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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.

BackgroundMicroglia play a critical role in neurodegenerative disorders, such as Alzheimer's disease, where alterations in microglial function may result in pathogenic amyloid-β (Aβ) accumulation, chronic neuroinflammation, and deleterious effects on neuronal function. However, studying these complex factors in vivo, where numerous confounding processes exist, is challenging, and until recently, in vitro models have not allowed sustained culture of critical cell types in the same culture.ObjectiveWe employed a rat primary tri-culture (neurons, astrocytes, and microglia) model and compared it to co-culture (neurons and astrocytes) and mono-culture (microglia) to study microglial function (i.e., motility and Aβ clearance) and proteomic response to exogenous Aβ.MethodsThe cultures were exposed to fluorescently-labeled Aβ (FITC-Aβ) particles for varying durations. Epifluorescence microscopy images were analyzed to quantify the number of FITC-Aβ particles and assess cytomorphological features. Cytokine profiles from conditioned media were obtained. Live-cell imaging was employed to extract microglia motility parameters.ResultsFITC-Aβ particles were more effectively cleared in the tri-culture compared to the co-culture. This was attributed to microglia engulfing FITC-Aβ particles, as confirmed via epifluorescence and confocal microscopy. FITC-Aβ treatment significantly increased microglia size, but had no significant effect on neuronal surface coverage or astrocyte size. Upon FITC-Aβ treatment, there was a significant increase in proinflammatory cytokines in tri-culture, but not in co-culture. Aβ treatment altered microglia motility evident as a swarming-like motion.ConclusionsThe results suggest that neuron-astrocyte-microglia interactions influence microglia function and highlight the utility of the tri-culture model for studies of neuroinflammation, neurodegeneration, and cell-cell communication.

BackgroundChronic pain leads to tau accumulation and hippocampal atrophy, which may be moderated through inflammation. In older men, we examined associations of chronic pain with Alzheimer's disease (AD)-related plasma biomarkers and hippocampal volume as moderated by systemic inflammation.MethodsParticipants were men without dementia. Chronic pain was defined as moderate-to-severe pain in 2+ study waves at average ages 56, 62, and 68. At age 68, we measured plasma amyloid-beta (Aβ42, n = 871), Aβ40 (n = 887), total tau (t-tau, n = 841), and neurofilament light chain (NfL, n = 915), and serum high-sensitivity C-reactive protein (hs-CRP, n = 968), a marker of systemic inflammation. A subgroup underwent structural MRI to measure hippocampal volume (n = 385). Analyses adjusted for medical morbidities, depressive symptoms, and opioid use.ResultsChronic pain was related to higher Aβ40 (β = 0.25, p = .009), but hs-CRP was unrelated to AD-related biomarkers (ps > .05). There was a significant interaction such that older men with both chronic pain and higher levels of hs-CRP had higher levels of Aβ42 (β = 0.36, p = .001) and Aβ40 (β = 0.29, p = .003). Chronic pain and hs-CRP did not interact to predict levels of Aβ42/Aβ40, t-tau, or NfL. Furthermore, there were significant interactions such that Aβ42 and Aβ40 were associated with lower hippocampal volume, particularly when levels of hs-CRP were elevated (hs-CRP × Aβ42: β = -0.19, p = .002; hs-CRP × Aβ40: β = -0.21, p = .001), regardless of chronic pain status.ConclusionsChronic pain was associated with higher plasma Aβ, especially when hs-CRP was also elevated. Higher hs-CRP and Aβ levels were both related to smaller hippocampal volumes. Chronic pain, when accompanied by systemic inflammation, may elevate the risk of neurodegeneration in AD-vulnerable regions.

Objectives: Alzheimer's disease (AD) is a progressive neurodegenerative disorder affecting approximately 55 million individuals globally. Diagnosis typically occurs in advanced stages, and there are limited options for reversing symptoms. Preventive strategies are, therefore, crucial. Time Restricted Eating (TRE) or Time Restricted Feeding (TRF) is one such strategy. Here we review recent research on AD and TRE/TRF in addition to AD biomarkers and gut microbiota. Methods: A comprehensive review of recent studies was conducted to assess the impact of TRE/TRF on AD-related outcomes. This includes the analysis of how TRE/TRF influences circadian rhythms, beta-amyloid 42 (Aß42), pro-inflammatory cytokines levels, and gut microbiota composition. Results: TRE/TRF impacts circadian rhythms and can influence cognitive performance as observed in AD. It lowers beta-amyloid 42 deposition in the brain, a key AD biomarker, and reduces pro-ininflammatory cytokines. The gut microbiome has emerged as a modifiable factor in AD treatment. TRE/TRF changes the structure and composition of the gut microbiota, leading to increased diversity and a decrease in harmful bacteria. Discussion: These findings underscore the potential of TRE/TRF as a preventive strategy for AD. By reducing Aß42 plaques, modulating pro-inflammatory cytokines, and altering gut microbiota composition, TRE/TRF may slow the progression of AD. Further research is needed to confirm these effects and to understand the mechanisms involved. This review highlights TRE/TRF as a promising non-pharmacological intervention in the fight against AD. [ABSTRACT FROM AUTHOR]

Although most children with cerebral malaria fully recover, more than a fifth of the survivors develop post-discharge neurodevelopmental sequelae suggestive of advanced neuronal injury. However, the cerebral molecular processes initiating neurological dysfunction in cerebral malaria are still debatable. In this article, we explore available data and hypothesise that cerebral malaria might be linked to APOE-mediated amyloidosis, one of the pathological processes associated with Alzheimer's disease. If our hypothesis is tested and found to be true, it could have far-reaching implications for what we know about cerebral malaria pathogenesis. [ABSTRACT FROM AUTHOR]

