Beta-amyloid Plaques Research Articles

Lecanemab for Alzheimer's Disease

Lecanemab is a novel drug developed by Sisai and Biogen aimed at treating Alzheimer’s Disease. Alzheimer’s Disease is characterized by the misfolding and accumulation of neurotoxic amyloid-beta plaques in the brain, leading to neuronal cell death and brain shrinkage. Lecanemab contains monoclonal antibodies that have a high affinity for soluble and insoluble forms of amyloid-beta peptides. These antibodies bind, neutralize, and eliminate amyloid-beta aggregates to slow Alzheimer’s Disease progression.2 Phase II dose-finding trial for Lecanemab conducted with 854 participants with early Alzheimer’s Disease demonstrated no significant difference between Lecanemab and placebo groups at the 12-month mark. However, a 27% reduction in clinical decline in the Lecanemab group was seen after 18 months compared to the placebo group. Adverse effects of Lecanemab include transient fever and asymptomatic fluid formation in the brain. The drug was approved by the Food and Drug Administration and launched in the United States on January 18, 2023. Manufacturing and marketing applications for Lecanemabwere also recently submitted in Europe, Japan, and Canada1 With FDA approval, the drug is currently priced at 26,500 USD per year, with Medicare pledging to cover 80% of the cost.3

Cutting-Edge Strategies for Overcoming Therapeutic Barriers in Alzheimer's Disease.

Alzheimer's disease (AD) remains one of the hardest neurodegenerative diseases to treat due to its enduring cognitive deterioration and memory loss. Despite extensive research, few viable treatment approaches have been found; these are mostly due to several barriers, such as the disease's complex biology, limited pharmaceutical efficacy, and the BBB. This presentation discusses current strategies for addressing these therapeutic barriers to enhance AD treatment. Innovative drug delivery methods including liposomes, exosomes, and nanoparticles may be able to pass the blood-brain barrier and allow medicine to enter specific brain regions. These innovative strategies of medicine distribution reduce systemic side effects by improving absorption. Moreover, the development of disease-modifying treatments that target tau protein tangles, amyloid-beta plaques, and neuroinflammation offers the chance to influence the course of the illness rather than only treat its symptoms. Furthermore, gene therapy and CRISPR-Cas9 technologies have surfaced as potentially groundbreaking methods for addressing the underlying genetic defects associated with AD. Furthermore, novel approaches to patient care may involve the utilization of existing medications having neuroprotective properties, such as those for diabetes and cardiovascular conditions. Furthermore, biomarker research and personalized medicine have made individualized therapy approaches possible, ensuring that patients receive the best care possible based on their unique genetic and molecular profiles.

Targeted Magnetic Nanoparticles for Beta-Amyloid Detection

Background/Objectivities: The presence of beta-amyloid plaques is a part of the pathogenesis of Alzheimer’s disease, but there is currently no universally accepted method for magnetic resonance (MR) imaging of the disease. However, it is known that magnetic nanoparticles (MNPs) can improve the T2 contrast in MR images of various targets. Methods: We used cubic MNPs, which were produced by thermal decomposition and then it was covalently bonded to a modified fluorescently labeled tetrapeptide, HAEE-Cy5, for visualizing beta-amyloid plaques. The interaction of MNPs-HAEE-Cy5 and beta-amyloid was determinate by confocal microscopy using SH-SY5Y cell line. Results: MNPs exhibit relatively high relaxivity (approximately 200 mM−1s−1), which is crucial for enhancing target visibility in MR imaging. HAEE provides targeted delivery of MNPs by specifically interacting with beta-amyloid, while the fluorescent label Cy5 enables monitoring the efficacy of the interaction through confocal microscopy. Conclusions: The MNPs modified with HAEE-Cy5 demonstrated excellent binding to beta-amyloid plaques in vitro, as shown by experiments on the SH-SY5Y cell line. These results suggest that the proposed method has potential for use in future MR imaging studies of Alzheimer’s disease.

