Alzheimer's Disease Biomarkers Research Articles

Correlation Between the Fractional Amplitude of Low-Frequency Fluctuation and Cognitive Defects in Alzheimer's Disease.

The fractional amplitude of low-frequency fluctuations (fALFFs) can detect spontaneous brain activity. However, the association between abnormal brain activity and cognitive function, amyloid protein (Aβ), and emotion in Alzheimer's disease (AD) patients remains unclear. This study aimed to survey alterations in fALFF in different frequency bands and the relationship between abnormal brain activity, depressive mood, and cognitive function to determine the potential mechanism of AD. We enrolled 34 AD patients and 32 healthy controls (HC). All the participants underwent resting-state magnetic resonance imaging, and slow-4 and slow-5 fALFF values were measured. Subsequently, the study determined the correlation of abnormal brain activity with mood and cognitive function scores. AD patients revealed altered mfALFF values in the slow-5 and slow-4 bands. In the slow-4 band, the altered mfALFF regions were the right cerebellar crus I, right inferior frontal orbital gyrus (IFOG), right supramarginal gyrus, right precuneus, angular gyrus, and left middle cingulate gyrus. Elevated mfALFF values in the right IFOG were negatively associated with Montreal Cognitive Assessment scores, Boston Naming Test, and Aβ1-42 levels. The mfALFF value of the AD group was lower than the HC group in the slow-5 band, primarily within the right inferior parietal lobule and right precuneus. Altered mfALFF values in AD patients are linked with cognitive dysfunction. Compared with HCs, Aβ1-42 levels in AD patients are related to abnormal IFOG activity. Therefore, mfALFF could be a potential biomarker of AD.

Chinese guideline for clinical application of fluid biomarkers for Alzheimer's disease(2024 edition)

Alzheimer's disease is the most prevalent neurodegenerative disorder leading to cognitive impairment, but its progression is subtle and the early recognition is difficult. With advancements in disease-modifying therapies, the need for precise early diagnosis of Alzheimer's disease is increasingly pressing. Fluid biomarkers of Alzheimer's disease, detectable in bodily fluid samples, are intricately associated with the disease.It can be used for screening, diagnosis, staging, prediction of disease progression, and clinical trials, playing an increasingly critical role in clinical practice.. This guideline systematically reviews and evaluates the spectrum of fluid biomarkers for Alzheimer's disease, propose standardized protocols for sample collection and processing, and delineates the application standards of fluid biomarkers in disease screening, diagnosis, staging, prognosis of disease progression, and clinical trials. A total of 24 recommendations have been formulated. The publication of this guideline aims to standardize the application of fluid biomarkers in clinical practice, thereby advancing research in Alzheimer's disease fluid biomarkers.

Associations between differential connectivity patterns of executive control networks and APOE ɛ4 in the Alzheimer continuum

The APOE ɛ4 allele and age are risk factors for Alzheimer’s disease (AD) and contribute to decreased executive function. However, the influence of APOE ɛ4 on the executive control network (ECN) in the AD continuum is still unclear. This study included 269 participants aged between 50 and 95 years old, based on ADNI data, including 104 cognitively normal (CN) individuals, 72 individuals with early mild cognitive impairment (EMCI), 55 individuals with late mild cognitive impairment (LMCI), and 38 AD patients. Within each disease group, participants were subdivided into APOE ɛ4 carriers and non-carriers. We explored brain regions within the ECN affected by the interactions between genes and disease states by resting-state functional magnetic resonance imaging (fMRI) and voxel-based two-way analysis of variance (ANOVA). Subsequently, functional connectivity (FC) between seeds and peak clusters were extracted and correlated with the cognitive performance. We found that the damages of carrying APOE ɛ4 in ECNs mainly distributed in the fronto-parietal and parietal-temporal systems. Functional network intergroup differences indicated increased intrafrontal and fronto-parietal connectivity at the early stage of AD and increased connectivity between the parietal lobe and related regions at late disease in these APOE ɛ4 carriers. Our conclusion is that the functional connectivity in the ECN exhibits different distinguishably patterns of impairment in the AD continuum under the influence of the APOE ɛ4 allele. Patients with different genotypes showed heterogeneity in functional network changes in the early stages of disease, which may be a potential biomarker for early AD.

