Understanding Of Alzheimer's Disease Research Articles

Research on Alzheimer's Disease (AD) Involving the Use of In vivo and In vitro Models and Mechanisms.

Alzheimer's Disease (AD) is a neurodegenerative disorder characterized by the progressive formation of extracellular amyloid plaques, intracellular neurofibrillary tangles, inflammation, and impaired antioxidant systems. Early detection and intervention are vital for managing AD effectively. This review scrutinizes both in-vivo and in-vitro screening models employed in Alzheimer's disease research. In-vivo models, including transgenic mice expressing AD-related mutations, offer profound insights into disease progression and potential therapeutic targets. A thorough understanding of these models and mechanisms will facilitate the development of novel therapies and interventions for Alzheimer's disease. This review aims to provide an overview of the current experimental models in AD research, assess their strengths and weaknesses as model systems, and underscore the future prospects of experimental AD modeling. We conducted a systematic literature search across multiple databases, such as Pub- Med, Bentham Science, Elsevier, Springer Nature, Wiley, and Research Gate. The search strategy incorporated pertinent keywords related to Alzheimer's disease, in-vivo models, in-vitro models, and screening mechanisms. Inclusion criteria were established to identify studies focused on in-vivo and in-vitro screening models and their mechanisms in Alzheimer's disease research. Studies not meeting the predefined criteria were excluded from the review. A well-structured experimental animal model can yield significant insights into the neurobiology of AD, enhancing our comprehension of its pathogenesis and the potential for cutting-edge therapeutic strategies. Given the limited efficacy of current AD medications, there is a pressing need for the development of experimental models that can mimic the disease, particularly in pre-symptomatic stages, to investigate prevention and treatment approaches. To address this requirement, numerous experimental models replicating human AD pathology have been established, serving as invaluable tools for assessing potential treatments. In summary, this comprehensive review underscores the pivotal role of in-vivo and in-vitro screening models in advancing our understanding of Alzheimer's disease. These models offer invaluable insights into disease progression, pathological mechanisms, and potential therapeutic targets. By conducting a rigorous investigation and evaluation of these models and mechanisms, effective screening and treatment methods for Alzheimer's disease can be devised. The review also outlines future research directions and areas for enhancing AD screening models.

Binding interactions and in silico ADME prediction of isoconessimine derivatives as potent acetylcholinesterase inhibitors

In pursuit of new acetylcholinesterase (AChE) inhibitors for treating Alzheimer's disease (AD), a series of ten previously synthesized isoconessimine compounds (7a-7j) was in silico investigated for their binding interactions with AChE and pharmacokinetics based on absorption, distribution, metabolism, and excretion (ADME) properties using molecular docking, ONIOM (Our own N-layered Integrated molecular Orbital and molecular Mechanics) method and SwissADME tools. Docking experiments showed that all compounds bind within the active site gorge of AChE (PDB entry 1C2B), posing its aryloxy-substitutional ethyl group to catalytic site and conessine skeleton to peripheral anionic site. ONIOM interaction energy was used as an ONIOM score to improve docking score, and it ranked 7b as the most potent AChE inhibitor, in agreement with previous experiment. Residues, ASP74, TRP86, GLY122, GLU202, TRP286, GLU292, SER293, ILE294, TYR337, TYR341, and HIS447 were identified as important for the binding of the AChE-isoconessimine complex. The SwissADME investigation suggested that four compounds (7a, 7c, 7d and 7f) agree with the rules of drug-likeness. The steric and electronic effects on the aryloxy-substitutional ethyl group as important factors in the AChE inhibition were also discussed, which brings a better understanding of Alzheimer's disease drug development.

