Highly BBB-permeable nanomedicine reverses neuroapoptosis and neuroinflammation to treat Alzheimer's disease.

The prevalence of Alzheimer's disease (AD) is increasing globally due to population aging. However, effective clinical treatment strategies for AD still remain elusive. The mechanisms underlying AD onset and the interplay between its pathological factors have so far been unclear. Evidence indicates that AD progression is ultimately driven by neuronal loss, which in turn is caused by neuroapoptosis and neuroinflammation. Therefore, the inhibition of neuroapoptosis and neuroinflammation could be a useful anti-AD strategy. Nonetheless, the delivery of active drug agents into the brain parenchyma is hindered by the blood-brain barrier (BBB). To address this challenge, we fabricated a black phosphorus nanosheet (BP)-based methylene blue (MB) delivery system (BP-MB) for AD therapy. After confirming the successful preparation of BP-MB, we proved that its BBB-crossing ability was enhanced under near-infrared light irradiation. In vitro pharmacodynamics analysis revealed that BP and MB could synergistically scavenge excessive reactive oxygen species (ROS) in okadaic acid (OA)-treated PC12 cells and lipopolysaccharide (LPS)-treated BV2 cells, thus efficiently reversing neuroapoptosis and neuroinflammation. To study in vivo pharmacodynamics, we established a mouse model of AD mice, and behavioral tests confirmed that BP-MB treatment could successfully improve cognitive function in these animals. Notably, the results of pathological evaluation were consistent with those of the in vitro assays. The findings demonstrated that BP-MB could scavenge excessive ROS and inhibit Tau hyperphosphorylation, thereby alleviating downstream neuroapoptosis and regulating the polarization of microglia from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype. Overall, this study highlights the therapeutic potential of a smart nanomedicine with the capability of reversing neuroapoptosis and neuroinflammation for AD treatment.

Gut microbiota metabolites: potential therapeutic targets for Alzheimer's disease?

Background: Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive decline in cognitive function, which significantly increases pain and social burden. However, few therapeutic interventions are effective in preventing or mitigating the progression of AD. An increasing number of recent studies support the hypothesis that the gut microbiome and its metabolites may be associated with upstream regulators of AD pathology. Methods: In this review, we comprehensively explore the potential mechanisms and currently available interventions targeting the microbiome for the improvement of AD. Our discussion is structured around modern research advancements in AD, the bidirectional communication between the gut and brain, the multi-target regulatory effects of microbial metabolites on AD, and therapeutic strategies aimed at modulating gut microbiota to manage AD. Results: The gut microbiota plays a crucial role in the pathogenesis of AD through continuous bidirectional communication via the microbiota-gut-brain axis. Among these, microbial metabolites such as lipids, amino acids, bile acids and neurotransmitters, especially sphingolipids and phospholipids, may serve as central components of the gut-brain axis, regulating AD-related pathogenic mechanisms including ß-amyloid metabolism, Tau protein phosphorylation, and neuroinflammation. Additionally, interventions such as probiotic administration, fecal microbiota transplantation, and antibiotic use have also provided evidence supporting the association between gut microbiota and AD. At the same time, we propose an innovative strategy for treating AD: a healthy lifestyle combined with targeted probiotics and other potential therapeutic interventions, aiming to restore intestinal ecology and microbiota balance. Conclusion: Despite previous efforts, the molecular mechanisms by which gut microbes act on AD have yet to be fully described. However, intestinal microorganisms may become an essential target for connecting the gut-brain axis and improving the symptoms of AD. At the same time, it requires joint exploration by multiple centers and multiple disciplines.

Widespread transposable element dysregulation in human aging brains with Alzheimer's disease.