LPS Priming Before Plaque Deposition Activates the Rho/ROCK Pathway to Regulate Microglial M1/M2 Polarization Through the NF-κB Pathway in the 5xFAD Mouse Model of Alzheimer’s Disease

Alzheimer’s Disease is a neurodegenerative disease which is characterized by continuous neuroinflammation, beta-amyloid plaques (Aβ) and tau clusters. Microglia is a type of immune cell that resides in the brain and plays a crucial role in disease progression and neuroprotection based on its extent of polarization. This research investigated the effect on microglial polarization caused by LPS priming before plaque deposition through the Rho/ROCK pathway and the NF-κB pathway in a 5xFAD mouse model. It is assumed that LPS priming will activate the Rho/ROCK pathway and then regulate the NF-κB pathway, causing microglial polarization from M1 (pro-inflammatory state) to M2 (inflammatory state). To achieve this goal, the techniques applied include immunohistochemistry, flow cytometry, Western blotting, and RT-qPCR. The expected result is the observation that LPS priming increased Rho/ROCK activation, inhibited the NF-κB pathway, and promoted M2 polarization. This observation indicates the complex relationship between systemic and neuroinflammatory pathways in AD. Moreover, it provides potential therapeutic approaches targeting Rho/ROCK and NF-κB pathways to reduce neuroinflammation and enhance neuroprotection.

Gamma Wave Stimulation Affects BACE1 Levels and Promotes the Transition of Microglia from M1 State to M2 State

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder and it presents with the hallmark neuropathological features of amyloid-beta (Aβ) plaques, tau tangles and active neuroinflammation. Beta-site amyloid precursor protein cleaving enzyme 1 (BACE-1), a key mediator of increased Aβ, has been identified as the primary enzymatic source for production of this pathologic peptide while reactive microglial cells contribute to ongoing neurodegeneration perhaps through activation into their aggressive M1 state. The present study endeavors for the first time to address how gamma wave stimulation modulates BACE1 and microglial polarization (from M1 to beneficial M2) in different AD models. We hypothesize that gamma wave stimulation will reduce BACE1, decrease Aβ plaque burden and shift microglials towards M2 phenotype leading to reduced neuroinflammation and maintain cognitive function. This study will target mouse models of AD which have undergone gamma wave stimulation and its effects on BACE1 expression, microglial polarisation markers, Aβ plaque load and cognitive performance. Hypotheses the treatment will reduce BACE1 activity, decrease M1/M2 microglial ratio, improve cognitive performance and delay Aβ plaque accumulation These data suggest promising therapeutic strategies for neuroinflammation and amyloidogenesis in AD.

Exploring the role of HIF-1α on pathogenesis in Alzheimer's disease and potential therapeutic approaches.

Hypoxia-inducible factor 1α (HIF-1α) is a crucial transcription factor that regulates cellular responses to low oxygen levels (hypoxia). In Alzheimer's disease (AD), emerging evidence suggests a significant involvement of HIF-1α in disease pathogenesis. AD is characterized by the accumulation of amyloid-beta (Aβ) plaques and neurofibrillary tangles (NFTs), leading to neuronal dysfunction and cognitive decline. HIF-1α is implicated in AD through its multifaceted roles in various cellular processes. Firstly, in response to hypoxia, HIF-1α promotes the expression of genes involved in angiogenesis, which is crucial for maintaining cerebral blood flow and oxygen delivery to the brain. However, in the context of AD, dysregulated HIF-1α activation may exacerbate cerebral hypoperfusion, contributing to neuronal damage. Moreover, HIF-1α is implicated in the regulation of Aβ metabolism. It can influence the production and clearance of Aβ peptides, potentially modulating their accumulation and toxicity in the brain. Additionally, HIF-1α activation has been linked to neuroinflammation, a key feature of AD pathology. It can promote the expression of pro-inflammatory cytokines and exacerbate neuronal damage. Furthermore, HIF-1α may play a role in synaptic plasticity and neuronal survival, which are impaired in AD. Dysregulated HIF-1α signaling could disrupt these processes, contributing to cognitive decline and neurodegeneration. Overall, the involvement of HIF-1α in various aspects of AD pathophysiology highlights its potential as a therapeutic target. Modulating HIF-1α activity could offer novel strategies for mitigating neurodegeneration and preserving cognitive function in AD patients. However, further research is needed to elucidate the precise mechanisms underlying HIF-1α dysregulation in AD and to develop targeted interventions.