Alzheimer's Disease - A Comprehensive Review

Introduction: Alzheimer's disease (AD) remains a pervasive and challenging neurodegenerative disorder with profound implications for individuals, families, and societies. As the most prevalent cause of dementia globally, AD's prevalence is set to rise significantly in the context of an aging population. This introductory section emphasizes the urgent need for a comprehensive understanding of the disease, encompassing both its molecular intricacies and the socio-economic burden. With age being the primary risk factor, recent research has delved into the complex interplay of genetic predisposition and environmental influences, reshaping our understanding of AD from a multifactorial perspective.
 Current State of Knowledge: Advancements in Alzheimer's research have led to a nuanced understanding of its pathology. Traditionally characterized by amyloid-beta plaques and tau tangles, recent insights from neuroimaging and biomarker studies have revealed the intricate nature of these pathologies and their roles in disease progression. Genetic studies, including genome-wide association analyses, have identified susceptibility loci, notably the APOE gene. Simultaneously, environmental factors, such as air pollution and lifestyle choices, are recognized contributors to AD risk. The therapeutic landscape has evolved, with ongoing investigations into anti-amyloid and anti-tau therapies, lifestyle interventions, and precision medicine approaches. The synthesis of these diverse findings highlights the dynamic nature of Alzheimer's research and its potential to shape future treatment modalities.
 Summary: In summary, this article provides a comprehensive overview of the current state of knowledge regarding Alzheimer's disease. From understanding its evolving pathology to exploring the interplay of genetic and environmental factors, the multifactorial nature of AD is underscored. The therapeutic landscape is actively advancing, presenting a hopeful outlook for future treatments.

A Qualitative Pilot Study of Adolescents’ Characteristics and Experiences Delivering a Digital, Intergenerational Music Program to Older Adults with Alzheimer’s and Dementia

ABSTRACT Music interventions show promise to support critical areas of decline for those living with dementia. There is a gap in identifying the skills and experiences necessary to facilitate the music activities in such an intervention. This pilot research creates an understanding of the characteristics and experiences of adolescent musicians who facilitated a digital, intergenerational music intervention. The research team conducted in-depth interviews with the adolescent participants and used descriptive phenomenological methodology. Eight adolescent musicians participated in the study, ranging from 14 to 18 years old. For characteristics, adolescents reported prior experience in music and key social supports. For experiences, adolescents reported decreased performance anxiety and increase in human connection and understanding of Alzheimer’s disease and dementia. There is potential for researchers to explore if adolescents who facilitate such a music intervention experience less performance anxiety as well as more empathy for those living with dementia.

ACCELERATING DEMENTIA RESEARCH AND EARLY-CAREER DEVELOPMENT THROUGH THE SUMMER RESEARCH INSTITUTE

Abstract Today, there are more than six million Americans living with Alzheimer’s disease and more than 11 million unpaid caregivers. By 2060, the number of Americans living with Alzheimer’s could reach 14 million. These statistics highlight the need for early career investigators to join the dementia research workforce and accelerate breakthroughs in this field. In 2020, the National Institutes on Aging (NIA) funded the Alzheimer’s Association Interdisciplinary Summer Research Institute (AA-ISRI) focused on early career investigators interested in psychosocial and public health research related to dementia. AA-ISRI is a five-day immersive experience in which 24 early career investigators are selected to come to Chicago, attend didactic lectures led by expert faculty, develop research proposals in small groups, and receive one-to-one mentoring. Participants leave AA-ISRI with a greater understanding of the tools needed to succeed in dementia research and an extensive network of colleagues and mentors. Based on evaluations collected from participants from the first two years of the program, 97% of respondents indicated they were satisfied with the program, 94% felt the program increased their understanding of Alzheimer’s, and 90% said the program improved their independent research skills. Participants have shared that AA-ISRI is a highly unique opportunity that every early career investigator in the field should attend. Alumni from the first two years of AA-ISRI have gone on to publish 40+ peer-reviewed publications and have been awarded 15+ grants. This poster will review the development of AA-ISRI, key outcomes, and its impact on the future of dementia research.