INTRODUCTION: Transposable element (TE) dysregulation is associated with neuroinflammation in Alzheimer's disease (AD) brains. Yet, TE quantitative trait loci (teQTL) have not been well characterized in human aged brains with AD. METHODS: We leveraged large-scale bulk and single-cell RNA sequencing, whole-genome sequencing (WGS), and xQTL from three human AD brain biobanks to characterize TE expression dysregulation and experimentally validate AD-associated TEs using CRISPR interference (CRISPRi) assays in human induced pluripotent stem cell (iPSC)-derived neurons. RESULTS: We identified 26,188 genome-wide significant TE expression QTLs (teQTLs) in human aged brains. Subsequent colocalization analysis of teQTLs with AD genetic loci identified AD-associated teQTLs and linked locus TEs. Using CRISPRi assays, we pinpointed a neuron-specific suppressive role of the activated short interspersed nuclear element (SINE; chr11:47608036-47608220) on expression of C1QTNF4 via reducing neuroinflammation in human iPSC-derived neurons. DISCUSSION: We identified widespread TE dysregulation in human AD brains and teQTLs offer a complementary analytic approach to identify likely AD risk genes. HIGHLIGHTS: Widespread transposable element (TE) dysregulations are observed in human aging brains with degrees of neuropathology, apolipoprotein E (APOE) genotypes, and neuroinflammation in Alzheimer's disease (AD). A catalog of TE quantitative trait loci (teQTLs) in human aging brains was created using matched RNA sequencing and whole-genome sequencing data. CRISPR interference assays reveal that an upregulated intergenic TE from the MIR family (chr11: 47608036-47608220) suppresses expression of its nearest anti-inflammatory gene C1QTNF4 in human induced pluripotent stem cell-derived neurons.

Plasmonic Nanogap-Enhanced Tunable Three-Dimensional Nanoframes in Application to Clinical Diagnosis of Alzheimer's Disease.

Advancements in nanotechnology led to significant improvements in synthesizing plasmon-enhanced nanoarchitectures for biosensor applications, and high-yield productivity at low cost is vital to step further into medical commerce. Metal nanoframes via wet chemistry are gaining attention for their homogeneous structure and outstanding catalytic and optical properties. However, nanoframe morphology should be considered delicately when brought to biosensors to utilize its superior characteristics thoroughly, and the need to prove its clinical applicability still remains. Herein, we controlled the frameworks of double-walled nanoframes (DWFs) precisely via wet chemistry to construct a homogeneous plasmon-enhanced nanotransducer for localized surface plasmon resonance biosensors. By tuning the physical properties considering the finite-difference time-domain simulation results, biomolecular interactions were feasible in the electromagnetic field-enhanced nanospace. As a result, DWF10 exhibited a 10-fold lower detection limit of 2.21 fM compared to DWF14 for tau detection. Further application into blood-based clinical and Alzheimer's disease (AD) diagnostics, notable improvement in classifying mild cognitive impairment patients against healthy controls and AD patients, was demonstrated along with impressive AUC values. Thus, in response to diverse detection methods, optimizing nanoframe dimensions such as nanogap and frame thickness to maximize sensor performance is critical to realize future POCT diagnosis.

Advanced nano delivery system for stem cell therapy for Alzheimer's disease.

Alzheimer's Disease (AD) represents one of the most significant neurodegenerative challenges of our time, with its increasing prevalence and the lack of curative treatments underscoring an urgent need for innovative therapeutic strategies. Stem cells (SCs) therapy emerges as a promising frontier, offering potential mechanisms for neuroregeneration, neuroprotection, and disease modification in AD. This article provides a comprehensive overview of the current landscape and future directions of stem cell therapy in AD treatment, addressing key aspects such as stem cell migration, differentiation, paracrine effects, and mitochondrial translocation. Despite the promising therapeutic mechanisms of SCs, translating these findings into clinical applications faces substantial hurdles, including production scalability, quality control, ethical concerns, immunogenicity, and regulatory challenges. Furthermore, we delve into emerging trends in stem cell modification and application, highlighting the roles of genetic engineering, biomaterials, and advanced delivery systems. Potential solutions to overcome translational barriers are discussed, emphasizing the importance of interdisciplinary collaboration, regulatory harmonization, and adaptive clinical trial designs. The article concludes with reflections on the future of stem cell therapy in AD, balancing optimism with a pragmatic recognition of the challenges ahead. As we navigate these complexities, the ultimate goal remains to translate stem cell research into safe, effective, and accessible treatments for AD, heralding a new era in the fight against this devastating disease.

Engineered 3D human neurovascular model of Alzheimer's disease to study vascular dysfunction.