Photobiomodulation as a Potential Treatment for Alzheimer’s Disease: A Review Paper

Background: Alzheimer’s disease (AD), the most prevalent form of dementia, is a leading neurodegenerative disorder currently affecting approximately 55 million individuals globally, a number projected to escalate to 139 million by 2050. Despite extensive research spanning several decades, the cure for AD remains at a developing stage. The only existing therapeutic options are limited to symptom management, and are often accompanied by adverse side effects. The pathological features of AD, including the accumulation of beta-amyloid plaques and tau protein tangles, result in progressive neuronal death, synaptic loss, and brain atrophy, leading to significant cognitive decline and a marked reduction in quality of life. Objective: In light of the shortcomings of existing pharmacological interventions, this review explores the potential of photobiomodulation (PBM) as a non-invasive therapeutic option for AD. PBM employs infrared light to facilitate cellular repair and regeneration, focusing on addressing the disease’s underlying biomechanical mechanisms. Method: This paper presents a comprehensive introduction to the mechanisms of PBM and an analysis of preclinical studies evaluating its impact on cellular health, cognitive function, and disease progression in AD.The review provides a comprehensive overview of the various wavelengths and application methods, evaluating their efficacy in mitigating AD-related symptoms. Conclusions: The findings underscore the significant potential of PBM as a safe and effective alternative treatment for Alzheimer’s disease, emphasizing the necessity for further research and clinical trials to establish its therapeutic efficacy conclusively.

Noradrenaline Protects Human Microglial Cells (HMC3) Against Apoptosis and DNA Damage Induced by LPS and Aβ1-42 Aggregates In Vitro

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder, characterized by the accumulation of amyloid-beta (Aβ) plaques and neuroinflammation. This study investigates the protective effects of noradrenaline (NA) on human microglial cells exposed to lipopolysaccharides (LPS) and Aβ aggregates—major contributors to inflammation and cellular damage in AD. The reduced Aβ aggregation in the HMC3 human microglial cells co-treated with Aβ and NA was confirmed by thioflavin T (ThT) assay, fluorescent ThT staining, and immunocytochemistry (ICC). The significantly increased viability of HMC3 cells after 48 h of incubation with NA at 50 µM, 25 µM, and 10 µM, exposed to IC50 LPS and IC50 Aβ, was confirmed by XTT and LDH assays. Moreover, we found that NA treatment at 25 μM and 50 μM concentrations in HMC3 cells exposed to IC50 LPS or IC50 Aβ results in an increased proliferation of HMC3 cells, their return to normal morphology, decreased levels of DNA damage, reduced caspase-3 activity, decreased expression of pro-apoptotic DDIT3 and BAX, and increased expression of anti-apoptotic BCL-2 genes and proteins, leading to enhanced cell survival, when compared to that of the HMC3 cells treated only with IC50 LPS or IC50 Aβ. Furthermore, we showed that NA induces the degradation of both extracellular and intracellular Aβ deposits and downregulates hypoxia-inducible factor 1α (HIF-1α), which is linked to impaired Aβ clearance and AD progression. These findings indicate that NA holds promise as a therapeutic target to address microglial dysfunction and potentially slow the progression of AD. Its neuroprotective effects, particularly in reducing inflammation and regulating microglial activity, warrant further investigation into its broader role in mitigating neuroinflammation and preserving microglial function in AD.