Purpose: Xixin Decoction (XXD) is a classical formula that has been used to effectively treat dementia for over 300 years. Modern clinical studies have demonstrated its significant therapeutic effects in treating Alzheimer's disease (AD) without notable adverse reactions. Nevertheless, the specific mechanisms underlying its efficacy remain to be elucidated. This investigation sought to elucidate XXD's impact on various aspects of AD pathology, including blood-brain barrier (BBB) impairment, neuroinflammatory processes, and amyloid-β (Aβ) deposition, as well as the molecular pathways involved in these effects. Methods: In vitro experiments were conducted using hCMEC/D3 and HBVP cell coculture to establish an in vitro blood-brain barrier (BBB) model. BBB damage was induced in this model by 24-h exposure to 1 μg/mL lipopolysaccharide (LPS). After 24, 48, and 72 h of treatment with 10% XXD-medicated serum, the effects of XXD were assessed through Western blotting, RT-PCR, and immunofluorescence techniques. In vivo , SAMP8 mice were administered various doses of XXD via gavage for 8 weeks, including high-dose XXD group (H-XXD) at 5.07 g kg-1·d-1, medium-dose XXD group (M-XXD) at 2.535 g kg-1·d-1, and low-dose XXD group (L-XXD) at 1.2675 g kg-1·d-1. Cognitive function was subsequently evaluated using the Morris water maze test. BBB integrity was evaluated using Evans blue staining, and protein expression levels were analyzed via ELISA, Western blotting, and immunofluorescence. Results: In vitro experiments revealed that XXD-containing serum, when cultured for 24, 48, and 72 h, could upregulate the expression of P-gp mRNA and protein, downregulate CB1 protein expression, and upregulate CB2 and Mfsd2a protein expression. In vivo studies demonstrated that XXD improved spatial learning and memory abilities in SAMP8 mice, reduced the amount of Evans blue extravasation in brain tissues, modulated the BBB-associated P-gp/ECS axis, RAGE/LRP1 receptor system, as well as MRP2 and Mfsd2a proteins, and decreased the accumulation of Aβ in the brains of SAMP8 mice. Additionally, XXD upregulated the expression of TREM2, downregulated IBA1, TLR1, TLR2, and CMPK2 expression, and reduced the levels of pro-inflammatory factors NLRP3, NF-κB p65, COX-2, TNF-α, and IL-1β in the hippocampal tissues. Conclusion: XXD may exert its effects by regulating the P-gp/ECS axis, the RAGE/LRP1 receptor system, and the expression of MRP2 and Mfsd2a proteins, thereby modulating the transport function of the BBB to expedite the clearance of Aβ, reduce cerebral Aβ accumulation, and consequently inhibit the activation of microglia induced by Aβ aggregation. This process may suppress the activation of the CMPK2/NLRP3 and TLRs/NF-κB pathways, diminish the production of inflammatory cytokines and chemokines, alleviate neuroinflammation associated with microglia in the brain of AD, and ultimately improve AD pathology. [ABSTRACT FROM AUTHOR]

Amyloid-β peptide (Aβ) is a critical cause of Alzheimer's disease (AD). It is generated from amyloid precursor protein (APP) through cleavages by β-secretase and γ-secretase. γ-Secretase, which includes presenilin, is regulated by several stimuli. Tau protein has also been identified as a significant factor in AD. In particular, Tau phosphorylation is crucial for neuronal impairment, as phosphorylated Tau detaches from microtubules, leading to the formation of neurofibrillary tangles and the destabilization of the microtubule structure. This instability in microtubules damages axons and dendrites, resulting in neuronal impairment. Notably, Aβ is linked to Tau phosphorylation. Another crucial factor in AD is neuroinflammation, primarily occurring in the microglia. Microglia possess several receptors that bind with Aβ, triggering the expression and release of an inflammatory factor, although their main physiological function is to phagocytose debris and pathogens in the brain. NF-κB activation plays a major role in neuroinflammation. Additionally, the production of reactive oxygen species (ROS) in the microglia contributes to this neuroinflammation. In microglia, superoxide is produced through NADPH oxidase, specifically NOX2. Rho GTPases play an essential role in regulating various cellular processes, including cytoskeletal rearrangement, morphology changes, migration, and transcription. The typical function of Rho GTPases involves regulating actin filament formation. Neurons, with their complex processes and synapse connections, rely on cytoskeletal dynamics for structural support. Other brain cells, such as astrocytes, microglia, and oligodendrocytes, also depend on specific cytoskeletal structures to maintain their unique cellular architectures. Thus, the aberrant regulation of Rho GTPases activity can disrupt actin filaments, leading to altered cell morphology, including changes in neuronal processes and synapses, and potentially contributing to brain diseases such as AD. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's Disease (AD) is a neurodegenerative disease with drastically altered astrocytic metabolism. Astrocytic GABA and H2O2 are associated with memory impairment in AD and synthesized through the Monoamine Oxidase B (MAOB)-mediated multi-step degradation of putrescine. However, the enzymes downstream to MAOB in this pathway remain unidentified. Methods: Using transcriptomics analysis, we identified two candidate enzymes, Aldehyde Dehydrogenase 1 family member A1 (ALDH1A1) and Sirtuin 2 (SIRT2) for the steps following MAOB in the astrocytic GABA production pathway. We used immunostaining, metabolite analysis and electrophysiology, both in vitro and in vivo, to confirm the participation of these enzymes in astrocytic GABA production. We checked for the presence of SIRT2 in human AD patients as well as the mouse model APP/PS1 and finally, we selectively ablated SIRT2 in the astrocytes of APP/PS1 mice to observe its effects on pathology. Results: Immunostaining, metabolite analysis, and electrophysiology recapitulated the participation of ALDH1A1 and SIRT2 in GABA production. Inhibition of SIRT2 reduced the production of astrocytic GABA but not H2O2, a key molecule in neurodegeneration. Elevated expression of these enzymes was found in hippocampal astrocytes of AD patients and APP/PS1 mice. Astrocyte-specific gene-silencing of SIRT2 in APP/PS1 mice restored GABA production and partially improved memory function. Conclusions: Our study is the first to identify the specific role of SIRT2 in reactive astrogliosis and determine the specific pathway and metabolic step catalyzed by the enzyme. We determine the partial, yet significant role of ALDH1A1 in this process, thereby highlighting 2 new players the astrocytic GABA production pathway. Our findings therefore, offer SIRT2 as a new tool to segregate GABA from H2O2 production, aiding future research in neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Epidemiological evidence suggests the presence of common risk factors for the development and prognosis of both cardio- and cerebrovascular diseases, including stroke, Alzheimer's disease, vascular dementia, heart, and peripheral vascular diseases. Accumulation of harmful blood signals may induce organotypic endothelial dysfunction affecting blood–brain barrier function and vascular health in age-related diseases. Genetic-, age-, lifestyle- or cardiovascular therapy–associated imbalance of amyloid-beta (Aβ) peptide metabolism in the brain and periphery may be the missing link between age-related neurocardiovascular diseases. Genetic polymorphisms of genes related to Aβ metabolism, lifestyle modifications, drugs used in clinical practice, and Aβ-specific treatments may modulate Aβ levels, affecting brain, vascular, and cardiac diseases. This narrative review elaborates on the effects of interventions on Aβ metabolism in the brain, cerebrospinal fluid, blood, and peripheral heart or vascular tissues. Implications for clinical applicability, gaps in knowledge, and future perspectives of Aβ as the link among age-related neurocardiovascular diseases are also discussed. [ABSTRACT FROM AUTHOR]

Sex and apolipoprotein E (APOE) genotype have been shown to influence the risk and progression of Alzheimer's disease (AD). However, the impact of these factors on the functional connectivity of the entorhinal cortex (ERC) in clinically unpaired older adults (CUOA) with amyloid-β (Aβ +) pathology remains unclear. A total of 1022 cognitively normal older adults with Aβ + (603 females and 586 APOE ε4 +) from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) study were included in this study. The 2 × 2 (gender, 2 APOE genotypes) analysis of covariance was performed to compare the demographic information, cognitive performance, and volumetric MRI data among these groups. Voxel-wise comparisons of bilateral ERC functional connectivity (FC) were conducted, and partial correlation analyses were used to explore the associations between cognitive performance and ERC-FC strength. We found that the APOE genotype influenced ERC functional connectivity mainly in the sensorimotor network (SMN). Males exhibited higher ERC-FC in the salience network (SN), while females displayed higher ERC-FC in the default mode network (DMN), executive control network (ECN), and reward network. The interplay of sex and APOE genotype on ERC-FC was observed in the SMN and cerebellar lobe. The ERC-FC was associated with executive function and memory performance in individuals with CUOA-Aβ +. Our findings provide evidence of sex-specific ERC functional connectivity compensation mechanism in cognitively normal older adults with Aβ + pathology. This study may contribute to a better understanding of the mechanisms underlying the early stages of AD and may help develop personalized interventions in preclinical AD. [ABSTRACT FROM AUTHOR]