The blood-brain barrier (BBB) serves as a selective filter that prevents harmful substances from entering the healthy brain. Dysfunction of this barrier is implicated in several neurological diseases. In the context of Alzheimer's disease (AD), BBB breakdown plays a significant role in both the initiation and progression of the disease. This study introduces a three-dimensional (3D) self-assembled in vitro model of the human neurovascular unit to recapitulate some of the complex interactions between the BBB and AD pathologies. It incorporates primary human brain endothelial cells, pericytes and astrocytes, and stem cell-derived neurons and astrocytes harboring Familial AD (FAD) mutations. Over an extended co-culture period, the model demonstrates increased BBB permeability, dysregulation of key endothelial and pericyte markers, and morphological alterations mirroring AD pathologies. The model enables visualization of amyloid-beta (Aß) accumulation in both neuronal and vascular compartments. This model may serve as a versatile tool for neuroscience research and drug development to provide insights into the dynamic relationship between vascular dysfunction and AD pathogenesis.

Real-time analysis of the biomolecular interaction between gelsolin and Aß1-42 monomer and its implication for Alzheimer's disease.

Biomolecular interaction acts a pivotal part in understanding the mechanisms underlying the development of Alzheimer's disease (AD). Herein, we built a biosensing platform to explore the interaction between gelsolin (GSN) and different ß-amyloid protein 1-42 (Aß1-42) species, including Aß1-42 monomer (m-Aß), Aß1-42 oligomers with both low and high levels of aggregation (LLo-Aß and HLo-Aß) via dual polarization interferometry (DPI). Real-time molecular interaction process and kinetic analysis showed that m-Aß had the strongest affinity and specificity with GSN compared with LLo-Aß and HLo-Aß. The impact of GSN on inhibiting aggregation of Aß1-42 and solubilizing Aß1-42 aggregates was evaluated by circular dichroism (CD) spectroscopy. The maintenance of random coil structure of m-Aß and the reversal of ß-sheet structure in HLo-Aß were observed, demonstrating the beneficial effects of GSN on preventing Aß from aggregation. In addition, the structure of m-Aß/GSN complex was analyzed in detail by molecular dynamics (MD) simulation and molecular docking. The specific binding sites and crucial intermolecular forces were identified, which are believed to stabilize m-Aß in its soluble state and to inhibit the fibrilization of Aß1-42. Combined theoretical simulations and experiment results, we speculate that the success of GSN sequestration mechanism and the balance of GSN levels in cerebrospinal fluid and plasma of AD subjects may contribute to a delay in AD progression. This research not only unveils the molecular basis of the interaction between GSN and Aß1-42, but also provides clues to understanding the crucial functions of GSN in AD and drives the development of AD drugs and therapeutic approaches.

Investigating the phytochemical profile, biological potentials, morphological, and anatomical characteristics of Cyclotrichium origanifolium (Labill.) Manden. & Scheng. (Lamiaceae) from Turkey.

Cyclotrichium origanifolium, a plant widely used in Eastern and Southern Anatolia for culinary purposes, was subject of this study, which aimed to comprehensively evaluate its potential therapeutic applications. This research stands out due to its holistic approach, combining morpho-anatomical studies, chemical, and biological analyses to explore antioxidant, antidiabetic, anticholinesterase, genotoxic, and anti-genotoxic effects of methanolic and aqueous extracts, as well as flowering aerial part essential oil. It is a perennial plant, typically ranging from 10 to 40 cm in height, with a suffrutescent and highly branched growth habit. Essential oils are produced within glandular trichomes. Oil, analyzed via GC-MS/MS, revealed 24 compounds accounting for 96.4% of oil, with isomenthone (52.4%), pulegone (23.4%), and ß-pinene (9.5%) as predominant components. These findings are significant as they provide new insights into chemical composition of oils, particularly highlighting pharmacologically active compounds. Methanol extract exhibited superior antioxidant activity, correlated with high phenol and tannin content. Essential oil showed moderate inhibition of α-amylase (49.54%) and mild inhibition of acetylcholinesterase (11.84%) and butyrylcholinesterase (16.93%), suggesting potential in managing oxidative stress and neurodegenerative diseases. Study also conducted biosafety evaluations using Ames/Salmonella and Allium tests, essential for assessing genotoxic and antigenotoxic potential of natural products. Notably, significant antimicrobial effects were identified, particularly against Pseudomonas aeruginosa and Enterococcus faecalis. Comprehensive analysis and discovery of significant bioactivities position this research as a valuable contribution to field, distinguishing it from previous studies on similar species. This study provides a foundational understanding of morpho-anatomical, pharmacological, biological properties of plant, opening avenues for future research.