NF-κB in Alzheimer’s Disease: Friend or Foe? Opposite Functions in Neurons and Glial Cells

Alzheimer’s disease (AD) is a devasting neurodegenerative disease afflicting mainly glutamatergic neurons together with a massive neuroinflammation mediated by the transcription factor NF-κB. A 65%-plus increase in Alzheimer’s patients by 2050 might be a major threat to society. Hallmarks of AD are neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau and amyloid beta (Aβ) plaques. Here, we review the potential involvement of transcription factor NF-κB by hereditary mutations of the tumor necrosis factor pathway in AD patients. One of the greatest genetic risk factors is APOE4. Recently, it was shown that the APOE4 allele functions as a null allele in human astrocytes not repressing NF-κB anymore. Moreover, NF-κB seems to be involved in the repair of DNA double-strand breaks during healthy learning and memory, a function blunted in AD. NF-κB could be a friend to healthy neurons by repressing apoptosis and necroptosis. But a loss of neuronal NF-κB and activation of glial NF-κB in AD makes it a foe of neuronal survival. Hopeful therapies include TNFR2 receptor bodies relieving the activation of glial NF-κB by TNFα.

Hypothesis-based investigation of known AD risk variants reveals the genetic underpinnings of neuropathological lesions observed in Alzheimer’s-type dementia

Alzheimer’s disease (AD) is the leading cause of dementia worldwide. Besides neurofibrillary tangles and amyloid beta (Aβ) plaques, a wide range of co-morbid neuropathological features can be observed in AD brains. Since AD has a very strong genetic background and displays a wide phenotypic heterogeneity, this study aims at investigating the genetic underpinnings of co-morbid and hallmark neuropathological lesions. This was realized by obtaining the genotypes for 75 AD risk variants from low-coverage whole-genome sequencing data for 325 individuals from the Leuven Brain Collection. Association testing with deeply characterized neuropathological lesions revealed a strong and likely direct effect of rs117618017, a SNP in exon 1 of APH1B, with tau-related pathology. Second, a relation between APOE and granulovacuolar degeneration, a proxy for necroptosis, was also discovered in addition to replication of the well-known association of APOE with AD hallmark neuropathological lesions. Additionally, several nominal associations with AD risk genes were detected for pTDP pathology, α-synuclein lesions and pTau-related pathology. These findings were confirmed in a meta-analysis with three independent cohorts. For example, we replicated a prior association between TPCN1 (rs6489896) and LATE-NC risk. Furthermore, we identified new putative LATE-NC-linked SNPs, including rs7068231, located upstream of ANK3. We found association between BIN1 (rs6733839) and α-synuclein pathology, and replicated a prior association between USP6NL (rs7912495) and Lewy body pathology. Additionally, we also found that UMAD1 (rs6943429) was nominally associated with Lewy body pathology. Overall, these results contribute to a broader general understanding of how AD risk variants discovered in large-scale clinical genome-wide association studies are involved in the pathological mechanisms of AD and indicate the importance of downstream elimination of phenotypic heterogeneity introduced in these studies.

Neuroprotective Effect of Artemisinin in an Animal Model of Alzheimer's Disease.

Alzheimer's disease (AD) is the most common neurodegenerative disease in older people, characterized by the accumulation of beta-amyloid (Aβ) plaques and neurofibrillary tangles composed of aggregated of hyperphosphorylated tau protein, which normally helps stabilize microtubules in neurons. Nowadays, artemisinin (ART) as well as its semisynthetic derivatives (ARTs) are seen as potential neuroprotectors. The goal of the present study is the assessment of neuroprotective, antibacterial activity of ART, as well as in silico studies of ART affinity to Aβ-peptides and the search of potential targets for ART. The study is referring to explores the impact of ART on an animal model of AD that is induced by the aggregated amyloidogenic peptide Aβ1-42 by electrophysiology and morphology analysis. Specifically, the focus is on the activation of the entorhinal cortex (ENT) as synaptic potentiation. Electrophysiological and histochemical have demonstrated that therapeutic injection of ART or its derivatives acts as a neuroprotective This treatment appears to prevent or slow down damage to brain tissue, and it promotes the restoration of neurons and their surrounding environment. The protective effects of ART may involve various mechanisms, including antioxidant activity, anti-inflammatory effects, and the inhibition of apoptosis. in silico studies revealed a direct, strong interaction of ART with the amyloidogenic peptides 5Aβ17-42, 12Aβ9-40, and 18Aβ9-40. in silico screening revealed several protein targets for ART, including cytochrome P-450 2B6 (CYP2B6). The highest binding affinity was found on the active site of CYP2B6. ART has great potential for discovering new drugs using combined therapies.