Neurodegeneration, which manifests as several chronic and incurable diseases, is an age-related condition that affects the central nervous system (CNS) and poses a significant threat to the public's health for the elderly. Recent decades have experienced an alarming increase in the incidence of neurodegenerative disorders (NDDs), a severe public health issue due to the ongoing development of people living in modern civilizations. Alzheimer's disease (AD) is a leading trigger of age-related dementia. Currently, there are no efficient therapeutics to delay, stop, or reverse the disease's course development. Several studies found that dietary bioactive phytochemicals, primarily flavonoids, influence the pathophysiological processes underlying AD. Flavonoids work well as a supplement to manufactured therapies for NDDs. Flavonoids are effective in complementing synthetic approaches to treat NDDs. They are biologically active phytochemicals with promising pharmacological activities, for instance, antiviral, anti-allergic, antiplatelet, anti-inflammatory, antitumor, anti-apoptotic, and antioxidant effects. The production of nitric oxide (NO), tumor necrosis factor (TNF-α), and oxidative stress (OS) are downregulated by flavonoids, which slow the course of AD. Hence, this research turned from preclinical evidence to feasible clinical applications to develop newer therapeutics, focusing on the therapeutic potential of flavonoids against AD. [ABSTRACT FROM AUTHOR]

The number of patients with Alzheimer's disease (AD) is expected to increase as the population ages. The amyloid cascade hypothesis is proposed as the pathogenic mechanism of AD. We report the isolation and structural determination of three new p-terphenyl compounds, thelephantin P (1), thelephantin Q (2), and thelephantin R (3), with four known compounds (4–7), from the fruiting bodies of Thelephora aurantiotincta Corner. We evaluated Aβ aggregation and BACE1 inhibitory activities and neuroprotective activities of these isolated compounds. Compound 1 was shown to be multi-inhibitors for AD. Compound 1 had an IC50 = 12.9 μM (Aβ), 6.3 μM (BACE1), and EC50 = 8.0 μM (neuroprotection), respectively. Therefore, these compounds are potential therapeutic agents for AD. [ABSTRACT FROM AUTHOR]

Background: Although separate lines of research indicated a moderating role of sex in both sleep-wake disruption and in the interindividual vulnerability to Alzheimer's disease (AD)-related processes, the quantification of sex differences in the interplay between sleep-wake dysregulation and AD pathology remains critically overlooked. Here, we examined sex-specific associations between circadian rest-activity patterns and AD-related pathophysiological processes across the adult lifespan. Methods: Ninety-two cognitively unimpaired adults (mean age = 59.85 ± 13.77 years, range = 30–85, 47 females) underwent 10 days of actigraphic recordings, and blood drawing. Standard non-parametric indices of 24-h rest-activity rhythm fragmentation (intradaily variability, IV) and stability (interdaily stability, IS) were extracted from actigraphy data using the GGIR package. Plasma concentrations of neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), amyloid-β42/40 (Aβ42/40), total tau, and tau phosphorylated at threonine 181 (p-tau181) or threonine 231 (p-tau231) were measured using Single molecule array technology. Multiple linear regression models were adjusted for age, sex, education, body mass index, and actigraphic recording duration. Results: Higher IV, indicating worse 24-h rest-activity rhythm fragmentation, was associated with elevated levels of plasma NfL (t(85) = 4.26, P < 0.0001), GFAP (t(85) = 2.49, P = 0.01), and at trend level with lower Aβ42/40 ratio values (t(85) = -1.95, P = 0.054). Lower IS, reflecting less day-to-day stability in the 24-h rest-activity rhythm, was linked to elevated levels of plasma NfL (t(85) = -2.24, P = 0.03), but not with the other plasma biomarkers. Importantly, interaction models demonstrated that male participants were driving the observed relationships between IV and plasma NfL (t(84) = 4.05, P < 0.001) or GFAP (t(84) = 3.60, P < 0.001), but also revealed a male vulnerability in models testing interactions with p-tau181 (IV: t(76) = 3.71, P < 0.001; IS: t(76) = -3.30, P = 0.001) and p-tau231 (IV: t(82) = 3.28, P = 0.002). Sensitivity analyses further showed that accounting for potential confounding factors such as APOE genotype, depression, and self-reported symptoms of possible sleep apnea did not modify the observed relationships. Conclusions: These findings suggest that the association between disrupted circadian rest-activity patterns and AD pathophysiological processes may be more evident in cognitively unimpaired males. Our results contribute to the precision medicine approach, and they have clinical implications for improved early detection and selection of at-risk individuals to be enrolled in preventive interventions. [ABSTRACT FROM AUTHOR]

Introduction: The differentiation between Alzheimer's disease (AD) and behavioral-variant frontotemporal dementia (bvFTD) can be complicated in the initial phase by shared symptoms and pathophysiological traits. Nevertheless, advancements in understanding AD's diverse pathobiology suggest the potential for establishing blood-based methods for differential diagnosis. Methods: We devised a novel assay combining immunoprecipitation and mass spectrometry (IP-MS) to quantify Amyloid-beta (Aβ) peptides in plasma. We then assessed its performance against existing assays (Shimadzu and Simoa) and evaluated a range of other blood-based biomarkers, including GFAP, NfL, and pTau-181, for differentiating between AD and bvFTD. Results: The novel IP-MS assay measuring the Aβ42/40 ratio demonstrated an AUC of 0.82 for differentiating AD from control subjects. While it did not significantly outperform the composite biomarker score from the Shimadzu assay (AUC = 0.79, P = 0.67), it significantly outperformed the Shimadzu Aβ42/40 ratio (AUC = 0.65, P = 0.037) and the Simoa Aβ42/40 assay (AUC = 0.57, P = 0.023). Aβ biomarkers provided limited utility in distinguishing AD from bvFTD. In contrast, pTau181 and GFAP exhibited strong discriminatory power for differentiating AD from bvFTD, with AUCs of 0.90 and 0.87, respectively. Combining pTau181 and GFAP enhanced diagnostic accuracy, achieving an AUC of 0.94. Conclusion: We introduced a novel IP-MS assay that demonstrated comparable precision to the Shimadzu composite score in differentiating AD from non-neurodegenerative control groups. However, Aβ levels did not enhance the discrimination between AD and bvFTD. Furthermore, our findings support the utility of combining pTau181 and GFAP as a robust strategy for the blood-based differentiation of AD and bvFTD. [ABSTRACT FROM AUTHOR]