Single cell multi‐omics implicates immune and vascular cells in Alzheimer’s etiology

AbstractBackgroundUnderstanding the genetic etiology of Alzheimer’s disease (AD) is critical to inform effective therapies but remains a challenge. Genetic heritability of late‐onset AD is ∼60‐80%, and genome‐wide association studies (GWAS) have uncovered dozens of noncoding single nucleotide polymorphisms (SNPs) that influence AD risk. Two challenges for the functional interpretation of AD genetic risk are (1) determining the cell types in which SNPs operate and (2) identifying the genes they dysregulate to drive AD pathogenesis. Single‐nucleus sequencing studies of human neurons, microglia, and other brain cell types have begun addressing these challenges. Yet, many AD risk SNPs remain unmapped. One possibility is that they are expressed in immunovascular brain cell types largely missed by current methods.MethodHere, we optimized Vessel Isolation and Nuclei Extraction for Sequencing (VINE‐seq) to capture multimodal gene expression and chromatin accessibility assays across all major brain cell types from 30 cognitively normal, MCI, and AD human prefrontal cortex samples.ResultWe discover early gene dysregulation in immune and vascular cell types along AD progression. We highlight the gene regulatory networks mediating this dysregulation and implicate processes associated with AD pathology and cognitive decline. Finally, we map noncoding AD risk variants to diverse immune and vascular cell types, thereby expanding our understanding of AD etiology.ConclusionDysfunction of diverse human brain immune and vascular cell types mediate the genetic risk for Alzheimer’s disease.

Explainable AI and its instantiation in Computational Pathology for a better understanding of Alzheimer’s disease

AbstractBackgroundEXplainable Artificial Intelligence (XAI) has an essential role to accelerate the AI adoption by empowering biomedical experts and catalyzing modern research through the emergence of a new generation of virtual actors, enabling traceable knowledge‐based quantification, as a guided qualification support. XAI instantiation is shown through our study, hypothesizing that rapid Alzheimer’s Disease (rAD) brains display subtle histological changes that would be undercovered by high‐throughput automated microscopic analysis. We study the topography and morphology of tau lesions’ aggregates to better understand the morphological substratum of Alzheimer’s Disease (AD) heterogeneity.MethodTo address this question at a large scale, we designed, tested and implemented a software for automatic segmentation, annotation and quantitation of brain lesions in histopathological whole slide images (WSI). A dataset of 15 whole slide images of postmortem human brain tissue is used in this study. These are fully annotated by neuropathologists yielding a set of more than 30,000 annotated plaques and tangle objects. A deep learning pipeline consisting of an attention‐UNet model with explainability features is trained for segmentation of tau aggregates in WSIs. The attention maps corresponding to segmentation predictions from the model are used by pathologists as a comparable reference to assist their decision making process.ResultThe DL‐based WSI analysis framework allows detecting a majority of the tau aggregates and refining tau aggregate boundaries with higher accuracy compared to manual annotations. Besides, with such a DL model based tau identification, the pathologist needs to annotate only a few samples for the DL model training. Overall, DL assisted analysis of tau aggregates could ease the effort of pathologists and facilitate analysis of hundreds of WSIs which are vital in AD research areas such as identifying different AD forms and AD patient stratification.ConclusionXAI is not only providing traceability by opening the way to an effective adoption, but also allows optimizing the ML/DL design, by keeping high performances. The green footprint is, therefore, considered, as well as the GDPR (European General Data Protection Regulation), towards Responsible Artificial Intelligence.

Exploring cultural differences in the understanding of Alzheimer’s Disease and related dementias among Alaska Natives and providers in Alaska

