHW participants (median 16 vs 12 years, p < 0.001) while APOE ε4 positivity was higher in AA participants (43% vs 34%; p = 0.04). We observed no differences in plasma AD biomarker levels between AA and NHW participants. These results were unchanged after stratifying by cognitive status (unimpaired vs impaired). Although the p-tau181-cognition association seemed stronger in NHW participants while the Aβ42/40-cognition association seemed stronger in AA participants, these findings did not survive after excluding individuals with CKD. Female participants displayed higher GFAP (177.5 pg/mL vs 157.73 pg/mL; p = 0.002) and lower p-tau181 (2.62 pg/mL vs 3.28 pg/mL; p = 0.001) levels than male participants. Diabetes was inversely associated with GFAP levels (β = -0.01; p < 0.001). In a biracial community-based sample of adults, we observed that sex differences, CKD, and vascular risk factors, but not self-reported race, contributed to variation in plasma AD biomarkers. Although some prior studies have reported primary effects of race/ethnicity, our results reinforce the need to account for broad-based medical and social determinants of health (including sex, systemic comorbidities, and other factors) in effectively and equitably deploying plasma AD biomarkers in the general population.

The complex genetic architecture of Alzheimer's disease: novel insights and future directions.

Alzheimer's disease (AD) is a complex multifactorial neurodegenerative disorder and the most common form of dementia. AD is highly heritable, with heritability estimates of ∼70% from twin studies. Progressively larger genome-wide association studies (GWAS) have continued to expand our knowledge of AD/dementia genetic architecture. Until recently these efforts had identified 39 disease susceptibility loci in European ancestry populations. Two new AD/dementia GWAS have dramatically expanded the sample sizes and the number of disease susceptibility loci. The first increased total sample size to 1,126,563-with an effective sample size of 332,376-by predominantly including new biobank and population-based dementia datasets. The second, expands on an earlier GWAS from the International Genomics of Alzheimer's Project (IGAP) by increasing the number of clinically-defined AD cases/controls in addition to incorporating biobank dementia datasets, resulting in a total sample size to 788,989 and an effective sample size of 382,472. Collectively both GWAS identified 90 independent variants across 75 AD/dementia susceptibility loci, including 42 novel loci. Pathway analyses indicate the susceptibility loci are enriched for genes involved in amyloid plaque and neurofibrillary tangle formation, cholesterol metabolism, endocytosis/phagocytosis, and the innate immune system. Gene prioritization efforts for the novel loci identified 62 candidate causal genes. Many of the candidate genes from known and newly discovered loci play key roles in macrophages and highlight phagocytic clearance of cholesterol-rich brain tissue debris by microglia (efferocytosis) as a core pathogenetic hub and putative therapeutic target for AD. WHERE NEXT?: While GWAS in European ancestry populations have substantially enhanced our understanding of AD genetic architecture, heritability estimates from population based GWAS cohorts are markedly smaller than those from twin studies. While this missing heritability is likely due to a combination of factors, it highlights that our understanding of AD genetic architecture and genetic risk mechanisms remains incomplete. These knowledge gaps result from several underexplored areas in AD research. First, rare variants remain understudied due to methodological issues in identifying them and the cost of generating sufficiently powered whole exome/genome sequencing datasets. Second, sample sizes of non-European ancestry populations in AD GWAS remain small. Third, GWAS of AD neuroimaging and cerebrospinal fluid endophenotypes remains limited due to low compliance and high costs associated with measuring amyloid-β and tau levels and other disease-relevant biomarkers. Studies generating sequencing data, including diverse populations, and incorporating blood-based AD biomarkers are set to substantially improve our knowledge of AD genetic architecture.

Potential of hsa-miR200a-3p and hsa-miR502-3p as blood-based biomarker for Alzheimer's disease.