Background Aim Materials and methods Results Discussion Conclusion Although some studies suggest that sleep deprivation may affect ejaculation regulation, related research is limited, and the mechanisms remain unclear.This study aimed to explore whether sleep deprivation influences ejaculation regulation through amyloid‐beta and to investigate its potential mechanisms.Normal ejaculating rats were randomly distributed into three separate groups for the study, and treated with sleep deprivation combined with saline gavage, sleep deprivation combined with sodium butyrate gavage, and control with saline gavage. The levels of amyloid‐beta and 5‐HT1A receptors were assessed through Western blotting, PCR, and immunohistochemical techniques. The levels of interleukin‐4 and serotonin (5‐hydroxytryptamine) in the brain were determined by enzyme‐linked immunosorbent assay.The experiment showed that the rats in the sleep deprivation combined with saline gavage group rats had a significantly faster ejaculation compared to the control combined with saline gavage group rats. Meanwhile, sleep deprivation combined with saline gavage group had the highest levels of amyloid‐beta oligomers in the brain tissue. Correlation results revealed that the levels of amyloid‐beta oligomers in brain tissue were inversely related to ejaculation latency and positively associated with ejaculation frequency. Furthermore, we found that elevated levels of amyloid‐beta oligomers in brain tissue led to upregulation of 5‐HT1A receptor expression. Additionally, elevated levels of amyloid‐beta oligomers in brain tissue were found to increase interleukin‐4 levels, thereby reducing 5‐hydroxytryptamine levels.Sleep deprivation indeed accelerates ejaculation, and this acceleration is closely related to amyloid‐beta. Sleep deprivation can increase amyloid‐beta levels in brain tissue, mediating a decrease in 5‐hydroxytryptamine levels and overexpression of 5‐HT1A receptors, thereby accelerating ejaculation.There is a significant correlation between elevated amyloid‐beta levels in brain tissue because of sleep deprivation and accelerated ejaculation. This study's main findings offer insights into the development of acquired premature ejaculation linked to poor sleep and establish a theoretical framework for investigating potential treatments for this condition. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) and Parkinson's disease (PD) are leading neurodegenerative disorders marked by protein aggregation, with AD featuring amyloid-beta (Aβ) and tau proteins, and PD alpha-synuclein (αSyn). Dementia with Lewy bodies (DLB) often presents with a mix of these pathologies. This study explores naturally occurring autoantibodies (nAbs), including Immunoglobulin (Ig)G, IgM, and IgA, which target αSyn, Aβ and tau to maintain homeostasis and were previously found altered in AD and PD patients, among others. Main text: We extended this investigation across AD, PD and DLB patients investigating both the affinities of IgGs and levels of IgGs, IgMs and IgAs towards αSyn, Aβ and tau utilizing chemiluminescence assays. We confirmed that AD and PD patients exhibited lower levels of high-affinity anti-Aβ and anti-αSyn IgGs, respectively, than healthy controls. AD patients also showed diminished levels of high-affinity anti-αSyn IgGs, while anti-tau IgG affinities did not differ significantly across groups. However, DLB patients exhibited increased anti-αSyn IgG but decreased anti-αSyn IgM levels compared to controls and PD patients, with AD patients showing a similar pattern. Interestingly, AD patients had higher anti-Aβ IgG but lower anti-Aβ IgA levels than DLB patients. DLB patients had reduced anti-Aβ IgM levels compared to controls, and anti-tau IgG levels were lower in AD than PD patients, who had reduced anti-tau IgM levels compared to controls. AD patients uniquely showed higher anti-tau IgA levels. Significant correlations were observed between clinical measures and nAbs, with negative correlations between anti-αSyn IgG affinity and levels in DLB patients and a positive correlation with anti-αSyn IgA levels in PD patients. Disease-specific changes in nAb levels and affinity correlations were identified, highlighting altered immune responses. Conclusion: This study reveals distinctive nAb profiles in AD, DLB, and PD, pinpointing specific immune deficiencies against pathological proteins. These insights into the autoreactive immune system's role in neurodegeneration suggest nAbs as potential markers for vulnerability to protein aggregation, offering new avenues for understanding and possibly diagnosing these conditions. [ABSTRACT FROM AUTHOR]

Most cases of dementia with Lewy bodies (DLB) follow a chronic course. However, some cases of rapidly progressive dementia (RPD) are difficult to distinguish from other diseases. Herein, we report how to differentiate DLB presenting with RPD from other diseases and its pathological features, with examples from our own experience. A 70‐year‐old man with RPD and psychiatric symptoms, including hallucinations and delusions, was transferred to our hospital. We suspected Creutzfeldt–Jakob disease (CJD), but disease‐specific tests were all negative. The patient was treated with corticosteroids on the suspicion of an autoimmune condition; however, his symptoms did not improve. Based on the results of nuclear medicine and other tests, we suspected DLB and administered anti‐Parkinsonian drugs; however, they were ineffective, and the patient died. Brain autopsy revealed extensive deposits of Lewy bodies, which were pathologically diagnosed as DLB. Additionally, extensive deposition of senile plaques was observed; however, neurofibrillary tangles (NFTs) were not prominent. DLB generally presents as a chronic disease. However, some patients with DLB present with RPD; therefore, the differential diagnosis of other diseases, such as CJD, is very important. In addition, although this case was not diagnosed with Alzheimer's disease (AD) due to the lack of NFTs, extensive amyloid deposition was observed in the brain tissue. Previous reports have described cases of RPD with amyloid deposition alone, and in this case too, it is suggested that amyloid deposition might have had a strong influence on the clinical course of RPD. [ABSTRACT FROM AUTHOR]

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. • The plasma Aβ42/38 ratio is a biomarker of early memory deficits in older adults. • The Aβ42/38 ratio is not associated with brain amyloid burden. • Correlations between the Aβ42/38 ratio and memory is independent of amyloid plaques. • The Aβ38 fragment may be protective against AD pathology. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD), which is characterized by deterioration in cognitive function and neuronal death, is the most prevalent age-related progressive neurodegenerative disease. Clinical and experimental research has revealed that gut microbiota dysbiosis may be present in AD patients. The changed gut microbiota affects brain function and behavior through several mechanisms, including tau phosphorylation and increased amyloid deposits, neuroinflammation, metabolic abnormalities, and persistent oxidative stress. The lack of effective treatments to halt or reverse the progression of this disease has prompted a search for non-pharmaceutical tools. Modulation of the gut microbiota may be a promising strategy in this regard. This review aims to determine whether specific dietary interventions, particularly antioxidant vitamins, either obtained from the diet or as supplements, may support the formation of beneficial microbiota in order to prevent AD development by contributing to the systemic reduction of chronic inflammation or by acting locally in the gut. Understanding their roles would be beneficial as it may have the potential to be used as a future therapy option for AD patients. [ABSTRACT FROM AUTHOR]

Abstract The U1 snRNP complex recognizes pre-mRNA splicing sites in the early stages of spliceosome assembly and suppresses premature cleavage and polyadenylation. Its dysfunction may precede Alzheimer’s disease (AD) hallmarks. Here we evaluated the effects of a synthetic single-stranded cDNA (APT20TTMG) that interacts with U1 snRNP, in iPSC-derived neurons from a donor diagnosed with AD and in the SAMP8 mouse model. APT20TTMG effectively binds to U1 snRNP, specifically decreasing TAU in AD neurons, without changing mitochondrial activity or glutamate. Treatment enhanced neuronal electrical activity, promoted an enrichment of differentially expressed genes related to key processes affected by AD. In SAMP8 mice, APT20TTMG reduced insoluble pTAU in the hippocampus, amyloid-beta and GFAP in the cortex, and U1-70 K in both brain regions, without cognitive changes. This study highlights the correction of the U1 snRNP complex as a new target for AD.