Age-dependent sex differences in cofilin1 pathway (LIMK1/SSH1) and its association with AD biomarkers after chronic systemic inflammation in mice

Chronic systemic inflammation (CSI) results in neuroinflammation and neurodegeneration. Cofilin1 is a stress protein that activates microglia and induces neuroinflammation, but its role in CSI at different aging stages remains unidentified. Therefore, the study aims to identify cofilin1 and its upstream regulators LIMK1 and SSH1 after CSI in young-, middle-, and advanced-aged mice. CSI was induced by injecting the male and female mice with a sub-lethal dose of Lipopolysaccharide weekly for six weeks. The results showed that normal male mice did not show cofilin pathway dysregulation, but a significant dysregulation was observed in CSI advanced-aged mice. In females, cofilin1 dysregulation was observed in healthy and CSI advanced-aged mice, while significant cofilin1 dysregulation was observed in middle-aged mice during CSI. Furthermore, cofilin1 pathway dysregulations correlated with Alzheimer's disease (AD) biomarkers in the brain and saliva, astrocyte activation, synaptic degeneration, neurobehavioral impairments, gut-microbiota abnormalities, and circulatory inflammation. These results provide new insights into cofilin1 sex and age-dependent mechanistic differences that might help identify targets for modulating neuroinflammation and early onset of AD.

CSF neurogranin levels as a biomarker in Alzheimer’s disease and frontotemporal lobar degeneration: a cross-sectional analysis

BackgroundThere is initial evidence suggesting that biomarker neurogranin (Ng) may distinguish Alzheimer’s disease (AD) from other neurodegenerative diseases. Therefore, we assessed (a) the discriminant ability of cerebrospinal fluid (CSF) Ng levels to distinguish between AD and frontotemporal lobar degeneration (FTLD) pathology and between different stages within the same disease, (b) the relationship between Ng levels and cognitive performance in both AD and FTLD pathology, and (c) whether CSF Ng levels vary by apolipoprotein E (APOE) polymorphism in the AD continuum.MethodsParticipants with subjective cognitive decline (SCD) (n = 33), amnestic mild cognitive impairment (aMCI) due to AD (n = 109), AD dementia (n = 67), MCI due to FTLD (n = 25), and FTLD dementia (n = 29) were recruited from the Czech Brain Aging Study. One-way analysis of covariance (ANCOVA) assessed Ng levels in diagnostic subgroups. Linear regressions evaluated the relationship between CSF Ng levels, memory scores, and APOE polymorphism.ResultsNg levels were higher in aMCI-AD patients compared to MCI-FTLD (F[1, 134] = 15.16, p < .001), and in AD-dementia compared to FTLD-dementia (F[1, 96] = 4.60, p = .029). Additionally, Ng levels were higher in FTLD-dementia patients compared to MCI-FTLD (F[1, 54]= 4.35, p = .034), lower in SCD participants compared to aMCI-AD (F[1, 142] = 10.72, p = .001) and AD-dementia (F[1, 100] = 20.90, p < .001), and did not differ between SCD participants and MCI-FTLD (F[1, 58]= 1.02, p = .491) or FTLD-dementia (F[1, 62]= 2.27, p = .051). The main effect of diagnosis across the diagnostic subgroups on Aβ1−42/Ng ratio was significant too (F[4, 263]=, p < .001). We found a non-significant association between Ng levels and memory scores overall (β=-0.25, p = .154) or in AD diagnostic subgroups, and non-significant differences in this association between overall AD APOE ε4 carriers and non-carriers (β=-0.32, p = .358).ConclusionsIn this first study to-date to assess MCI and dementia due to AD or FTLD within one study, elevated CSF Ng appears to be an early biomarker of AD-related impairment, but its role as a biomarker appears to diminish after dementia diagnosis, whereby dementia-related underlying processes in AD and FTLD may begin to merge. The Aβ1−42/Ng ratio discriminated AD from FTLD patients better than Ng alone. CSF Ng levels were not related to memory in AD or FTLD, suggesting that Ng may be a marker of the biological signs of disease state rather than cognitive deficits.