Transcultural Adaptation of the "Caregiver Guilt Questionnaire" (CGQ).

OBJECTIVES: To implement a transcultural adaptation of the Caregiver Guilt Questionnaire (CGQ) for the Brazilian population. METHODS: Five stages were involved in the adaptation: two independent translations by Brazilian nationals fluent in Spanish; summary of translations produced; back-translation; evaluation by expert panel of judges (n = 5); and lastly, assessment by family caregivers (n = 30). RESULTS: semantic changes were made to render the items more relevant to Brazilian culture and replicate the five factors of guilt proposed by the original questionnaire. CONCLUSIONS: A Brazilian version of the questionnaire was produced and transculturally adapted for use in Brazil, allowing future validation and application. CLINICAL IMPLICATIONS: The CGQ allows healthcare professionals to quantify feelings of guilt. Clinicians and clinical researcher can use the scale to obtain more precise interventions.

A novel peptide-based tau aggregation inhibitor as a potential therapeutic for Alzheimer's disease and other tauopathies.

INTRODUCTION: As aggregation underpins Tau toxicity, aggregation inhibitor peptides may have disease-modifying potential. They are therefore currently being designed and target either the 306VQIVYK311 aggregation-promoting hotspot found in all Tau isoforms or the 275VQIINK280 aggregation-promoting hotspot found in 4R isoforms. However, for any Tau aggregation inhibitor to potentially be clinically relevant for other tauopathies, it should target both hotspots to suppress aggregation of Tau isoforms, be stable, cross the blood-brain barrier, and rescue aggregation-dependent Tau phenotypes in vivo. METHODS: We developed a retro-inverso, stable D-amino peptide, RI-AG03 [Ac-rrrrrrrrGpkyk(ac)iqvGr-NH2], based on the 306VQIVYK311 hotspots which exhibit these disease-relevant attributes. RESULTS: Unlike other aggregation inhibitors, RI-AG03 effectively suppresses aggregation of multiple Tau species containing both hotspots in vitro and in vivo, is non-toxic, and suppresses aggregation-dependent neurodegenerative and behavioral phenotypes. DISCUSSION: RI-AG03 therefore meets many clinically relevant requirements for an anti-aggregation Tau therapeutic and should be explored further for its disease-modifying potential for Tauopathies. HIGHLIGHTS: Our manuscript describes the development of a novel peptide inhibitor of Tau aggregation, a retro-inverso, stable D-amino peptide called RI-AG03 that displays many clinically relevant attributes. We show its efficacy in preventing Tau aggregation in both in vitro and in vivo experimental models while being non-toxic to cells. RI-AG03 also rescues a biosensor cell line that stably expresses Tau repeat domains with the P301S mutation fused to Cer/Clo and rescues aggregation-dependent phenotypes in vivo, suppressing neurodegeneration and extending lifespan. Collectively our data describe several properties and attributes of RI-AG03 that make it a promising disease-modifying candidate to explore for reducing pathogenic Tau aggregation in Tauopathies such as Alzheimer's disease. Given the real interest in reducing Tau aggregation and the potential clinical benefit of using such agents in clinical practice, RI-AG03 should be investigated further for the treatment of Tauopathies after validation in mammalian models. Tau aggregation inhibitors are the obvious first choice as Tau-based therapies as much of Tau-mediated toxicity is aggregation dependent. Indeed, there are many research efforts focusing on this therapeutic strategy with aggregation inhibitors being designed against one of the two aggregation-promoting hotspots of the Tau protein. To our knowledge, RI-AG03 is the only peptide aggregation inhibitor that inhibits aggregation of Tau by targeting both aggregation-promoting hotspot motifs simultaneously. As such, we believe that our study will have a significant impact on drug discovery efforts in this arena.

Discovering Effective Chiral Dipeptides against Aß(1-42) Aggregation by the Computational Screening Strategy.