The relative amount of AMPA receptors expressed at the surface of neurons can be measured using superecliptic pHluorin (SEP) labeling at their N-terminus. However, the high signal variability resulting from protein overexpression in neurons and the low signal observed in intracellular vesicles make quantitative characterization of receptor trafficking difficult. Here, we establish a real-time live-cell assay of AMPAR trafficking based on fluorescence lifetime imaging (FLIM), which allows for simultaneous visualization of both surface and intracellular receptors. Using this assay, we found that elevating amyloid-beta (Aβ) levels leads to a strong increase in intracellular GluA1 and GluA2-containing receptors, indicating that Aβ triggers the endocytosis of these AMPARs. In APP/PS1 Alzheimer's disease model mouse neurons, FLIM revealed strikingly different AMPAR trafficking properties for GluA1- and GluA3-containing receptors, suggesting that chronic Aβ exposure triggered the loss of both surface and intracellular GluA3-containing receptors. Interestingly, overexpression of protein phosphatase 1 (PP1) also resulted in GluA1 endocytosis as well as depressed synaptic transmission, confirming the important role of phosphorylation in regulating AMPAR trafficking. This new approach allows for the quantitative measurement of extracellular pH, small changes in receptor trafficking, as well as simultaneous measurement of surface and internalized AMPARs in living neurons, and could therefore be applied to several different studies in the future.

Abstract Background Phosphorylated tau (p-tau) and amyloid beta (Aβ) in human plasma may provide an affordable and minimally invasive method to evaluate Alzheimer’s disease (AD) pathophysiology. The medial temporal lobe (MTL) is susceptible to changes in structural integrity that are indicative of the disease progression. Among healthy adults, higher dynamic network flexibility within the MTL was shown to mediate better generalization of prior learning, a measure which has been demonstrated to predict cognitive decline and neural changes in preclinical AD longitudinally. Recent developments in cognitive, neural, and blood-based biomarkers of AD risk that may correspond with MTL changes. However, there is no comprehensive study on how these generalization biomarkers, long-term memory, MTL dynamic network flexibility, and plasma biomarkers are interrelated. This study investigated (1) the relationship between long-term memory, generalization performance, and MTL dynamic network flexibility and (2) how plasma p-tau231, p-tau181, and Aβ42/Aβ40 influence generalization, long-term memory, and MTL dynamics in cognitively unimpaired older African Americans. Methods 148 participants (Mean age : 70.88,SD age : 6.05) were drawn from the ongoing longitudinal study, Pathways to Healthy Aging in African Americans conducted at Rutgers University–Newark. Cognition was evaluated with the Rutgers Acquired Equivalence Task (generalization task) and Rey Auditory Learning Test (RAVLT) delayed recall. MTL dynamic network connectivity was measured from functional Magnetic Resonance Imaging data. Plasma p-tau231, p-tau181, and Aβ42/Aβ40 were measured from blood samples. Results There was a significant positive correlation between generalization performance and MTL Dynamic Network Flexibility (t = 3.372, β = 0.280, p

Alzheimer’s disease (AD) is the most prevalent type of dementia; therefore, there is a high demand for therapeutic medication targeting it. In this context, extensive research has been conducted to identify molecular targets for drugs. AD manifests through two primary pathological signs: senile plaques and neurofibrillary tangles, caused by accumulations of amyloid-beta (Aβ) and phosphorylated tau, respectively. Thus, studies concerning the molecular mechanisms underlying AD etiology have primarily focused on Aβ generation and tau phosphorylation, with the anticipation of uncovering a signaling pathway impacting these molecular processes. Over the past two decades, studies using not only experimental model systems but also examining human brains have accumulated fragmentary evidences suggesting that REELIN signaling pathway is deeply involved in AD. Here, we explore REELIN signaling pathway and its involvement in memory function within the brain and review studies investigating molecular connections between REELIN signaling pathway and AD etiology. This review aims to understand how the manipulation (activation) of this pathway might ameliorate the disease’s etiology.

Abstract Background The medial temporal lobe (MTL) is hypothesized to be relatively spared in early-onset Alzheimer’s disease (EOAD). Yet, detailed examination of MTL subfields and drivers of atrophy in amnestic EOAD is lacking. Methods BioFINDER-2 participants with memory impairment, abnormal amyloid-β and tau-PET were included. Forty-one amnestic EOAD individuals ≤65 years and, as comparison, late-onset AD (aLOAD, ≥70 years, n = 154) and amyloid-β-negative cognitively unimpaired controls were included. MTL subregions and biomarkers of (co-)pathologies were measured. Results AD groups showed smaller MTL subregions compared to controls. Atrophy patterns were similar across AD groups: aLOAD showed thinner entorhinal cortices than aEOAD; aEOAD showed thinner parietal regions than aLOAD. aEOAD showed lower white matter hyperintensities than aLOAD. No differences in MTL tau-PET or transactive response DNA binding protein 43-proxy positivity were found. Conclusions We found evidence for MTL atrophy in amnestic EOAD and overall similar levels to aLOAD of MTL tau pathology and co-pathologies.

Background: Phosphorylated tau (p-tau) and amyloid beta (Aβ) in human plasma may provide an affordable and minimally invasive method to evaluate Alzheimer's disease (AD) pathophysiology. The medial temporal lobe (MTL) is susceptible to changes in structural integrity that are indicative of the disease progression. Among healthy adults, higher dynamic network flexibility within the MTL was shown to mediate better generalization of prior learning, a measure which has been demonstrated to predict cognitive decline and neural changes in preclinical AD longitudinally. Recent developments in cognitive, neural, and blood-based biomarkers of AD risk that may correspond with MTL changes. However, there is no comprehensive study on how these generalization biomarkers, long-term memory, MTL dynamic network flexibility, and plasma biomarkers are interrelated. This study investigated (1) the relationship between long-term memory, generalization performance, and MTL dynamic network flexibility and (2) how plasma p-tau231, p-tau181, and Aβ42/Aβ40 influence generalization, long-term memory, and MTL dynamics in cognitively unimpaired older African Americans. Methods: 148 participants (Meanage: 70.88,SDage: 6.05) were drawn from the ongoing longitudinal study, Pathways to Healthy Aging in African Americans conducted at Rutgers University–Newark. Cognition was evaluated with the Rutgers Acquired Equivalence Task (generalization task) and Rey Auditory Learning Test (RAVLT) delayed recall. MTL dynamic network connectivity was measured from functional Magnetic Resonance Imaging data. Plasma p-tau231, p-tau181, and Aβ42/Aβ40 were measured from blood samples. Results: There was a significant positive correlation between generalization performance and MTL Dynamic Network Flexibility (t = 3.372, β = 0.280, p < 0.001). There were significant negative correlations between generalization performance and plasma p-tau231 (t = -3.324, β = -0.265, p = 0.001) and p-tau181 (t = -2.408, β = -0.192, p = 0.017). A significant negative correlation was found between plasma p-tau231 and MTL Dynamic Network Flexibility (t = -2.825, β = -0.232, p = 0.005). Conclusions: Increased levels of p-tau231 are associated with impaired generalization abilities and reduced dynamic network flexibility within the MTL. Plasma p-tau231 may serve as a potential biomarker for assessing cognitive decline and neural changes in cognitively unimpaired older African Americans. [ABSTRACT FROM AUTHOR]