Real-time detection of Tau-381 protein using liquid crystal-based sensors for Alzheimer's disease diagnosis

Tau is a protein found in the central nervous system (CNS) and is involved in stabilizing microtubules in axons. Given the link between Tau levels in the body and Alzheimer's disease (AD), there is a demand for straightforward and precise strategies to detect Tau in body fluids. In this study, we report liquid crystal (LC)-based sensors for the real-time detection of Tau protein, a well-known AD biomarker. The sensor uses a detection method based on the orientation change of the LC because of the competitive biomolecular interaction between Tau and Tau aptamers with the cationic polymer poly-L-lysine (PLL). Tau and its aptamers form stable complexes through electrostatic interactions. Owing to the consumption of the aptamer, the positively charged PLL fails to interact with the aptamer but binds to the negatively charged 1.2-dioleoyl-sn-glycero-3-phospho-(1′-rac-glycerol) sodium salt (DOPG). The PLL and DOPG complex alters the orientation of the LC to ensure a planar anchoring of the 4-cyano-4′-pentylbiphenyl (5CB)/aqueous interface; this anchoring intensifies with increasing Tau concentration, thus enabling the observation of a bright optical image. Our LC-based sensor demonstrated a low detection limit of 2.77 pg/mL in phosphate buffered saline (PBS) and 10.86 pg/mL and 19.31 pg/mL in human serum and plasma, respectively. Moreover, it is anticipated to be suitable for point-of-care diagnosis of AD because it does not require specialized analytical equipment and only requires microliters of sample.

Gut Microbiome Compositional and Functional Features Associate with Alzheimer's Disease Pathology.

The gut microbiome is a potentially modifiable factor in Alzheimer's disease (AD); however, understanding of its composition and function regarding AD pathology is limited. Shallow-shotgun metagenomic data was used to analyze fecal microbiome from participants enrolled in the Wisconsin Microbiome in Alzheimer's Risk Study, leveraging clinical data and cerebrospinal fluid (CSF) biomarkers. Differential abundance and ordinary least squares regression analyses were performed to find differentially abundant gut microbiome features and their associations with CSF biomarkers of AD and related pathologies. Gut microbiome composition and function differed between people with AD and cognitively unimpaired individuals. The compositional difference was replicated in an independent cohort. Differentially abundant gut microbiome features were associated with CSF biomarkers of AD and related pathologies. These findings enhance our understanding of alterations in gut microbial composition and function in AD, and suggest that gut microbes and their pathways are linked to AD pathology.

Neurodegenerative Plasma Biomarkers for Prediction of Hippocampal Atrophy in Older Adults with Suspected Alzheimer's Disease in Kinshasa, Democratic Republic of Congo.

The hippocampus is one of the first brain structures affected by Alzheimer's disease (AD), and its atrophy is a strong indicator of the disease. This study investigates the ability of plasma biomarkers of AD and AD-related dementias-amyloid-β (Aβ42/40), phosphorylated tau-181 (p-tau181), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP)-to predict hippocampal atrophy in adult individuals in Kinshasa, Democratic Republic of Congo (DRC). Eighty-five adult individuals (40 healthy and 45 suspected AD) over 65 years old were evaluated using the Community Screening Instrument for Dementia and Alzheimer's Questionnaire (AQ). Core AD biomarkers (Aβ42/40 and p-tau181) and non-specific neurodegeneration biomarkers (NfL, GFAP) were measured in blood samples collected at the study visit. Hippocampal volumes were measured using magnetic resonance imaging (MRI). General linear regression was used to evaluate differences in biomarker concentrations by neurological status. Logistic regression models were used to create receiver operating characteristic curves and calculate areas under the curve (AUCs) with and without clinical covariates to determine the ability of biomarker concentrations to predict hippocampal atrophy. Plasma biomarkers were used either individually or in combination in the models. Elevated p-tau181 was associated with left hippocampal (LH) atrophy p= 0.020). Only higher p-tau181 concentrations were significantly associated with 4.2-fold increased odds [OR=4.2 (1.5-18.4)] of hippocampal atrophy per standard deviation. The AUC of plasma biomarkers without clinical covariates to discriminate LH, RH, and total hippocampal (TH) or both hippocampi atrophy ranged between 90% to 94%, 76% to 82%, and 85% to 87%, respectively. The AUC of models including clinical covariates and AD biomarkers used in combination to discriminate LH, RH, and TH ranged between 94%-96%, 81%-84%, and 88%-90%, respectively. These results indicate that, consistent with studies in other settings, core AD plasma biomarkers can predict hippocampal atrophy in a population in Sub-Saharan Africa.