The ß-sheet-breaker (BSB) peptides inhibiting amyloidogenic aggregation have been extensively studied. However, the inhibition efficacy of ultrashort chiral dipeptides remains inadequately understood. In this study, we proposed a computational screening strategy to identify chiral dipeptides as BSB with optimal antiaggregation performance against Aß(1-42) aggregation. We constructed a complete dipeptide library encompassing all possible chiral sequence arrangements and then filtered the library by cascaded molecular docking-molecular dynamics (MD) simulation. Our screening strategy discovered dipeptide DWDP (superscript for chirality) that displayed strong interactions with Aß fibrils and inhibitory effects on Aß aggregation, validated by subsequent experiments. Mechanistic investigation by both MD and replica-exchange molecular dynamics (REMD) simulations revealed that DWDP interacts with Aß by hydrophobic contacts and hydrogen bonds and thus inhibits Aß intermolecular contacts and salt bridge formation, therefore inhibiting Aß aggregation and disrupting Aß aggregates. Totally, our strategy presents a viable approach to discover potential dipeptides with effective antiaggregation ability as potential therapeutic agents for Alzheimer's disease.

Prevalence Estimation of Dementia/Alzheimer's Disease Using Health and Retirement Study Database in the United States.

BACKGROUND: Updated prevalence estimates along the continuum of Alzheimer's disease (AD) can foster a more nuanced and effective approach to managing AD within the current healthcare landscape. OBJECTIVES: This study aims to estimate the prevalence and severity distribution of dementia/AD (including mild, moderate, and severe stages) and all-cause mild cognitive impairment (MCI) in the United States using data from the Health and Retirement Study (HRS). DESIGN: Retrospective study. SETTING: Data from the bi-annual HRS surveys involving in-depth interviews of a representative sample of Americans aged >50 years. PARTICIPANTS: Dementia/AD and all-cause MCI patients from the 4 most recent HRS surveys (2014, 2016, 2018 and 2020). MEASUREMENTS: AD was identified based on diagnosis (self-report). Cognitive performance (modified Telephone Interview of Cognitive Status [TICS-m]) scores in the dementia/AD range were also captured; all-cause MCI was similarly identified using the TICS-m. Dementia/AD and MCI prevalence, as well as the distribution by dementia/AD stage (mild, moderate, or severe), were estimated. Sampling weights developed by HRS were applied to ensure the sample's representativeness of the target population and unbiased estimates for population parameters. RESULTS: Across the four HRS surveys, the total number of HRS respondents ranged from 15,000 to 21,000 (unweighted); 7,000 to 14,000 had TICS-m scores. The estimated prevalence of AD (all severity categories combined) in the 2014, 2016, 2018, and 2020 HRS surveys was 1.2%, 1.2%, 1.3% and 1.0%, respectively using the diagnosis-based approach; using the cognitive performance-based approach, 23-27% patients had scores in the dementia/AD ranges across the 4 surveys. The estimated prevalence of all-cause MCI was consistently 23% in each survey. In the 2020 survey, the distribution of mild, moderate, and severe disease stages was 34%, 45%, and 21%, respectively, in patients self-reporting an AD diagnosis, and 55%, 40%, and 5%, respectively in all patients meeting TICS-m threshold for dementia/AD. CONCLUSION: The prevalence of AD diagnosis based on self-report was approximately 1% across the 4 most recent HRS surveys and may reflect the proportion of patients who have actively sought healthcare for AD. Among HRS survey respondents with cognitive scores available, over 20% were in the dementia/AD range. The distribution of disease by stage differed for self-reported AD diagnosis vs dementia/AD based on cognitive scores. Discordance in estimates of dementia/AD and stage distributions underscores a need for better understanding of clinical practice patterns in AD diagnosis, use of clinical assessment tools, and severity classification in the United States. Accurate patient identification is needed, especially early in the AD disease continuum, to allow for timely and appropriate initiation of new anti-amyloid treatments.

A Statistical Framework for Assessing the Relationship between Biomarkers and Clinical Endpoints in Alzheimer's Disease.