The mTOR Pathway: A Common Link Between Alzheimer’s Disease and Down Syndrome

Down syndrome (DS) is a chromosomal condition that causes many systemic dysregulations, leading to several possible age-related diseases including Alzheimer’s disease (AD). This may be due to the triplication of the Amyloid precursor protein (APP) gene or other alterations in mechanistic pathways, such as the mTOR pathway. Impairments to upstream regulators of mTOR, such as insulin, PI3K/AKT, AMPK, and amino acid signaling, have been linked to amyloid beta plaques (Aβ) and neurofibrillary tangles (NFT), the most common AD pathologies. However, the mechanisms involved in the progression of pathology in human DS-related AD (DS-AD) are not fully investigated to date. Recent advancements in omics platforms are uncovering new insights into neurodegeneration. Genomics, spatial transcriptomics, proteomics, and metabolomics are novel methodologies that provide more data in greater detail than ever before; however, these methods have not been used to analyze the mTOR pathways in connection to DS-AD. Using these new techniques can unveil unexpected insights into pathological cellular mechanisms through an unbiased approach.

Exploration of neuroprotective and cognition boosting effects of Mazus pumilus in Alzheimer's disease model.

Mazus pumilus (MP) an Asian flowering plant, known for various reported pharmacological activities including antioxidant, anti-nociceptive, anti-inflammatory, anticancer, antibacterial, antifungal, and hepatoprotective effects. This study focused on further exploring Mazus pumilus's methanol leaf extract (MPM) for bioactive principles and investigating its neuroprotective and cognition-enhancing potential in Alzheimer's disease models. For the phytochemical screening and identification, TLC, HPLC, and Fourier transform infrared (FTIR) were employed. In-vitro antioxidant potential was assayed by DPPH Free Radical Scavenging method, followed by in-vivo neuroprotective effect of MPM (100, 200, 300 mg/kg) using Wistar-albino rats, sodium azide for induction of AD and rivastigmine as standard. Over 21days, we observed neurobehavioral changes and performed biochemical (GSH, CAT, SOD, and AchE activity) and histopathological evaluations. Results revealed the presence of alkaloids, flavonoids, amino acids, terpenoids, glycosides, sterols, and saponins. HPLC analysis confirmed the presence of gallic acids, sinapic acid, and caffeic acid. DPPH confirmed the antioxidant effect of MPM, which served as a base for its potential neuroprotective activity. Biochemically, oxidative stress markers improved significantly post-treatment, with decreased GSH, SOD, CAT levels, and increased AchE activity, indicating a reversal of AD-induced changes. Behavioral assessments showed improvements in locomotion, memory, spatial learning, and cognition. Histologically, there was a dose-dependent reduction in neurodegenerative features like neurofibrillary tangles and amyloid beta plaques. Hence, this study concluded MPM is a promising candidate for prophylaxis and treatment of behavioral deficits and cognitive dysfunction in Alzheimer's disease.

Down regulation of the c-Fos/MAP kinase signaling pathway during learning memory processes coincides with low GnRH levels in aluminum chloride-induced Alzheimer's male rats.