The amyloid beta 42/38 ratio as a plasma biomarker of early memory deficits in cognitively unimpaired older adults

The amyloid beta (Aβ) 42/40 ratio has been widely studied as a biomarker in Alzheimer’s disease (AD); however, other Aβ peptides could also represent relevant biomarkers. We measured levels of Aβ38/40/42 in plasma samples from cognitively-unimpaired older adults and determined the relationships between Aβ levels and amyloid positron-emission-tomography (PET) and performance on a learning and memory task. We found that all Aβ peptides individually and the Aβ42/40 ratio, but not the Aβ42/38 ratio, were significantly correlated with brain amyloid (Aβ-PET). Multiple linear modeling, adjusting for age, sex, education, APOE4 and Aβ-PET showed significant associations between the Aβ42/38 ratio and memory. Further, associations between the Aβ42/38 ratio and learning scores were stronger in males and in Aβ-PET-negative individuals. In contrast, no significant associations were detected between the Aβ42/40 ratio and any learning measure. These studies implicate the Aβ42/38 ratio as a biomarker to assess early memory deficits and underscore the utility of the Aβ38 fragment as an important biomarker in the AD field.

Capturing biomarkers associated with Alzheimer disease subtypes using data distribution characteristics.

Late-onset Alzheimer disease (AD) is a highly complex disease with multiple subtypes, as demonstrated by its disparate risk factors, pathological manifestations, and clinical traits. Discovery of biomarkers to diagnose specific AD subtypes is a key step towards understanding biological mechanisms underlying this enigmatic disease, generating candidate drug targets, and selecting participants for drug trials. Popular statistical methods for evaluating candidate biomarkers, fold change (FC) and area under the receiver operating characteristic curve (AUC), were designed for homogeneous data and we demonstrate the inherent weaknesses of these approaches when used to evaluate subtypes representing less than half of the diseased cases. We introduce a unique evaluation metric that is based on the distribution of the values, rather than the magnitude of the values, to identify analytes that are associated with a subset of the diseased cases, thereby revealing potential biomarkers for subtypes. Our approach, Bimodality Coefficient Difference (BCD), computes the difference between the degrees of bimodality for the cases and controls. We demonstrate the effectiveness of our approach with large-scale synthetic data trials containing nearly perfect subtypes. In order to reveal novel AD biomarkers for heterogeneous subtypes, we applied BCD to gene expression data for 8,650 genes for 176 AD cases and 187 controls. Our results confirm the utility of BCD for identifying subtypes of heterogeneous diseases.

From Organotypic Mouse Brain Slices to Human Alzheimer Plasma Biomarkers: A Focus on Microglia.

Alzheimer's disease is a severe neurodegenerative disorder, and the discovery of biomarkers is crucial for early diagnosis. While the analysis of biomarkers in cerebrospinal fluid is well accepted, there are currently no blood biomarkers available. Our research focuses on identifying novel plasma biomarkers for Alzheimer's disease. To achieve this, we employed a technique that involves coupling human plasma to mouse organotypic brain slices via microcontact prints. After culturing for two weeks, we assessed Iba1-immunopositive microglia on these microcontact prints. We hypothesized that plasma from Alzheimer's patients contains factors that affect microglial migration. Our data indicated that plasma from Alzheimer's patients significantly inhibited the migration of round Iba1-immunoreactive microglia (13 ± 3, n = 24, p = 0.01) compared to healthy controls (50 ± 16, n = 23). Based on these findings, we selected the most promising plasma samples and conducted mass spectrometry using a differential approach, and we identified four potential biomarkers: mannose-binding protein C, macrophage receptor MARCO, complement factor H-related protein-3, and C-reactive protein. Our method represents a novel and innovative approach to translate research findings from mouse models to human applications.

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.

Cerebrovascular disease is associated with Alzheimer's plasma biomarker concentrations in adults with Down syndrome.