Alzheimer's disease (AD) is one of the most important known dementia which affects thousands of people every year. Many factors are involved in this process, such as aberrant expression of miRNAs. Firstly, we analyzed two microarray datasets related to AD (GSE48552, GSE129053) to identify the differentially expressed miRNAs, and two miRNAs were selected for further validation. Dataset analysis showed that the expression of hsa-miR200a-3p and hsa-miR502-3p were up-regulated in AD. These findings were validated in plasma samples by qRT-PCR. ROC curve analysis showed that plasma levels of both miRNAs might discriminate the AD and healthy controls. In addition, in silico analysis revealed that the upregulation of these miRNAs could promote AD progression via affecting the expression of target molecules mainly ATF6 and dynactin. Totally, hsa-miR200a-3p and hsa-miR502-3p are upregulated in AD and their plasma levels can discriminate AD and healthy people, highlighting their potential as blood-based biomarker for AD.

Alzheimer's disease diagnosis by blood plasma molecular fluorescence spectroscopy (EEM)

Despite tremendous research advances in detecting Alzheimer's disease (AD), traditional diagnostic tests remain expensive, time-consuming or invasive. The search for a low-cost, rapid, and minimally invasive test has marked a new era of research and technological developments toward establishing blood-based AD biomarkers. The current study has employed excitation-emission matrices (EEM) of fluorescence spectroscopy combined with machine learning to diagnose AD using blood plasma samples from 230 individuals (83 AD patients from 147 healthy controls). To evaluate the performance of the classification algorithms, we calculated the commonly used figures of merit (accuracy, sensitivity and specificity) and figures of merit that take into account the samples unbalance and the discrimination power of the models, as F2-score (F2), Matthews correlation coefficient (MCC) and test effectiveness (delta). The classification models achieved satisfactory results: Parallel Factor Analysis with Quadratic Discriminant Analysis (PARAFAC-QDA) with 83.33% sensitivity, 100% specificity, 86.21% F2; and Tucker3-QDA with 91.67% sensitivity, 95.45% specificity and 91.67% F2. In addition, the classifiers show high overall performance with 94.12% accuracy and 0.87 MCC. Regarding the discrimination power between healthy and AD patients, the classification algorithms showed high effectiveness with the mean scores separated by three or more standard deviations. The PARAFAC's spectral profiles and the wavelength values from both models loading profiles can be used in future research to relate this information to plasma AD biomarkers. Our results point to a rapid, low-cost and minimally invasive blood-based method for AD diagnosis.

The Association Between Alzheimer's Disease-Related Markers and Physical Activity in Cognitively Normal Older Adults.

Previous studies have indicated that physical activity may be beneficial in reducing the risk for Alzheimer's disease (AD), although the underlying mechanisms are not fully understood. The goal of this study was to evaluate the relationship between habitual physical activity levels and brain amyloid deposition and AD-related blood biomarkers (i.e., measured using a novel high-performance mass spectrometry-based assay), in apolipoprotein E (APOE) ε4 carriers and noncarriers. We evaluated 143 cognitively normal older adults, all of whom had brain amyloid deposition assessed using positron emission tomography and had their physical activity levels measured using the International Physical Activity Questionnaire (IPAQ). We observed an inverse correlation between brain amyloidosis and plasma beta-amyloid (Aβ)1−42 but found no association between brain amyloid and plasma Aβ1−40 and amyloid precursor protein (APP)669−711. Additionally, higher levels of physical activity were associated with lower plasma Aβ1−40, Aβ1−42, and APP669−711 levels in APOE ε4 noncarriers. The ratios of Aβ1−40/Aβ1−42 and APP669−711/Aβ1−42, which have been associated with higher brain amyloidosis in previous studies, differed between APOE ε4 carriers and non-carriers. Taken together, these data indicate a complex relationship between physical activity and brain amyloid deposition and potential blood-based AD biomarkers in cognitively normal older adults. In addition, the role of APOE ε4 is still unclear, and more studies are necessary to bring further clarification.