Changes in biomarker levels of Alzheimer's disease (AD) reflect underlying pathophysiological changes in the brain and can provide evidence of direct and downstream treatment effects linked to disease modification. Recent results from clinical trials of anti-amyloid ß (Aß) treatments have raised the question of how to best characterize the relationship between AD biomarkers and clinical endpoints. Consensus methodology for assessing such relationships is lacking, leading to inconsistent evaluation and reporting. In this review, we provide a statistical framework for reporting treatment effects on early and late accelerating AD biomarkers and assessing their relationship with clinical endpoints at the subject and group levels. Amyloid positron emission tomography (PET), plasma p-tau, and tau PET follow specific trajectories during AD and are used as exemplar cases to contrast biomarkers with early and late progression. Subject-level correlation was assessed using change from baseline in biomarkers versus change from baseline in clinical endpoints, and interpretation of the correlation is dependent on the biomarker and disease stage. Group-level correlation was assessed using the placebo-adjusted treatment effects on biomarkers versus those on clinical endpoints in each trial. This correlation leverages the fundamental advantages of randomized placebo-controlled trials and assesses the predictivity of a treatment effect on a biomarker or clinical benefit. Harmonization in the assessment of treatment effects on biomarkers and their relationship to clinical endpoints will provide a wealth of comparable data across clinical trials and may yield new insights for the treatment of AD.

Plasma Biomarkers of Alzheimer's Disease and Neurodegeneration According to Sociodemographic Characteristics and Chronic Health Conditions.

Ultrasensitive assays have been developed which enable biomarkers of Alzheimer's disease pathology and neurodegeneration to be measured in blood. These biomarkers can aid in diagnosis, and have been used to predict risk of cognitive decline and Alzheimer's disease. The ease and cost-effectiveness of blood collections means that these biomarkers could be applied more broadly in population-based screening, however it is critical to first understand what other factors could affect blood biomarker levels. The aim of this review was to determine the extent that sociodemographic, lifestyle and health factors have been associated with blood biomarkers of Alzheimer's disease and neuropathology. Of the 32 studies included in this review, all but one measured biomarker levels in plasma, and age and sex were the most commonly investigated factors. The most consistent significant findings were a positive association between age and neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP), and females had higher GFAP than men. Apolipoprotein ε4 allele carriers had lower Aß42 and Aß42/40 ratio. Body mass index was negatively associated with GFAP and NfL, and chronic kidney disease with higher levels of all biomarkers. Too few studies have investigated other chronic health conditions and this requires further investigation. Given the potential for plasma biomarkers to enhance Alzheimer's disease diagnosis in primary care, it is important to understand how to interpret the biomarkers in light of factors that physiologically impact blood biomarker levels. This information will be critical for the establishment of reference ranges and thus the correct interpretation of these biomarkers in clinical screening.

Performance of Plasma Biomarkers Combined with Structural MRI to Identify Candidate Participants for Alzheimer's Disease-Modifying Therapy.

BACKGROUND: Recently, two monoclonal antibodies that lower amyloid plaques have shown promising results for the treatment of Mild Cognitive Impairment (MCI) and mild dementia due to Alzheimer's disease (AD). These treatments require the identification of cognitively impaired older adults with biomarker evidence of AD pathology using CSF biomarkers or amyloid-PET. Previous studies showed plasma biomarkers (plasma Aß42/Aß40 and p-tau181) and hippocampal volume from structural MRI correlated with brain amyloid pathology. We hypothesized plasma biomarkers with hippocampal volume would identify patients who are suitable candidates for disease-modifying therapy. OBJECTIVES: To evaluate the performance of plasma AD biomarkers and hippocampal atrophy to detect MCI or AD with amyloid pathology confirmed by amyloid-PET or CSF biomarkers in ADNI. DESIGN: A cross-sectional and longitudinal study. SETTING AND PARTICIPANTS: Data were from the Alzheimer's Disease Neuroimaging Initiative. Participants were aged 55-90 years old with plasma biomarker and structural MRI brain data. MEASUREMENTS: The optimum cut-off point for plasma Aß42/Aß40, p-tau181, and NFL and the performance of combined biomarkers and hippocampal atrophy for detecting cognitive impairment with brain amyloid pathology were evaluated. The association between baseline plasma biomarkers and clinical progression, defined by CDR-Sum of Boxes (CDR-SB) and diagnostic conversion over two years, was evaluated using a Weibull time-to-event analysis. RESULTS: A total of 428 participants were included; 167 had normal cognition, 245 had MCI, and 16 had mild AD. Among MCI and AD, 140 participants had elevated amyloid levels by PET or CSF. Plasma Aß42/Aß40 provided the best accuracy (sensitivity 79%, specificity 66%, AUC 0.73, 95% CI 0.68-0.77) to detect drug candidate participants at baseline. Combined plasma Aß42/40, p-tau181, and hippocampal atrophy increased the specificity for diagnosis (96%), but had lower sensitivity (34%), and AUC (0.65). Hippocampal atrophy combined with the abnormal plasma p-tau181 or hippocampal atrophy alone showed high sensitivity to detect clinical progression (by CDR-SB worsening) of the drug-candidate participants within the next 2 years (sensitivity 93% and 89%, respectively). CONCLUSION: Plasma biomarkers and structural MRI can help identify patients who are currently eligible for anti-amyloid treatment and are likely to progress clinically, in cases where amyloid-PET or CSF biomarkers are not available.