By age 40 years, over 90% of adults with Down syndrome have Alzheimer's disease pathology and most progress to dementia. Despite having few systemic vascular risk factors, individuals with Down syndrome have elevated cerebrovascular disease markers that track with the clinical progression of Alzheimer's disease, suggesting a role of cerebrovascular disease that is hypothesized to be mediated by inflammatory factors. This study examined the pathways through which small vessel cerebrovascular disease contributes to Alzheimer's disease-related pathophysiology and neurodegeneration in adults with Down syndrome. One hundred eighty-five participants from the Alzheimer's Biomarkers Consortium-Down Syndrome [mean (SD) age = 45.2 (9.3) years] with available MRI and plasma biomarker data were included in this study. White matter hyperintensity (WMH) volumes were derived from T2-weighted fluid-attenuated inversion recovery MRI scans, and plasma biomarker concentrations of amyloid beta 42/40, phosphorylated tau 217, astrocytosis (glial fibrillary acidic protein) and neurodegeneration (neurofilament light chain) were measured with ultrasensitive immunoassays. We examined the bivariate relationships of WMH, amyloid beta 42/40, phosphorylated tau 217 and glial fibrillary acidic protein with age-residualized neurofilament light chain across Alzheimer's disease diagnostic groups. A series of mediation and path analyses examined statistical pathways linking WMH and Alzheimer's disease pathophysiology to promote neurodegeneration in the total sample and groups stratified by clinical diagnosis. There was a direct and indirect bidirectional effect through the glial fibrillary acidic protein of WMH on phosphorylated tau 217 concentration, which was associated with neurofilament light chain concentration in the entire sample. Amongst cognitively stable participants, WMH was directly and indirectly, through glial fibrillary acidic protein, associated with phosphorylated tau 217 concentration, and in those with mild cognitive impairment, there was a direct effect of WMH on phosphorylated tau 217 and neurofilament light chain concentrations. There were no associations of WMH with biomarker concentrations among those diagnosed with dementia. The findings from this cross-sectional study suggest that among individuals with Down syndrome, cerebrovascular disease promotes neurodegeneration by increasing astrocytosis and tau pathophysiology in the presymptomatic phases of Alzheimer's disease, but future studies will need to confirm these associations with longitudinal data. This work joins an emerging literature that implicates cerebrovascular disease and its interface with neuroinflammation as a core pathological feature of Alzheimer's disease in adults with Down syndrome.

Effect of blood collection tube containing protease inhibitors on the pre-analytical stability of Alzheimer's disease plasma biomarkers.

The reliability of plasma biomarkers of Alzheimer's disease (AD) can be compromised by protease-induced degradation. This can limit the feasibility of conducting plasma biomarker studies in environments that lack the capacity for immediate processing and appropriate storage of blood samples. We hypothesized that blood collection tube supplementation with protease inhibitors can improve the stability of plasma biomarkers at room temperatures (RT). In this study, we conducted a comparative analysis of blood biomarker stability in traditional ethylenediaminetetraacetic acid (EDTA) tubes versus BD™ P100 collection tubes, the latter being coated with a protease inhibitor cocktail. The stability of six plasma AD biomarkers was evaluated over time under RT conditions. We evaluated three experimental approaches. In Approach 1, pooled plasma samples underwent storage at RT for up to 96 h. In Approach 2, plasma samples isolated upfront from whole blood collected into EDTA or P100 tubes were stored at RT for 0 h or 24 h before biomarker measurements. In Approach 3, whole blood samples were collected into paired EDTA and P100 tubes, followed by storage at RT for 0 h or 24 h before isolating the plasma for analyses. Biomarkers were measured with Single Molecule Array (Simoa) and immunoprecipitation-mass spectrometry (IP-MS) assays. Both the IP-MS and Simoa methods revealed that the use of P100 tubes significantly improves the stability of Aβ42 and Aβ40 across all approaches. However, the Aβ42/Aβ40 ratio levels were significantly stabilized only in the IP-MS assay in Approach 3. No significant differences were observed in the levels of plasma p-tau181, GFAP, and NfL for samples collected using either tube type in any of the approaches. Supplementation of blood collection tubes with protease inhibitors could reduce the protease-induced degradation of plasma Aβ42 and Aβ40, and the Aβ42/40 ratio for the IP-MS assay. These findings have crucial implications for preanalytical procedures, particularly in resource-limited settings.