AbstractBackgroundThe proportion of the Native population aged 65+ is projected to increase between 2015 and 2045, from 7‐12%, and informal caregivers and health care providers are ill‐prepared to meet the demand of Alzheimer’s Disease and related disorders (ADRD). There is an increasing urgency to better understand Alaska Native views of ADRD.MethodGuided by Kleinman’s explanatory model of illness, a qualitative, research design was utilized to gather data on experiences with ADRD. 21 interviews with Alaska Native caregivers and 12 interviews with health care providers in rural and urban communities were completed. Using Nvivo qualitative software, thematic analysis was used to obtain cultural perspectives on ADRD. This study was approved by the University and tribal review boards.ResultMany Alaska Natives view ADRD as a natural part of the aging process, resulting in not always seeking medical care. Caregivers challenges included family denial, exhaustion and isolation, and family distancing themselves due to fear and limited understanding of ADRD. Caregiving benefits included spending time with older adult, learning family history, and sharing experiences with other caregivers. Healthcare provider challenges included rigidity of the healthcare system, no research on Alaska Natives, limited health literacy, limited community resources, and no knowledge of Alaska Native views of ADRD.ConclusionUnderstanding the cultural underpinnings of ADRD provides insight into how health care providers can integrate cultural beliefs into treatment to improve the processes of care that may mitigate the impact of ADRD on individuals and families. Culturally‐responsive education and training about ADRD is crucial to connecting Alaska Natives with ADRD to care that can assist them in aging more comfortably

Promising Prospects for Human Cerebral Organoids to Advance Alzheimer's Disease Research

The causes of the alterations found in the brains of patients with alzheimer's disease (AD) begin before the first signs of memory loss appear, and are still unclear. Adequate research models are essential to understand the mechanisms that cause the onset of these alterations, as well as to advance in the diagnosis, development and testing of treatments for the AD. Animal research models fail to recreate the great diversity and complexity inherent to the human brain, so in vitro systems based on human pluripotent stem cells (hPSCs) present themselves as an important alternative. Differentiation of hPSCs into two-dimensional (2D) cell culture models allows recreation of various brain functional processes and the three-dimensional (3D) cell culture models or human brain organoids (hCOs) recapitulate the cellular diversity and structure of the human brain. hCOs from human induced pluripotent stem cells (hiPSCs) from patients with familial (APP, PSEN1 and PSEN2 mutations) or sporadic AD allow identifying and studying changes due to this pathology. This review presents an overview of the research models used to study the AD, and recapitulates the advantages and discusses the challenges of the hCOs as an innovative and promising technology that will aid in the understanding of AD.

Targeting epigenetics: A novel promise for Alzheimer's disease treatment.

So far, the search for a cure for Alzheimer Disease (AD) has been unsuccessful. The only approved drugs attenuate some symptoms, but do not halt the progress of this disease, which affects 50 million people worldwide and will increase its incidence in the coming decades. Such scenario demands new therapeutic approaches to fight against this devastating dementia. In recent years, multi-omics research and the analysis of differential epigenetic marks in AD subjects have contributed to our understanding of AD; however, the impact of epigenetic research is yet to be seen. This review integrates the most recent data on pathological processes and epigenetic changes relevant for aging and AD, as well as current therapies targeting epigenetic machinery in clinical trials. Evidence shows that epigenetic modifications play a key role in gene expression, which could provide multi-target preventative and therapeutic approaches in AD. Both novel and repurposed drugs are employed in AD clinical trials due to their epigenetic effects, as well as increasing number of natural compounds. Given the reversible nature of epigenetic modifications and the complexity of gene-environment interactions, the combination of epigenetic-based therapies with environmental strategies and drugs with multiple targets might be needed to properly help AD patients.

Validation of a Multivariate Prediction Model of the Clinical Progression of Alzheimer's Disease in a Community-Dwelling Multiethnic Cohort.