Aluminum chloride (Al) is associated with Alzheimer's disease (AD) and reproductive disorders. But the relationship between gonadotropin-releasing hormone (GnRH) and c-Fos levels, the end product of MAP-kinase signaling, in AD is unknown, so we aimed to investigate this relationship. We exposed rats to Al dissolved in drinking water (10 and 50mg/kg) for two and four weeks. The control group received only drinking water. At the end, the blood sample was collected under deep anesthesia and the brain was dissected on ice, and the testicular tissue was fixed in formalin. Amyloid beta (βA) plaques in brain regions and the number of CA1 neurons were evaluated by Congo red staining and cresyl violet staining. Activation of neuronal nitric oxide synthase (nNOS) was studied using NADPH-diaphorase. The levels of c-Fos and testosterone receptors in the target area were examined immunohistochemically. Brain GnRH levels were determined by blotting, and serum levels of gonadotropins and steroids were measured by enzyme-linked immunosorbent assay (ELISA). All data were analyzed using analysis of variance (ANOVA) at α = 0.05 level. The accumulation of βA plaque was observed along with a decrease in the number of CA1 pyramidal neurons and a significant decrease in the levels of c-Fos and GnRH in the brains of rats receiving Al, which was aligned with a significant decrease in serum levels of testosterone and LH. This study, for the first time, showed a link between dementia and a concomitant decrease in brain GnRH and c-Fos levels.

Isotope Encoded chemical Imaging Identifies Amyloid Plaque Age Dependent Structural Maturation, Synaptic Loss, and Increased Toxicity.

It is of critical importance to our understanding of Alzheimer's disease (AD) pathology to determine how key pathological factors are interconnected and implicated in nerve cell death, clinical symptoms, and disease progression. The formation of extracellular beta-amyloid (Aβ) plaques is the major pathological hallmark of AD and Aβ has been suggested to be a critical inducer of AD, driving disease pathogenesis. Exactly how Aβ plaque formation begins and how ongoing plaque deposition proceeds and initiates subsequent neurotoxic mechanisms is not well understood. The primary aim of our research is to elucidate the biochemical processes underlying early Aβ plaque formation in brain tissue. We recently introduced a chemical imaging paradigm based on mass spectrometry imaging (MSI) and metabolic isotope labelling to follow stable isotope labelling kinetics (iSILK) in vivo to track the in vivo build-up and deposition of Aβ. Herein, knock-in Aβ mouse models ( App NL-F ) that develop Aβ pathology gradually are metabolically labeled with stable isotopes. This chemical imaging approach timestamps amyloid plaques during the period of initial deposition allowing the fate of aggregating Aβ species from before and during the earliest events of plaque pathology through plaque maturation to be tracked. To identify the molecular and cellular response to plaque maturation, we integrated iSILK with single plaque transcriptomics performed on adjacent tissue sections. This enabled changes in gene expression to be tracked as a function of plaque age (as encoded in the Aβ peptide isotopologue pattern) distinct from changes due to the chronological age or pathological severity. This approach identified that plaque age correlates negatively with gene expression patterns associated with synaptic function as early as in 10-month-old animals but persists into 18 months. Finally, we integrated hyperspectral confocal microscopy into our multiomic approach to image amyloid structural isomers, revealing a positive correlation between plaque age and amyloid structural maturity. This analysis identified three categories of plaques, each with a distinct impact on the surrounding microenvironment. Here, we identified that older, more compact plaques were associated with the most significant synapse loss and toxicity. These data show how isotope-encoded MS imaging can be used to delineate Aβ toxicity dynamics in vivo. Moreover, we show for the first time a functional integration of dynamic MSI, structural plaque imaging and whole genome-wide spatial transcriptomics at the single plaque level. This multiomic approach offers an unprecedented combination of temporal and spatial resolution enabling a description of the earliest events of precipitating amyloid pathology and how Aβ modulates synaptotoxic mechanisms.

Alzheimer's Disease: Exploring the Landscape of Cognitive Decline.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory loss, and impaired daily functioning. The pathology of AD is marked by the accumulation of amyloid beta plaques and tau protein tangles in the brain, along with neuroinflammation and synaptic dysfunction. Genetic factors, such as mutations in APP, PSEN1, and PSEN2 genes, as well as the APOE ε4 allele, contribute to increased risk of acquiring AD. Currently available treatments provide symptomatic relief but do not halt disease progression. Research efforts are focused on developing disease-modifying therapies that target the underlying pathological mechanisms of AD. Advances in identification and validation of reliable biomarkers for AD hold great promise for enhancing early diagnosis, monitoring disease progression, and assessing treatment response in clinical practice in effort to alleviate the burden of this devastating disease. In this paper, we analyze data from the CAS Content Collection to summarize the research progress in Alzheimer's disease. We examine the publication landscape in effort to provide insights into current knowledge advances and developments. We also review the most discussed and emerging concepts and assess the strategies to combat the disease. We explore the genetic risk factors, pharmacological targets, and comorbid diseases. Finally, we inspect clinical applications of products against AD with their development pipelines and efforts for drug repurposing. The objective of this review is to provide a broad overview of the evolving landscape of current knowledge regarding AD, to outline challenges, and to evaluate growth opportunities to further efforts in combating the disease.