Developing diagnostic biomarkers for Alzheimer's disease based on histone lactylation-related gene

BackgroundResearch underscores the significant influence of histone lactylation pathways in the progression of Alzheimer's disease (AD), though the molecular mechanisms associated with histone lactylation-related genes (HLRGs) in AD are still insufficiently investigated. MethodsThis study employed datasets GSE85426 and GSE97760 to identify candidate genes by intersecting weighted gene co-expression network analysis (WGCNA) module genes with AD-control differentially expressed genes (DEGs). Subsequently, machine learning refined key genes, validated by receiver operating characteristic (ROC) curve performance. Gene-set enrichment analysis (GSEA) explored the molecular mechanisms of these diagnostic markers. Concurrently, the association between the diagnostic genes and both differential immune cells and immune responses was examined. Furthermore, a ceRNA and gene-drug network was developed. Finally, the expression of the selected genes was validated using brain tissues from AD model mice. ResultsThis study identified five genes (ARID5B, NSMCE4A, SESN1, THADA, and XPA) with significant diagnostic utility, primarily enriched in olfactory transduction and N-glycan biosynthesis pathways. Correlation analysis demonstrated a strong positive association between all diagnostic genes and naive B cells. The ceRNA regulatory network comprised 7 miRNAs, 2 mRNAs, and 25 lncRNAs. Additionally, 33 drugs targeting the diagnostic genes were predicted. Following expression validation through training and validation sets, three genes (ARID5B, SESN1, XPA) were ultimately confirmed as biomarkers for this study. RT-qPCR and Western blot analyses revealed upregulated expression of ARID5B, SESN1, and XPA in the cerebral tissue of AD model mice. ConclusionThree histone lactylation-linked genes (ARID5B, SESN1, XPA) were identified as potential AD biomarkers, indicating a strong association with disease progression.

Neuropsychiatric symptoms: Risk factor or disease marker? A study of structural imaging biomarkers of Alzheimer's disease and incident cognitive decline.

Neuropsychiatric symptoms (NPS) are risk factors for Alzheimer's disease (AD) but can also manifest secondary to AD pathology. Mild behavioral impairment (MBI) refers to later-life emergent and persistent NPS that may mark early-stage AD. To distinguish MBI from NPS that are transient or which represent psychiatric conditions (non-MBI NPS), we investigated the effect of applying MBI criteria on NPS associations with AD structural imaging biomarkers and incident cognitive decline. Data for participants (n = 1273) with normal cognition (NC) or mild cognitive impairment (MCI) in the National Alzheimer's Coordinating Center Uniform Data Set were analyzed. NPS status (MBI, non-MBI NPS) was derived from the Neuropsychiatric Inventory Questionnaire and psychiatric history. Normalized measures of bilateral hippocampal (HPC) and entorhinal cortex (EC) volume, and AD meta-region of interest (ROI) mean cortical thickness were acquired from T1-weighted magnetic resonance imaging scans. Multivariable linear and Cox regressions examined NPS associations with imaging biomarkers and incident cognitive decline, respectively. MBI was associated with lower volume and cortical thickness in all ROIs in both NC and MCI, except for EC volume in NC. Non-MBI NPS were only associated with lower HPC volume in NC. Although both of the NPS groups showed higher hazards for MCI/dementia than No NPS, MBI participants showed more rapid decline. Although both types of NPS were linked to HPC atrophy, only NPS that emerged and persisted in later-life, consistent with MBI criteria, were related to AD neurodegenerative patterns beyond the HPC. Moreover, MBI predicted faster progression to dementia than non-MBI NPS.