The major aims of the three Predictors Studies have been to further our understanding of Alzheimer's disease (AD) progression sufficiently to predict the length of time from disease onset to major disease outcomes in individual patients with AD. To validate a longitudinal Grade of Membership (L-GoM) prediction algorithm developed using clinic-based, mainly white patients from the Predictors 2 Study in a statistically representative community-based sample of Hispanic (N = 211) and non-Hispanic (N = 62) older adults (with 60 males and 213 females) from the Predictors 3 Study and extend the algorithm to mild cognitive impairment (MCI). The L-GoM model was applied to data collected at the initial Predictors 3 visit for 150 subjects with AD and 123 with MCI. Participants were followed annually for up to seven years. Observed rates of survival and need for full-time care (FTC) were compared to those predicted by the algorithm. Initial MCI/AD severity in Predictors 3 was substantially higher than among clinic-based AD patients enrolled at the specialized Alzheimer's centers in Predictors 2. The observed survival and need for FTC followed the L-GoM model trajectories in individuals with MCI or AD, except for N = 32 subjects who were initially diagnosed with AD but reverted to a non-AD diagnosis on follow-up. These findings indicate that the L-GoM model is applicable to community-dwelling, multiethnic older adults with AD. They extend the use of the model to the prediction of outcomes for MCI. They also justify release of our L-GoM calculator at this time.

Amyloid Precursor Protein (APP) Regulates Gliogenesis and Neurogenesis of Human Neural Stem Cells by Several Signaling Pathways.

Numerous studies have focused on the pathophysiological role of amyloid precursor protein (APP) because the proteolytic processing of APP to β-amyloid (Aβ) peptide is a central event in Alzheimer's disease (AD). However, many authors consider that alterations in the physiological functions of APP are likely to play a key role in AD. Previous studies in our laboratory revealed that APP plays an important role in the differentiation of human neural stem cells (hNSCs), favoring glial differentiation (gliogenesis) and preventing their differentiation toward a neuronal phenotype (neurogenesis). In the present study, we have evaluated the effects of APP overexpression in hNSCs at a global gene level by a transcriptomic analysis using the massive RNA sequencing (RNA-seq) technology. Specifically, we have focused on differentially expressed genes that are related to neuronal and glial differentiation processes, as well as on groups of differentially expressed genes associated with different signaling pathways, in order to find a possible interaction between them and APP. Our data indicate a differential expression in genes related to Notch, Wnt, PI3K-AKT, and JAK-STAT signaling, among others. Knowledge of APP biological functions, as well as the possible signaling pathways that could be related to this protein, are essential to advance our understanding of AD.

Mapping Research Trends and Hotspots in the Link between Alzheimer's Disease and Gut Microbes over the Past Decade: A Bibliometric Analysis.

Alzheimer's disease (AD) is a globally prevalent neurodegenerative disorder, the underlying causes and mechanisms of which remain elusive. The emerging interest in the potential connection between gut microbes and AD prompted our study to investigate this field through bibliometric analysis. To examine research trends over the past decade, we collected relevant data using search terms associated with gut microbiota and AD from the Web of Science Core Collection. Our analysis involved various tools, including R (version 4.2.2), VOSviewer (version 1.6.18), CiteSpace software (version 6.2.R1), and an online bibliometric platform. Our findings identified a total of 1170 articles published between 2012 and 2022, indicating a consistent growth of research interest in this area. Notably, China significantly contributed with 40.7% (374) of the publications, signifying its prominent role in this field. Among the journals, the Journal of Alzheimer's Disease published the highest number of articles (57; 4.9%). In terms of author influence, Wang Y, with an H-index of 13, emerged as the most influential author. Additionally, Shanghai Jiaotong University was the most productive institution, accounting for 66 articles (5.6%). Through keyword analysis, we grouped high-frequency keywords into six clusters: gut microbiota, AD, neuroinflammation, gut-brain axis, oxidative stress, and chain fatty acids. Chain fatty acids, oxidative stress, and the gut-brain axis emerged as dominant research topics in the past five years. Recent studies have specifically focused on "nlrp3 inflammasome" and "clearance" (2020-2022), indicating shifting research interests within this field. This bibliometric analysis aims to provide insights into the evolving landscape of research on the gut microbiota and AD. Our results identify key research trends and themes while highlighting potential research gaps. The findings offer valuable perspectives for future investigations, advancing our understanding of AD and exploring potential therapeutic strategies.

Amyloid beta-correlated plasma metabolite dysregulation in Alzheimer's disease: an untargeted metabolism exploration using high-resolution mass spectrometry toward future clinical diagnosis.