A molecular dynamics investigation into the inhibitory function of hydroxypropyl-beta-cyclodextrin (HPBCD) in its interaction with amyloid-beta (Aβ) plaques near the cell membrane in the context of Alzheimer's disease.

Although Alzheimer`s disease has been known for a long time, it is interesting that scientists are still doing widespread research on it. Meanwhile, in parallel with experimental research, computational research is also yielding interesting results. In this study, we investigated the inhibitory behavior of hydroxypropyl-beta-cyclodextrin (HPBCD) drug candidates, which are more soluble than beta-cyclodextrin (BCD), using molecular dynamics simulations and compared them with AC0107 new drug. Parameters such as cell membrane stability, protein stability, drug inhibition rate, protein permeability, hydrogen bonding agents, the study of the energy content of interactions between different groups, and interactions between different species were of interest. The outcomes indicate that the drug candidate HPBCD has a role in inhibiting protein membrane penetration and has better performance than new AC0107 drug. In other words, HPBCD not only act as a drug carrier of Alzheimer's disease, but also as an inhibitor of it and can play a double role in its improvement.

A-120 Analytical and Clinical Verification of the Elecsys® Alzheimer’s Disease Cerebrospinal Fluid Biomarkers pTau/Abeta42 and Total-Tau/Abeta42

Abstract Background Alzheimer’s disease (AD) is the most common form of dementia characterized by amyloid beta (Abeta) plaques and neurofibrillary tau tangles in the brain. Cerebrospinal fluid (CSF) biomarkers Abeta42, total tau (tTau), and phosphorylated tau (pTau181) offer a high degree of sensitivity and specificity in the diagnosis of AD and have utility in monitoring disease progression. AD biomarker ratios, pTau181/Abeta42 and tTau/Abeta42, correlate with amyloid positron emission tomography (PET) imaging, and several assays have received FDA clearance. This study was designed to evaluate the analytical performance and clinical utility of AD-related Abeta and tau biomarkers on the Roche cobas e601. Methods Precision studies were performed using Roche PreciControl kits. Intra- and inter-precision samples were tested ten times in a single day or twice a day for ten days, respectively. Five levels of Roche Calcheck material were measured in triplicate for linearity. Method comparison was carried out using 39 samples from the Elecsys CSF Correlation Sample Panel from Roche. Qualitative comparisons to amyloid PET Centiloid scores were performed using 35 CSF samples (n=11 PET negative, n=24 PET positive). CSF samples and PET interpretation were obtained from the Cleveland Clinic Institutional Review Board approved Cleveland Alzheimer's Disease Research Center (CADRC) and Cleveland Clinic Lou Ruvo Center for Brain Health Aging and Neurodegenerative Disease Biobank (LRCBH-Biobank). Results Conclusions Evaluation of AD biomarkers on the Roche cobas e601 revealed reliable precision and analytical accuracy. The pTau181/Abeta42 and tTau/Abeta42 ratios demonstrated excellent positive agreement when compared to amyloid PET, but poor negative agreement. This may be due to the small sample size of PET-negative patients. Alternatively, as amyloid PET detects neuritic plaque accumulation, the CSF biomarker-positive/PET-negative patients may have early non-neuritic amyloid plaque pathology not detectable by imaging. Overall, this assay is suitable for use and may serve as a valuable tool in AD diagnosis.