Introduction: AD is a progressive neurodegenerative disorder causing significant cognitive decline and impaired daily functioning. Current treatments offer only modest relief, and many amyloid-targeting therapies have failed, prompting exploration of alternative approaches such as PE with albumin replacement. Objectives: This scoping review systematically maps the literature on PE with albumin replacement in AD management, focusing on outcomes, methodologies, and reported benefits and risks. Methods: A comprehensive search in PubMed, supplemented by reference scanning and hand-searching, identified studies involving PE with albumin replacement in AD patients. Data charting and critical appraisal were conducted using standardized tools. Results: Seven primary studies from the AMBAR (Alzheimer Management by Albumin Replacement) trial met the inclusion criteria, consistently reporting improvements in cognitive function, positive neuroimaging results, and favorable neuropsychiatric outcomes. For instance, one study found a significant slowing of cognitive decline (p < 0.05) among patients receiving PE with albumin replacement. Another study showed better preservation of hippocampal volume and improved brain perfusion metrics in the treatment group (p < 0.05). The intervention was generally well-tolerated with manageable side effects. Conclusion: PE with albumin replacement is a promising therapeutic approach for AD, warranting further investigation to confirm its efficacy and safety across broader settings. Scoping review registration: https://osf.io/v6dez/?view_only=1cd9637e7e0347d39713bf19aac0dfe8. [ABSTRACT FROM AUTHOR]

Purpose: There is an unmet need for compounds to detect fibrillar forms of alpha-synuclein (αSyn) and 4-repeat tau, which are critical in many neurodegenerative diseases. Here, we aim to develop an efficient surface plasmon resonance (SPR)-based assay to facilitate the characterization of small molecules that can bind these fibrils. Methods: SPR measurements were conducted to characterize the binding properties of fluorescent ligands/compounds toward recombinant amyloid-beta (Aβ)42, K18-tau, full-length 2N4R-tau and αSyn fibrils. In silico modeling was performed to examine the binding pockets of ligands on αSyn fibrils. Immunofluorescence staining of postmortem brain tissue slices from Parkinson's disease patients and mouse models was performed with fluorescence ligands and specific antibodies. Results: We optimized the protocol for the immobilization of Aβ42, K18-tau, full-length 2N4R-tau and αSyn fibrils in a controlled aggregation state on SPR-sensor chips and for assessing their binding to ligands. The SPR results from the analysis of binding kinetics suggested the presence of at least two binding sites for all fibrils, including luminescent conjugated oligothiophenes, benzothiazole derivatives, nonfluorescent methylene blue and lansoprazole. In silico modeling studies for αSyn (6H6B) revealed four binding sites with a preference for one site on the surface. Immunofluorescence staining validated the detection of pS129-αSyn positivity in the brains of Parkinson's disease patients and αSyn preformed-fibril injected mice, 6E10-positive Aβ in arcAβ mice, and AT-8/AT-100-positivity in pR5 mice. Conclusion: SPR measurements of small molecules binding to Aβ42, K18/full-length 2N4R-tau and αSyn fibrils suggested the existence of multiple binding sites. This approach may provide efficient characterization of compounds for neurodegenerative disease-relevant proteinopathies. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a devastating kind of dementia that is becoming more common worldwide. Toxic amyloid-beta (Aβ) aggregates are the primary cause of AD onset and development. Superparamagnetic iron oxide nanoparticles (SPIONs) have received a lot of interest in AD therapy over the last decade because of their ability to redirect the Aβ fibrillation process and improve associated brain dysfunction. The potential diagnostic application of SPIONs in AD has dramatically increased this interest. Furthermore, surface-modified engineered SPIONs function as drug carriers to improve the efficacy of current therapies. Various preclinical and clinical studies on the role of SPIONs in AD pathology have produced encouraging results. However, due to their physicochemical properties (e.g., size, surface charge, and particle concentration) in the biological milieu, SPIONs may play the role of a preventive or accelerative agent in AD. Even though SPIONs are potential therapeutic and diagnostic options in AD, significant efforts are still needed to overcome the inconsistencies and safety concerns. This review evaluated the current understanding of how various SPIONs interact with AD models and explored the discrepancies in their efficacy and safety. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) and its associated pathology have been primarily identified in humans, who have relatively large brains and long lifespans. To expand what is known about aging and neurodegeneration across mammalian species, we characterized amyloid‐beta (Aβ) and tau lesions in five species of aged felids (n = 9; cheetah, clouded leopard, African lion, serval, Siberian tiger). We performed immunohistochemistry to detect Aβ40 and Aβ42 in plaques and vessels and hyperphosphorylated tau in the temporal lobe gyrus sylvius and in the CA1 and CA3 subfields of the hippocampus. We also quantified the densities and morphological types of microglia expressing IBA1. We found that diffuse Aβ42 plaques, but not dense‐core plaques, were present more frequently in the temporal cortex and tended to be more common than Aβ40 plaques across species. Conversely, vascular Aβ was labeled more consistently with Aβ40 for each species on average. Although all individuals showed some degree of Aβ40 and/or Aβ42 immunoreactivity, only the cheetahs and clouded leopards exhibited intraneuronal hyperphosphorylated tau (i.e., pretangles), which was more common in the hippocampus. Reactive, intermediate microglia were significantly associated with total Aβ40 vessel area and pretangle load in the hippocampus. This study demonstrates the co‐occurrence of Aβ and tau pathology in two felid species, cheetahs and clouded leopards. Overall, these results provide an initial view of the manifestation of Aβ and tau pathology in aged, large‐brained felids, which can be compared with markers of neurodegeneration across different taxa, including domestic cats, nonhuman primates, and humans. [ABSTRACT FROM AUTHOR]