Alzheimer's disease (AD) is a leading cause of dementia, and it has rapidly become an increasingly burdensome and fatal disease in society. Despite medical research advances, accurate recognition of AD remains challenging. Epidemiological evidence suggests that metabolic abnormalities are tied to higher AD risk. This study utilized case-control analyses with plasma samples and identified a panel of 27 metabolites using high-resolution mass spectrometry in both the Alzheimer's disease (AD) and cognitively normal (CN) groups. All identified variables were confirmed using MS/MS with detected fragmented ions and public metabolite databases. To understand the expression of amyloid beta proteins in plasma, ELISA assays were performed for both amyloid beta 42 (Aβ42) and amyloid beta 40 (Aβ40). The levels of plasma metabolites PAGln and L-arginine were found to significantly fluctuate in the peripheral blood of AD patients. In addition, ELISA results showed a significant increase in amyloid beta 42 (Aβ42) in AD patients compared to those who were cognitively normal (CN), while amyloid beta 40 (Aβ40) did not show any significant changes between the groups. Furthermore, positive correlations were observed between Aβ42/Aβ40 and PAGln or L-arginine, suggesting that both metabolites could play a role in the pathology of amyloid beta proteins. Binary regression analysis with these two metabolites resulted in an optimal model of the ROC (AUC = 0.95, p < 0.001) to effectively discriminate between AD and CN. This study highlights the potential of advanced high-resolution mass spectrometry (HRMS) technology for novel plasma metabolite discovery with high stability and sensitivity, thus paving the way for future clinical studies. The results of this study suggest that the combination of PAGln and L-arginine holds significant potential for improving the diagnosis of Alzheimer's disease (AD) in clinical settings. Overall, these findings have important implications for advancing our understanding of AD and developing effective approaches for its future clinical diagnosis.

Common Signaling Pathways Involved in Alzheimer's Disease and Stroke: Two Faces of the Same Coin.

Alzheimer's disease (AD) and stroke are two interrelated neurodegenerative disorders which are the leading cause of death and affect the neurons in the brain and central nervous system. Although amyloid-β aggregation, tau hyperphosphorylation, and inflammation are the hallmarks of AD, the exact cause and origin of AD are still undefined. Recent enormous fundamental discoveries suggest that the amyloid hypothesis of AD has not been proven and anti-amyloid therapies that remove amyloid deposition have not yet slowed cognitive decline. However, stroke, mainly ischemic stroke (IS), is caused by an interruption in the cerebral blood flow. Significant features of both disorders are the disruption of neuronal circuitry at different levels of cellular signaling, leading to the death of neurons and glial cells in the brain. Therefore, it is necessary to find out the common molecular mechanisms of these two diseases to understand their etiological connections. Here, we summarized the most common signaling cascades including autotoxicity, ApoE4, insulin signaling, inflammation, mTOR-autophagy, notch signaling, and microbiota-gut-brain axis, present in both AD and IS. These targeted signaling pathways reveal a better understanding of AD and IS and could provide a distinguished platform to develop improved therapeutics for these diseases.

Investigating the Glucagon-like Peptide-1 and Its Receptor in Human Brain: Distribution of Expression, Functional Implications, Age-related Changes and Species Specific Characteristics