Recent progresses on p-tau as a blood-based Alzheimer’s disease biomarker

Introduction. The amyloid cascade hypothesis proposes that extracellular senile plaques - largely composed of aggregated beta-amyloid (Aβ) peptides - are responsible for the events that lead to neuronal death that occurs in Alzheimer's disease (AD). On the other hand, the hyperphosphorylated (p-tau) and unstructured tau protein is responsible for intracellular neurofibrillary tangles, also common in AD. Clinical diagnostic criteria for AD include Aβ and p-tau biomarker tests in cerebrospinal fluid (CSF), in addition to neuroimaging measures, clinical history, and psychometric tests. However, due to their invasive nature, side effects and need for trained personnel in a hospital environment for their collection, CSF biomarkers are not suitable for large-scale screening. Therefore, alternative blood-based biomarkers are under intense investigation. Objective. Focus on recent advances in different p-tau isoforms as blood-based AD biomarkers. Method. Review performed by searches in Medline/PubMed databases. Results. The p-tau isoforms 181 and 217 represent accessible and scalable molecules for screening and diagnosing AD, mainly due to their ability to differentiate patients with the disease from cognitively healthy participants. These results should be reproduced in larger and more representative cohorts of population diversity. Conclusions. This review provides a more comprehensive exploration of blood p-tau as a specific molecular biomarker for AD, which could contribute not only to screening pre-symptomatic patients for clinical trials, but also to monitoring disease progression and evaluating modifying therapies. of the disease.

Serum Repressor Element-1 Silencing Transcription Factor Levels in Alzheimer's Patients from a National Institute of Health in Mexico City, Elderly and Young Controls.

Decreased levels of repressor element-1 silencing transcription (REST) factor in the brain, plasma, and neuronderived exosomes are associated with Alzheimer's disease (AD). The objective of the study was to test the viability of serum REST as a possible blood-based biomarker for AD, comparing serum REST levels in AD patients from a National Institute of Health in Mexico City (with different levels of severity and comorbidities), with elderly controls (EC) and young controls (YC). We used an enzyme-linked immunosorbent assay to determine serum REST levels in AD patients (n = 28), EC (n = 19), and YC (n = 24); the AD patients were classified by dementia severity and comorbidities (depression and microangiopathy) using clinimetric tests and magnetic resonance imaging. Mean serum REST levels did not differ between AD patients, EC, and YC. The severity of AD and the presence of depression or microangiopathy were not associated with serum REST levels. Our results differ from previously published patterns found for plasma and cerebral REST levels. Free serum REST levels may not be a viable AD blood-based biomarker.

Blood-based Biomarkers of Alzheimer's Disease: The Long and Winding Road.

Blood-based biomarkers can be very useful in formulating new diagnostic and treatment proposals in the field of dementia, especially in Alzheimer's disease (AD). However, due to the influence of several factors on the reproducibility and reliability of these markers, their clinical use is still very uncertain. Thus, up-to-date knowledge about the main blood biomarkers that are currently being studied is extremely important in order to discover clinically useful and applicable tools, which could also be used as novel pharmacological strategies for the AD treatment. A narrative review was performed based on the current candidates of blood-based biomarkers for AD to show the main results from different studies, focusing on their clinical applicability and association with AD pathogenesis. The aim of this paper was to carry out a literature review on the major blood-based biomarkers for AD, connecting them with the pathophysiology of the disease. Recent advances in the search of blood-based AD biomarkers were summarized in this review. The biomarkers were classified according to the topics related to the main hallmarks of the disease such as inflammation, amyloid, and tau deposition, synaptic degeneration and oxidative stress. Moreover, molecules involved in the regulation of proteins related to these hallmarks were described, such as non-coding RNAs, neurotrophins, growth factors and metabolites. Cells or cellular components with the potential to be considered as blood-based AD biomarkers were described in a separate topic. A series of limitations undermine new discoveries on blood-based AD biomarkers. The lack of reproducibility of findings due to the small size and heterogeneity of the study population, different analytical methods and other assay conditions make longitudinal studies necessary in this field to validate these structures, especially when considering a clinical evaluation that includes a broad panel of these potential and promising blood-based biomarkers.

Altered Expression Profile of Phosphatidylinositols in Erythrocytes of Alzheimer's Disease and Amnestic Mild Cognitive Impairment Patients.