Introduction: The importance of cerebrospinal fluid (CSF) biomarkers in Alzheimer's disease (AD) diagnosis is rapidly increasing, and there is a growing interest in the use of CSF biomarkers in monitoring the response to therapy, especially in the light of newly available approaches to the therapy of neurodegenerative diseases. Areas covered: In this review we discuss the most relevant measures of neurodegeneration that are being used to distinguish patients with AD from healthy controls and individuals with mild cognitive impairment, in order to provide an overview of the latest information available in the scientific literature. We focus on markers related to amyloid processing, markers associated with neurofibrillary tangles, neuroinflammation, neuroaxonal injury and degeneration, synaptic loss and dysfunction, and markers of α-synuclein pathology. Expert opinion: In addition to neuropsychological evaluation, core CSF biomarkers (Aβ42, t-tau, and p-tau181) have been recommended for improvement of timely, accurate and differential diagnosis of AD, as well as to assess the risk and rate of disease progression. In addition to the core CSF biomarkers, various other markers related to synaptic dysfunction, neuroinflammation, and glial activation (neurogranin, SNAP-25, Nfl, YKL-40, TREM2) are now investigated and have yet to be validated for future potential clinical use in AD diagnosis. [ABSTRACT FROM AUTHOR]

Background: Oxidative stress and chronic inflammation, at both the systemic and the central level, are critical early events in atherosclerosis and Alzheimer's disease (AD). Purpose: To investigate the oxidative stress-, inflammation-, and Tau-phosphorylation-lowering effects of pomegranate polyphenols (PPs) (punicalagin, ellagic acid, peel, and aril extracts). Methods: We used flow cytometry to quantify the protein expression of proinflammatory cytokines (IL-1β) and anti-inflammatory mediators (IL-10) in THP-1 macrophages, as well as M1/M2 cell-specific marker (CD86 and CD163) expression in human microglia HMC3 cells. The IL-10 protein expression was also quantified in U373-MG human astrocytes. The effect of PPs on human amyloid beta 1-42 (Aβ1-42)-induced oxidative stress was assessed in the microglia by measuring ROS generation and lipid peroxidation, using 2′,7′-dichlorofluorescein diacetate (DCFH-DA) and thiobarbituric acid reactive substance (TBARS) tests, respectively. Neuronal viability and cell apoptotic response to Aβ1-42 toxicity were assayed using the MTT (3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide) assay and the annexin-V-FITC apoptosis detection kit, respectively. Finally, flow cytometry analysis was also performed to evaluate the ability of PPs to modulate Aβ1-42-induced Tau-181 phosphorylation (pTau-181). Results: Our data indicate that PPs are significantly (p < 0.05) effective in countering Aβ1-42-induced inflammation through increasing the anti-inflammatory cytokines (IL-10) in U373-MG astrocytes and THP1 macrophages and decreasing proinflammatory marker (IL-1β) expression in THP1 macrophages. The PPs were also significantly (p < 0.05) effective in inducing the phenotypic transition of THP-1 macrophages and microglial cells from M1 to M2 by decreasing CD86 and increasing CD163 surface receptor expression. Moreover, our treatments have a significant (p < 0.05) beneficial impact on oxidative stress, illustrated in the reduction in TBARS and ROS generation. Our treatments have significant (p < 0.05) cell viability improvement capacities and anti-apoptotic effects on human H4 neurons. Furthermore, our results suggest that Aβ1-42 significantly (p < 0.05) increases pTau-181. This effect is significantly (p < 0.05) attenuated by arils, peels, and punicalagin and drastically reduced by the ellagic acid treatment. Conclusion: Overall, our results attribute to PPs anti-inflammatory, antioxidant, anti-apoptotic, and anti-Tau-pathology potential. Future studies should aim to extend our knowledge of the potential role of PPs in Aβ1-42-induced neurodegeneration, particularly concerning its association with the tauopathy involved in AD. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is characterized by complex interactions between neuropathological markers, metabolic dysregulation, and structural brain changes. In this study, we utilized a multimodal approach, combining immunohistochemistry, functional metabolic mapping, and microstructure sensitive diffusion MRI (dMRI) to progressively investigate these interactions in the 5xFAD mouse model of AD. Our analysis revealed age-dependent and region-specific accumulation of key AD markers, including amyloid-beta (Aβ), GFAP, and IBA1, with significant differences observed between the hippocampal formation and upper and lower regions of the cortex by 6 months of age. Functional metabolic mapping validated localized disruptions in energy metabolism, with glucose hypometabolism in the hippocampus and impaired astrocytic metabolism in the cortex. Notably, increased cortical glutaminolysis suggested a shift in microglial metabolism, reflecting an adaptive response to neuroinflammatory processes. While dMRI showed no significant microstructural differences between 5xFAD and wild-type controls, the study highlights the importance of metabolic alterations as critical events in AD pathology. These findings emphasize the need for targeted therapeutic strategies addressing specific metabolic disturbances and underscore the potential of integrating advanced imaging with metabolic and molecular analyses to advance our understanding of AD progression. [ABSTRACT FROM AUTHOR]

Purpose: In the emerging field of antibody treatments for neurodegenerative diseases, reliable tools are needed to evaluate new therapeutics, diagnose and select patients, monitor disease progression, and assess therapy response. Immuno-PET combines the high affinity and exceptional specificity of monoclonal antibodies with the non-invasive imaging technique positron emission tomography (PET). Its application in neurodegenerative disease brain imaging has been limited due to the marginal uptake across the blood–brain barrier (BBB). The emergence of BBB-shuttle antibodies with enhanced uptake across the BBB extended immuno-PET to brain imaging. We recently reported about specific brain uptake of a bispecific aducanumab mTfR antibody in APP/PS1 TG mice using 89Zr-immuno-PET. However, a sufficient target-to-background ratio was reached at a relatively late scanning time point of 7 days post-injection. To investigate if a better target-to-background ratio could be achieved earlier, an aducanumab BBB-shuttle with a mutated Fc region for reduced FcRn affinity was evaluated. Procedures: AduH310A-8D3 and Adu-8D3 were modified with DFO*-NCS and subsequently radiolabeled with 89Zr. The potential influence of the H310A mutation, modification with DFO*-NCS, and subsequent radiolabeling on the in vitro binding to amyloid-beta and mTfR1 was investigated via amyloid-beta peptide ELISA and FACS analysis using mTfR1 transfected CHO-S cells. Blood kinetics, brain uptake, in vivo PET imaging and target engagement of radiolabeled AduH310A-8D3 were evaluated and compared to non-mutated Adu-8D3 in APP/PS1 TG mice and wild-type animals as controls. Results: Radiolabeling was performed with sufficient radiochemical yields and radiochemical purity. In vitro binding to amyloid-beta and mTfR1 showed no impairment. [89Zr]Zr-AduH310A-8D3 showed faster blood clearance and earlier differentiation of amyloid-beta-related brain uptake compared to [89Zr]Zr-Adu-8D3. However, only half of the brain uptake was observed for [89Zr]Zr-AduH310A-8D3. Conclusions: Although a faster blood clearance of AduH310A-8D3 was observed, it was concluded that no beneficial effects for 89Zr-immuno-PET imaging of brain uptake were obtained. [ABSTRACT FROM AUTHOR]