Introduction: Emerging evidence has shown that the glucagon-like peptide-1 (GLP-1) agonist can be used to treat Alzheimer disease; however, knowledge of its neural targets is limited. To understand the neural substrates of GLP-1, we have done whole brain mapping for GLP-1 and its receptor (GLP-1R), in 30 human brains. Methods: GLP-1 expression was studied by immuno-histochemistry and confirmed by the western blot method. The GLP-1R gene expression was studied by reverse transcription polymerase chain reaction. Results: GLP-1 expression was observed in most of the cortical areas (maximum in frontal, prefrontal and parietal cortex), diencephalon, and brainstem, but not in the cerebellum. Protein expression studies validated these results. The highest expression of GLP-1R was found in the frontal cortex. The orbitofrontal cortex and cerebellum had negligible expression. Hippocampus demonstrated a significant presence of GLP-1R but patchy immunoreactivity to GLP-1. GLP-1R presence in most of the human cortical regions and absence in the cerebellum is the major deviation from the animal brain. Sites that might be of interest in Alzheimer have been identified. GLP-1 demonstrated an age-related decline in most of the areas after the fifth decade. At 60 years, GLP-1 was not found in any of the cortical areas except in the prefrontal cortex; however, it was present in the sub-cortical areas. Conclusion: Age-related profiling of GLP-1 in various brain areas has been analyzed, which can have an important bearing on understanding Alzheimer disease. This study provides a detailed description of GLP-1 and an brain mapping for the first time and may lead to novel treatment options targeting the GLP-1 receptors.

Protection against toxic amyloid-beta oligomers by PMN310, a monoclonal antibody rationally designed for greater therapeutic potency in Alzheimer’s disease (P1-6.006)

<h3>Objective:</h3> Evaluate the protective activity of PMN310 against toxic amyloid-beta oligomers (AßO) in vitro and in vivo <h3>Background:</h3> Advances in the understanding of Alzheimer’s disease (AD) suggest that pathogenesis is not directly related to plaque burden, but rather to soluble toxic AßO. Therapeutic antibodies targeting Aß monomers and/or plaque have shown limited efficacy and dose-limiting adverse events in clinical trials. These findings suggest that antibodies capable of selectively neutralizing toxic AßO may achieve improved efficacy and safety. Monoclonal antibody PMN310 was raised against a conformational Aß epitope predicted by computational modeling to be exposed on toxic AßO but not monomers or fibrils. <h3>Design/Methods:</h3> The binding selectivity of PMN310 was characterized by surface plasmon resonance (SPR) and immunohistochemistry (IHC). Its ability to neutralize the propagation and toxicity of AßO was assessed in vitro in a thioflavin-T propagation assay and in cultures of primary rodent neurons, respectively. In vivo protection was tested in wild-type mice injected intracerebroventricularly (ICV) with AßO and in the APP/L transgenic mouse model of AD. <h3>Results:</h3> In SPR analysis, PMN310 showed little or no interaction with Aß monomers and, compared to other Aß-directed antibodies, was among the least impacted by excess monomer competition in binding to synthetic oligomers or naturally occurring toxic oligomers in AD brain extract. PMN310 additionally avoided interaction with plaque and vascular deposits as determined by IHC. In vitro, PMN310 inhibited AßO propagation and neuronal toxicity. In vivo, PMN310 prevented AßO-induced loss of memory formation after ICV injection, and systemic administration to APP/L transgenic mice preserved memory and learning in the water maze task. <h3>Conclusions:</h3> The antibody PMN310 was shown to selectively bind toxic AßO and protect against their pathogenic activity in vitro. In two rodent models of AD, PMN310 protected memory function, suggesting that PMN310 may offer a new therapeutic option for the treatment or prevention of AD. <b>Disclosure:</b> Dr. Kaplan has received personal compensation for serving as an employee of ProMIS Neurosciences. Dr. Kaplan has stock in ProMIS Neurosciences. Dr. Kaplan has received intellectual property interests from a discovery or technology relating to health care. Dr. Gibbs has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for Promis Neuroscinces. Judith Silverman has received personal compensation for serving as an employee of Bill &amp; Melinda Gates Foundation. Beibei Zhao has received intellectual property interests from a discovery or technology relating to health care. Ms. Coutts has nothing to disclose. Xubiao Peng has nothing to disclose. Steven S. Plotkin has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for ProMIS Neurosciences. Steven S. Plotkin has stock in ProMIS Neurosciences. The institution of Steven S. Plotkin has received research support from Canadian Institutes of Health Research. The institution of Steven S. Plotkin has received research support from Digital Technology Supercluster. Steven S. Plotkin has received intellectual property interests from a discovery or technology relating to health care. Dr. Cashman has received personal compensation for serving as an employee of ProMIS Neurosciences. Dr. Cashman has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Mitsubishi-Tanabe. Dr. Cashman has stock in ProMIS Neurosciences. The institution of Dr. Cashman has received research support from ProMIS Neurosciences. Dr. Cashman has received intellectual property interests from a discovery or technology relating to health care. Dr. Cashman has a non-compensated relationship as a BoD memeber with ALS Society of BC that is relevant to AAN interests or activities.