Studies have demonstrated that the levels of phospholipids, including phosphatidylinositols (PIs), were decreased in Alzheimer's disease (AD) brain, presenting as a potential biomarker for AD. The plasma phospholipids levels have also been discovered to predict the conversion of cognitively normal elderly adults to amnestic mild cognitive impairment (aMCI) or demented patients. To investigate the expression profile of PIs in erythrocytes of AD and aMCI patients, which would serve as a blood-based method to distinguish AD and aMCI patients from normal controls (NC). In this study, we used anion-exchange high-performance liquid chromatography to analyze PIs alterations in erythrocytes from a total of 86 prospectively recruited subjects (including 24 NC, 21 aMCI patients, and 41 AD patients). We found that the levels of PI40 : 4, PI3/5P, and PI(3,4)P2 in aMCI patients, and the levels of PI4P, PI(3,4)P2, and PI3/5P in AD patients were significantly decreased compared to NC. The changed expression profile of PIs could effectively discriminate AD and aMCI patients from NC (AUC = 0.964, 0.938, respectively). The altered expression profile of erythrocytes PIs might be a potential blood-based biomarker for AD and aMCI. This alteration of PIs probably reflected the impaired deformability and oxygen-carrying capacity of erythrocytes in AD and aMCI patients.

Long Non-coding RNA BACE1-AS May Serve as an Alzheimer’s Disease Blood-Based Biomarker

Circulating long noncoding RNAs (lncRNAs) might serve as biomarkers for different pathological conditions. BACE1-AS lncRNA upregulates in the brain of people with Alzheimer's disease (AD) and might be detected in the bloodstream. To reveal if lncRNA BACE1-AS may serve as a blood-based biomarker for AD, we compared its levels in plasma and plasma-derived exosomes between AD (n = 45) and healthy people (n = 36). Exosomes were purified from plasma by Invitrogen™ Total Exosome Isolation Kit and characterized by scanning electron microscopy (SEM) and dynamic light scattering (DLS). Total RNA was extracted from whole plasma, and plasma-derived exosomes using TRIzol® LS or TRIzol® Reagents respectively were then reverse transcribed to the cDNA using PrimeScript II cDNA synthesis kit. The BACE1-AS levels were quantified by real-time PCR, and their biomarker potencies were evaluated using ROC curve analysis. Results obtained verified the presence of BACE1-AS in the plasma samples of both AD and healthy controls. We did not observe any significant differences between the levels of BACE1-AS in the plasma or plasma-derived exosomes of AD and control people. However, there were significant differences between AD subgroups and control in the whole plasma samples. The BACE1-AS level was low in pre-AD subgroup but it was high in full-AD people compared to the healthy controls. Moreover, ROC curve analysis revealed that lncRNA BACE1-AS may discriminate pre-AD and healthy control (75% sensitivity and 100% specificity), full-AD and healthy control (68% sensitivity and 100% specificity), and pre-AD and full-AD subgroups (78% sensitivity and 100% specificity), highlighting its potential as a biomarker for AD development. In conclusion, plasma BACE1-AS level may serve as a potent blood-based biomarker for Alzheimer's disease.

Platelets Bioenergetics Screening Reflects the Impact of Brain Aβ Plaque Accumulation in a Rat Model of Alzheimer.

Alzheimer's disease (AD) is associated to depressed brain energy supply and impaired cortical and hippocampal synaptic function. It was previously reported in McGill-R-Thy1-APP transgenic (Tg(+/+)) rats that Aβ deposition per se is sufficient to cause abnormalities in glucose metabolism and neuronal connectivity. These data support the utility of this animal model as a platform for the search of novel AD biomarkers based on bioenergetic status. Recently, it has been proposed that energy dysfunction can be dynamically tested in platelets (PLTs) of nonhuman primates. PLTs are good candidates to find peripheral biomarkers for AD because they may reflect in periphery the bioenergetics deficits and the inflammatory and oxidative stress processes taking place in AD brain. In the present study, we carried out a PLTs bioenergetics screening in advanced-age (12-14months old) control (WT) and Tg(+/+) rats. Results indicated that thrombin-activated PLTs of Tg(+/+) rats showed a significantly lower respiratory rate, as compared to that measured in WT animals, when challenged with the same dose of FCCP (an uncoupler of oxidative phosphorylation). In summary, our results provide original evidence that PLTs bioenergetic profiling may reflect brain bioenergetics dysfunction mediated by Aβ plaque accumulation. Further studies on human PLTs from control and AD patients are required to validate the usefulness of PLTs bioenergetics as a novel blood-based biomarker for AD.

Blood-based biomarkers for Alzheimer disease: mapping the road to the clinic.