Progress in the Treatment of Alzheimer's Disease Is Needed - Position Statement of European Alzheimer's Disease Consortium (EADC) Investigators.

ß-amyloid-targeting antibodies represent the first generation of effective causal treatment of Alzheimer's disease (AD) and can be considered historical research milestones. Their effect sizes, side effects, implementation challenges and costs, however, have stimulated debates about their overall value. In this position statement academic clinicians of the European Alzheimer's Disease Consortium (EADC) discuss the critical relevance of introducing these new treatments in clinical care now. Given the complexity of AD it is unlikely that molecular single-target treatments will achieve substantially larger effects than those seen with current ß-amyloid-targeting antibodies. Larger effects will most likely only be achieved incrementally by continuous optimization of molecular approaches, patient selection and combinations therapies. To be successful in this regard, drug development must be informed by the use of innovative treatments in real world practice, because full understanding of all facets of novel treatments requires experience and data of real-world care beyond those of clinical trials. Regarding the antibodies under discussion we consider their effects meaningful and potential side effects manageable. We assume that the number of eventually treated patient will only be a fraction of all early AD patients due to narrow eligibility criteria and barriers of access. We strongly endorse the use of these new compound in clinical practice in selected patients with treatment documentation in registries. We understand this as a critical step in advancing the field of AD treatment, and in shaping the health care systems for the new area of molecular-targeted treatment of neurodegenerative diseases.

Japanese Subgroup Analyses from EMERGE and ENGAGE, Phase 3 Clinical Trials of Aducanumab in Patients with Early Alzheimer's Disease.

BACKGROUND: Global prevalence and incidence of dementia continue to rise at a rapid rate. There is a need for new Alzheimer's disease (AD) treatments globally. Aducanumab is a human monoclonal antibody that selectively targets aggregated soluble amyloid beta oligomers and insoluble amyloid beta fibrils. In June 2021, aducanumab was approved by the US Food and Drug Administration for the treatment of AD under the accelerated approval pathway. OBJECTIVES: We evaluated the efficacy, safety, biomarker and pharmacokinetics (PK) of aducanumab in Japanese subgroups in EMERGE and ENGAGE studies. DESIGN: EMERGE and ENGAGE were two randomized, double-blind, placebo-controlled, global, phase 3 studies of aducanumab in patients with early AD (mild cognitive impairment due to AD or mild AD dementia). SETTING: These studies involved 348 sites in 20 countries. PARTICIPANTS: Participants enrolled in Japan included 121 (7.4% of total 1638 in EMERGE) and 100 (6.1% of total 1647 in ENGAGE) patients (aged 50-85 years with confirmed amyloid pathology) who met clinical criteria for mild cognitive impairment due to AD or mild AD dementia. INTERVENTION: Participants were randomly assigned 1:1:1 to receive aducanumab low dose (3 or 6 mg/kg target dose), high dose (6 or 10 mg/kg target dose) or placebo via IV infusion once every 4 weeks over 76 weeks. MEASUREMENTS: The primary outcome measure was change from baseline to Week 78 on the Clinical Dementia Rating Sum of Boxes (CDR-SB), an integrated scale that assesses both function and cognition. Other measures included safety assessments; secondary and tertiary clinical outcomes that assessed cognition, function, and behavior; biomarker endpoints (amyloid PET and plasma p-tau181); serum PK profiles and immunogenicity. RESULTS: Results from the Japanese subgroup analyses were generally consistent with those of the overall study population across endpoints, while a lower mean body weight (kg) and a smaller proportion of ApoE ε4 carriers were observed in the Japanese subgroup population. A treatment effect was observed in favor of aducanumab on the primary and secondary efficacy endpoints at Week 78 in EMERGE, but not ENGAGE. The incidence and type of adverse events in the Japanese subgroups were generally comparable to those observed in the overall study population; amyloid related imaging abnormalities (ARIA) were common treatment-related adverse events that appeared to be related to the aducanumab dose. ARIA incidence was generally lower in the Japanese subgroup compared with the overall population. Consistent with the overall data set, a robust dose-dependent decrease in amyloid beta levels as assessed with amyloid-PET and plasma p-tau181 was observed. Serum PK profiles and immunogenicity of aducanumab in Japanese population were consistent with the non-Japanese population. CONCLUSION: Efficacy, safety, biomarker, and PK profiles of aducanumab were consistent between the Japanese subgroup and the overall population. A positive treatment effect of aducanumab on efficacy endpoints was observed in EMERGE, but not in ENGAGE.