A Nature Medicine paper published in January 2024 describes eight cases of iatrogenic Alzheimer's disease in individuals who received cadaveric pituitary‐derived human growth hormone. The paper's conclusions argue for the transmissibility of Alzheimer's disease, which, if true, would create a significant public health crisis. For example, neurosurgical practices would require substantial revision, and many individuals who have undergone neurosurgical procedures would now be at considerable risk of Alzheimer's disease. A detailed review of the presented cases reveals that they do not have Alzheimer's disease, and there are alternative explanations for the cognitive decline described. In people with progressive cognitive decline, the diagnosis of Alzheimer's disease requires a demonstration of amyloid and tau pathology or amyloid and tau biomarkers. Extensive tau pathology is not demonstrated, and some also lack amyloid beta pathology. The cases described in this paper do not meet the criteria for dementia due to Alzheimer's disease by clinical and pathological standards. Highlights: Creutzfeldt‐Jakob disease has been transmitted by cadaveric growth hormone.There is no evidence for the transmission of Alzheimer's disease by cadaveric growth hormone.There is no evidence that Alzheimer's disease is transmissible. [ABSTRACT FROM AUTHOR]

Reactive astrocytes play an important role in the development of Alzheimer's disease (AD). Here, we aimed to investigate the temporospatial relationships among monoamine oxidase-B, tau and amyloid-β (Aβ), translocator protein, and glucose metabolism by using multitracer imaging in AD transgenic mouse models. Positron emission tomography (PET) imaging with [18F]SMBT-1 (monoamine oxidase-B), [18F]florbetapir (Aβ), [18F]PM-PBB3 (tau), [18F]fluorodeoxyglucose (FDG), and [18F]DPA-714 (translocator protein) was carried out in 5- and 10-month-old APP/PS1, 11-month-old 3×Tg mice, and aged-matched wild-type mice. The brain regional referenced standard uptake value (SUVR) was computed with the cerebellum as the reference region. Immunofluorescence staining was performed on mouse brain tissue slices. [18F]SMBT-1 and [18F]florbetapir SUVRs were greater in the cortex and hippocampus of 10-month-old APP/PS1 mice than in those of 5-month-old APP/PS1 mice and wild-type mice. No significant difference in the regional [18F]FDG or [18F]DPA-714 SUVRs was observed in the brains of 5- or 10-month-old APP/PS1 mice or wild-type mice. No significant difference in the SUVRs of any tracer was observed between 11-month-old 3×Tg mice and age-matched wild-type mice. A positive correlation between the SUVRs of [18F]florbetapir and [18F]DPA-714 in the cortex and hippocampus was observed among the transgenic mice. Immunostaining validated the distribution of MAO-B and limited Aβ and tau pathology in 11-month-old 3×Tg mice; and Aβ deposits in brain tissue from 10-month-old APP/PS1 mice. In summary, these findings provide in vivo evidence that an increase in astrocyte [18F]SMBT-1 accompanies Aβ accumulation in APP/PS1 models of AD amyloidosis. [ABSTRACT FROM AUTHOR]

Background: The medial temporal lobe (MTL) is hypothesized to be relatively spared in early-onset Alzheimer's disease (EOAD). Yet, detailed examination of MTL subfields and drivers of atrophy in amnestic EOAD is lacking. Methods: BioFINDER-2 participants with memory impairment, abnormal amyloid-β and tau-PET were included. Forty-one amnestic EOAD individuals ≤65 years and, as comparison, late-onset AD (aLOAD, ≥70 years, n = 154) and amyloid-β-negative cognitively unimpaired controls were included. MTL subregions and biomarkers of (co-)pathologies were measured. Results: AD groups showed smaller MTL subregions compared to controls. Atrophy patterns were similar across AD groups: aLOAD showed thinner entorhinal cortices than aEOAD; aEOAD showed thinner parietal regions than aLOAD. aEOAD showed lower white matter hyperintensities than aLOAD. No differences in MTL tau-PET or transactive response DNA binding protein 43-proxy positivity were found. Conclusions: We found evidence for MTL atrophy in amnestic EOAD and overall similar levels to aLOAD of MTL tau pathology and co-pathologies. [ABSTRACT FROM AUTHOR]

Background: Down syndrome (DS) is one of the most commonly occurring chromosomal conditions. Most individuals with DS develop Alzheimer's disease (AD) by 50 years of age. Recent evidence suggests that AD pathology in the locus coeruleus (LC) is an early event in sporadic AD. It is likely that the widespread axonal network of LC neurons contributes to the spread of tau pathology in the AD brain, although this has not been investigated in DS-AD. Objective: The main purpose of this study was to profile AD pathology and neuroinflammation in the LC, comparing AD and DS-AD in postmortem human tissues. Methods: We utilized immunofluorescence and semi-quantitative analyses of pTau (4 different forms), amyloid-β (Aβ), glial, and neuronal markers in the LC across 36 cases (control, DS-AD, and AD) to compare the different pathological profiles. Results: Oligomeric tau was highly elevated in DS-AD cases compared to LOAD or EOAD cases. The distribution of staining for pT231 was elevated in DS-AD and EOAD compared to the LOAD group. The DS-AD group exhibited increased Aβ immunostaining compared to AD cases. The number of tau-bearing neurons was also significantly different between the EOAD and DS-AD cases compared to the LOAD cases. Conclusions: While inflammation, pTau, and Aβ are all involved in AD pathology, their contribution to disease progression may differ depending on the diagnosis. Our results suggest that DS-AD and EOAD may be more similar in pathology than LOAD. Our study highlights unique avenues to further our understanding of the mechanisms governing AD neuropathology. [ABSTRACT FROM AUTHOR]

The elimination of amyloid‐beta (Aβ) plaques in Alzheimer's disease patients after treatment with anti‐Aβ antibodies such as lecanemab and aducanumab is supported by a substantially decreased signal in amyloid positron emission tomography (PET) imaging. However, this decreased PET signal has not been matched by a similar substantial effect on cognitive function. There may be several reasons for this, including short treatment duration and advanced disease stages among the patients. However, one aspect that has not been investigated, and the subject of this study, is whether antibody engagement with amyloid plaques inhibits the binding of amyloid‐PET ligands, leading to a false impression of Aβ removal from the brain. In the present study, tg‐ArcSwe mice received three injections of RmAb158, the murine version of lecanemab or phosphate‐buffered saline (PBS) before the administration of the amyloid‐PET radioligand [11C]PiB, followed by isolation of brain tissue. Autoradiography showed that RmAb158‐ and PBS‐treated mice displayed similar [11C]PiB binding. Moreover, the total Aβ1–40 levels, representing the major Aβ species of plaques in the tg‐ArcSwe model, as well as soluble triggering receptor on myeloid cells 2 (sTREM2) levels, were similar in both groups. Interestingly, the concentration of soluble Aβ aggregates was decreased in the RmAb158‐treated group, along with a small but significant decrease in the total Aβ1–42 levels. In conclusion, this study indicates that the binding of [11C]PiB to Aβ accurately mirrors the load of Aβ plaques in the brain, aligning with how amyloid‐PET is interpreted in clinical studies of anti‐Aβ antibodies. However, early treatment effects on soluble Aβ aggregates and Aβ1–42 levels were not detected. [ABSTRACT FROM AUTHOR]