BCL2 interacting protein 3 as a potential biomarker for Alzheimer’s disease: an observational study

As important organelles for energy production, mitochondria exhibit dysfunction as an early hallmark of Alzheimer’s disease, potentially leading to cell death and impaired brain function. The mitophagy receptors BCL2 interacting protein 3 and BCL2 interacting protein 3 like (NIX), which are regulated by protein phosphatase targeting COQ7 (PPTC7), play crucial roles in controlling the quantity of mitochondria within cells. In this study, we found that the expression level of BCL2 interacting protein 3 was positively correlated with Mini-Mental State Examination scores, indicating that a lower BCL2 interacting protein 3 expression was associated with a higher degree of dementia. Under pathological conditions of Alzheimer’s disease, the expression levels of protein phosphatase targeting COQ7, BCL2 interacting protein 3, and BCL2 interacting protein 3 like were decreased. Overall, BCL2 interacting protein 3 may serve as a potential biomarker of Alzheimer’s disease.

Stable potassium isotope ratios in human blood serum towards biomarker development in Alzheimer's disease.

The Alzheimer's disease (AD)-affected brain purges K with concurrently increasing serum K, suggesting brain-blood K transferal. Here, natural stable K isotope ratios-δ41K-of human serum samples were characterized in an AD biomarker pilot study (plus two paired Li-heparin and potassium ethylenediaminetetraacetic acid [K-EDTA] plasma samples). AD serum was found to have a significantly lower mean δ41K relative to controls. To mechanistically explore this change, novel ab initio calculations (density functional theory) of relative K isotope compositions between hydrated K+ and organically bound K were performed, identifying hydrated K+ as isotopically light (lower δ41K) compared to organically bound K. Taken together with literature, serum δ41K and density functional theory results are consistent with efflux of hydrated K+ from the brain to the bloodstream, manifesting a measurable decrease in serum δ41K. These data introduce serum δ41K for further investigation as a minimally invasive AD biomarker, with cost, scalability, and stability advantages over current techniques.

A New Strategy for Ultrasensitive Detection Based on Target microRNA-Triggered Rolling Circle Amplification in the Early Diagnosis of Alzheimer's Disease.

There is an urgent need to accurately quantify microRNA (miRNA)-based Alzheimer's disease (AD) biomarkers, which have emerged as promising diagnostic biomarkers. In this study, we present a rapid and universal approach to establishing a target miRNA-triggered rolling circle amplification (RCA) detection strategy, which achieves ultrasensitive detection of several targets, including miR-let7a-5p, miR-34a-5p, miR-206-3p, miR-9-5p, miR-132-3p, miR-146a-5p, and miR-21-5p. Herein, the padlock probe contains three repeated signal strand binding regions and a target miRNA-specific region. The target miRNA-specific region captures miRNA, and then the padlock probe is circularized with the addition of T4 DNA ligase. Subsequently, an RCA reaction is triggered, and RCA products containing multiple signal strand binding regions are generated to trap abundant fluorescein-labeled signal strands. The addition of exonuclease III (Exo III) causes signal strand digestion and leads to RCA product recycling and liberation of fluorescein. Ultimately, graphene oxide (GO) does not absorb the liberated fluorescein because of poor mutual interaction. This method exhibited high specificity, sensitivity, repeatability, and stability toward let-7a, with a detection limit of 19.35 fM and a linear range of 50 fM to 5 nM. Moreover, it showed excellent applicability for recovering miRNAs in normal human serum. Our strategy was applied to detect miRNAs in the plasma of APP/PS1 mice, demonstrating its potential in the diagnosis of miRNA-associated disease and biochemical research.

Towards early diagnosis and screening of Alzheimer’s disease using frequency locked whispering gallery mode microtoroids

Alzheimer’s disease (AD) is a form of dementia marked by amyloid plaques and neurofibrillary tangles in the brain. Amyloid beta (Aβ) is an AD biomarker which is linked to these plaques and tangles. Measuring Aβ levels can help with early AD diagnosis and aid in drug studies and delaying dementia. This is challenging, however, due to low AD biomarker levels in biofluids. Here we use FLOWER (frequency-locked optical whispering evanescent resonator) to quantify levels of post-mortem cerebrospinal fluid (CSF) Aβ42 in control, mild cognitive impairment (MCI), and AD participants. FLOWER measures the resonant wavelength shift of a microtoroid due to changes in the refractive index within its evanescent field. FLOWER can measure CSF Aβ42 (area under curve, AUC = 0.92) with higher performance than ELISA (AUC = 0.82) and can distinguish between control and MCI samples. This demonstrates FLOWER’s ability to screen CSF samples for diagnosis of AD.