Biomarker discovery and development for clinical research, diagnostics and therapy monitoring in clinical trials have advanced rapidly in key areas of medicine - most notably, oncology and cardiovascular diseases - allowing rapid early detection and supporting the evolution of biomarker-guided, precision-medicine-based targeted therapies. In Alzheimer disease (AD), breakthroughs in biomarker identification and validation include cerebrospinal fluid and PET markers of amyloid-β and tau proteins, which are highly accurate in detecting the presence of AD-associated pathophysiological and neuropathological changes. However, the high cost, insufficient accessibility and/or invasiveness of these assays limit their use as viable first-line tools for detecting patterns of pathophysiology. Therefore, a multistage, tiered approach is needed, prioritizing development of an initial screen to exclude from these tests the high numbers of people with cognitive deficits who do not demonstrate evidence of underlying AD pathophysiology. This Review summarizes the efforts of an international working group that aimed to survey the current landscape of blood-based AD biomarkers and outlines operational steps for an effective academic-industry co-development pathway from identification and assay development to validation for clinical use.

Alzheimer's disease and blood-based biomarkers - potential contexts of use.

Alzheimer’s disease (AD) is an irreversible, incurable, progressive neurodegenerative illness, where dementia symptoms gradually worsen over a number of years. The research of validated biomarkers for AD is essential to improve diagnosis and accelerate the development of new therapies. Biochemical markers including neuroimaging could facilitate diagnosis, predict AD progression from a pre-AD state of mild cognitive impairment, and be used to detect the efficacies of disease-modifying therapies. Established biomarkers of AD from cerebrospinal fluid and neuroimaging are highly accurate, but barriers to clinical implementation exist. The focus on blood-based AD biomarkers has grown exponentially during the past few decades. An ideal diagnostic test for AD should be noninvasive and easily applicable. Clinical cost-effectiveness also needs to be established.

MICRO-RNA 221 INHIBITS ADAM10 PROTEIN EXPRESSION IN SH-SY5Y CELLS

In Alzheimer's disease (AD) non-amyloidogenic pathway, A Disintegrin And Metalloprotease 10 (ADAM10) acts as α-secretase, avoiding amyloid β (Aβ) production. We propose to analyze the overexpression of miR-144–5p, miR-374 and miR-221 in SH-SY5Y cells and verify their ADAM10 protein expression correlation. The research project was approved by Brazil Ethics Platform (CAAE:02760312.0.0000.5504/112.543). Total blood of 21 AD subjects and 17 cognitively healthy elderly controls was collected and analyzed by RT-qPCR. Relative expression of approximately 700 miRNAs was performed and 21 miRNAs differentially expressed were validated. Among them, mir-144–5p, miR-374 and miR-221 were found to be downregulated in AD subjects compared to healthy controls. From this observation, we transiently transfected human neuroblastoma SH-SY5Y cells with mirVana™ mimics of three selected miRNAs. Cells were lysed and protein samples were analysed by western blotting using an anti-ADAM10 antibody. ADAM10 and endogen control (β-actin) protein expression were quantified and the adjusted volume was used to determine the arbitrary units (AU) of ADAM10 expression. ADAM10 protein levels are significantly decreased upon transient overexpression of miR-221 in SH-SY5Y cells, but not altered after overexpression of miR-144–5p and miR-374, indicating the specificity of miR-221 in the regulation of ADAM10 levels. These findings place the miR-221 as a potential blood-based biomarker for AD. Moreover, the inhibition of miRNA-221 can be a new potential therapeutic target for increasing ADAM10 in AD, thus avoiding Aβ production.

Plasma Proteomics Biomarkers in Alzheimer's Disease: Latest Advances and Challenges.

The recent paradigm shift towards a more biologically oriented definition of Alzheimer's disease (AD) in clinical settings increases the need for sensitive biomarkers that can be applied in population-based settings. Blood plasma is easily accessible and contains a large number of proteins related to cerebral processes. It is therefore an ideal candidate for AD biomarker discovery. The present chapter provides an overview of the current research landscape in relation to blood-based AD biomarkers. Both clinical and methodological issues are covered. A brief summary is given on two relevant laboratory techniques to ascertain blood biomarker changes due to AD; methodological and clinical challenges in the field are also discussed.