Metabolic Syndrome Status Changes and Cognitive Functioning: Insights from the Lifelines Cohort Study.

BACKGROUND: Metabolic syndrome is associated with increased risk of dementia. Yet, findings on how longitudinal development of metabolic syndrome status affects cognition remain controversial. OBJECTIVES: This study examines whether individuals with different changes in metabolic syndrome status differ in cognitive functioning. Additionally, the prevalence of metabolic syndrome within the Lifelines population-based study is investigated. DESIGN: 14609 Lifelines participants (mean age 60.8, 56.4% women) were divided into four groups based on their metabolic syndrome status changes between 2007-2013 (1) and between 2014-2017 (2): without metabolic syndrome (N=10863; absent at 1 and 2), de novo metabolic syndrome (N=1340; absent at 1 and present at 2), remitting metabolic syndrome (N=825; present at 1 and absent at 2), and persistent metabolic syndrome (N=1581; present at 1 and 2). ANCOVA models were employed to assess group differences in psychomotor function, visual attention, visual learning, and working memory assessed using the Cogstate Brief Battery. RESULTS: Accounting for education, age, sex, and time between examinations, groups did not statistically differ in any of the four cognitive outcomes. The prevalence of metabolic syndrome within the Lifelines population increased with age and differed among men and women. CONCLUSION: Performance in psychomotor function, visual attention, visual learning, and working memory measured by the Cogstate Brief Battery did not differ between individuals with different changes in metabolic syndrome. The length of metabolic syndrome exposure was unknown, making our results exploratory and calling for future studies addressing this gap.

Lower Incidence of Dementia Following Cancer Diagnoses: Evidence from a Large Cohort and Mendelian Randomization Study.

BACKGROUND: The reported inverse association between cancer and subsequent Alzheimer's disease and related dementias (ADRD) remains uncertain. OBJECTIVES: To investigate the association between these common conditions of old age and explore possible causal factors. DESIGN, SETTING, PARTICIPANTS AND MEASUREMENTS: We conducted a large population-based cohort analysis using data from 3,021,508 individuals aged 60 and over in the UK Clinical Practice Research Datalink (CPRD), over a period up to 30 years (1988-2018). Cox proportional hazards models were fitted to estimate hazard ratios (HR) for risk of dementia associated with previous cancer diagnosis. Competing risk models were employed to account for competing risk of death. Two-sample Mendelian Randomization analysis based on meta-analysis data from large-scale GWAS studies was also conducted. RESULTS: In the CPRD cohort, 412,903 participants had cancer diagnosis and 230,558 were subsequently diagnosed with dementia over a median follow-up period of 7.9 years. Cancer survivors had a 25% lower risk of developing dementia (HR=0.75, 95% CI:0.74-0.76) after adjustment for potential confounders. Accounting for competing risk of death provided a sub-distribution HR of 0.56 (95% CI:0.55-0.56). Results were consistent for prevalent and incident cancer and different common cancer types. Two-sample Mendelian Randomization analysis, using 357 cancer-related instrumental single-nucleotide polymorphisms (SNPs) revealed evidence of vertical pleiotropy between genetically predicted cancer and reduced risk of Alzheimer's disease (OR=0.97,95% CI:0.95-0.99). CONCLUSION: Our results provide strong epidemiological evidence of the inverse association between cancer and risk of ADRD and support the potential causal nature of this association via genetic instruments. Further investigations into the precise underlying biological mechanisms may reveal valuable information for new therapeutic approaches.