B-236 New real-time PCR test for APOE genotyping in patients with Alzheimer’s disease before anti-amyloid therapy

Abstract Background In 2023, the US Food and Drug Administration approved LEQEMBI, a monoclonal antibody therapy targeting beta-amyloid plaques, for patients with early-stage Alzheimer’s disease (AD). However, anti-amyloid drug trials demonstrated an elevated risk for amyloid-related imaging abnormalities with cerebral edema (ARIA-E) in carriers of the AD risk allele apolipoprotein E epsilon 4 (APOE-ɛ4), especially in ɛ4/ɛ4 homozygous individuals [1-3]. Here, we report on the evaluation of a new real-time polymerase chain reaction (PCR) test for APOE genotyping. Methods The EURORealTime APOE (EUROIMMUN), which enables simultaneous testing for all six APOE genotypes (ɛ2/ɛ2, ɛ2/ɛ3, ɛ2/ɛ4, ɛ3/ɛ3, ɛ3/ɛ4, and ɛ4/ɛ4) by real-time PCR, was performed using genomic DNA (gDNA) isolated from EDTA blood samples. The PCR amplification results were evaluated using the EURORealTime Analysis Software (EUROIMMUN). Samples from healthy blood donors (HBD) were used to assess intra-assay, inter-assay and between-lot precision (n=6) as well as analytical sensitivity (n=21), with each APOE genotype represented by at least one sample. Assay accuracy was analyzed by comparing genotype assignments to the results of the CE-IVD-marked EUROArray APOE (EUROIMMUN) and bidirectional Sanger sequencing using 110 samples (100 AD, 10 HBD). APOE genotype frequencies were compared between patients (100 AD) and controls (250 HBD). Results Precision testing of the EURORealTime APOE resulted in 100% correct genotype calls. Assessment of the analytical sensitivity revealed valid and correct genotype assignment in all 21 samples, confirming 1 ng/µl as the recommended minimum gDNA concentration. The analytical accuracy amounted to 100% based on agreement with the two reference methods in 110/110 cases. Comparison of the APOE genotype distribution showed a higher proportion of ɛ4 allele carriers (i.e., ɛ2/ɛ4, ɛ3/ɛ4, and ɛ4/ɛ4) in AD patients than in HBD (50.0% vs. 25.2%). The prevalence of the ɛ4/ɛ4 genotype in these cohorts was 25.0% for AD patients compared with 2.8% for HBD. Conclusions The well-established high prevalence of the APOE-ɛ4/ɛ4 genotype in AD patients, together with the increased risk of ARIA-E in these homozygous carriers, substantiates the relevance of APOE genotyping prior to anti-amyloid treatment. The EURORealTime APOE test provides sensitive and reliable determination of APOE alleles, thus presenting a suitable tool to improve risk stratification for potential LEQEMBI recipients.

Distinct regional vulnerability to Aβ and iron accumulation in post mortem AD brains.

The paramagnetic iron, diamagnetic amyloid beta (Aβ) plaques and their interaction are crucial in Alzheimer's disease (AD) pathogenesis, complicating non-invasive magnetic resonance imaging for prodromal AD detection. We used a state-of-the-art sub-voxel quantitative susceptibility mapping method to simultaneously measure Aβ and iron levels in post mortem human brains, validated by histology. Further transcriptomic analysis using Allen Human Brain Atlas elucidated the underlying biological processes. Regional increased paramagnetic and diamagnetic susceptibility were observed in medial prefrontal, medial parietal, and para-hippocampal cortices associated with iron deposition (R=0.836, p=0.003) and Aβ accumulation (R=0.853, p=0.002) in AD brains. Higher levels of gene expression relating to cell cycle, post-translational protein modifications, and cellular response to stress were observed. These findings provide quantitative insights into the variable vulnerability of cortical regions to higher levels of Aβ aggregation, iron overload, and subsequent neurodegeneration, indicating changes preceding clinical symptoms. The vulnerability of distinct brain regions to amyloid beta (Aβ) and iron accumulation varies. Histological validation was performed on stained sections of ex-vivo human brains. Regional variations in susceptibility were linked to gene expression profiles. Iron and Aβ levels in ex-vivo brains were simultaneously quantified.