The Eye as a Diagnostic Tool for Alzheimer’s Disease

Alzheimer's disease (AD) is a progressive neurodegenerative disorder impacting cognition, function, and behavior in the elderly population. While there are currently no disease-modifying agents capable of curing AD, early diagnosis and management in the preclinical stage can significantly improve patient morbidity and life expectancy. Currently, the diagnosis of Alzheimer's disease is a clinical one, often supplemented by invasive and expensive biomarker testing. Over the last decade, significant advancements have been made in our understanding of AD and the role of ocular tissue as a potential biomarker. Ocular biomarkers hold the potential to provide noninvasive and easily accessible diagnostic and monitoring capabilities. This review summarizes current research for detecting biomarkers of Alzheimer's disease in ocular tissue.

Contributions of blood-brain barrier imaging to neurovascular unit pathophysiology of Alzheimer's disease and related dementias.

The blood-brain barrier (BBB) plays important roles in the maintenance of brain homeostasis. Its main role includes three kinds of functions: (1) to protect the central nervous system from blood-borne toxins and pathogens; (2) to regulate the exchange of substances between the brain parenchyma and capillaries; and (3) to clear metabolic waste and other neurotoxic compounds from the central nervous system into meningeal lymphatics and systemic circulation. Physiologically, the BBB belongs to the glymphatic system and the intramural periarterial drainage pathway, both of which are involved in clearing interstitial solutes such as β-amyloid proteins. Thus, the BBB is believed to contribute to preventing the onset and progression for Alzheimer's disease. Measurements of BBB function are essential toward a better understanding of Alzheimer's pathophysiology to establish novel imaging biomarkers and open new avenues of interventions for Alzheimer's disease and related dementias. The visualization techniques for capillary, cerebrospinal, and interstitial fluid dynamics around the neurovascular unit in living human brains have been enthusiastically developed. The purpose of this review is to summarize recent BBB imaging developments using advanced magnetic resonance imaging technologies in relation to Alzheimer's disease and related dementias. First, we give an overview of the relationship between Alzheimer's pathophysiology and BBB dysfunction. Second, we provide a brief description about the principles of non-contrast agent-based and contrast agent-based BBB imaging methodologies. Third, we summarize previous studies that have reported the findings of each BBB imaging method in individuals with the Alzheimer's disease continuum. Fourth, we introduce a wide range of Alzheimer's pathophysiology in relation to BBB imaging technologies to advance our understanding of the fluid dynamics around the BBB in both clinical and preclinical settings. Finally, we discuss the challenges of BBB imaging techniques and suggest future directions toward clinically useful imaging biomarkers for Alzheimer's disease and related dementias.

Establishing the Validity and Reliability of an Online Motor Learning Game: Applications for Alzheimer's Disease Research Within MindCrowd.

Objective: Motor practice effects (i.e., improvements in motor task performance with practice) are emerging as a unique variable that can predict Alzheimer's disease (AD) progression and biomarker positivity. However, the tasks used to study motor practice effects have involved face-to-face assessment, making them difficult to integrate into large internet-based cohorts that represent the next generation of AD research. The purpose of this study was to validate an online computer game against its in-lab version, which has been shown previously to characterize motor practice effects. Materials and Methods: This study leveraged young adult participants within the MindCrowd electronic cohort, a large nationwide cohort for AD research collected entirely through the internet. Validation compared performance on the online version among MindCrowd users against an age-matched cohort's performance on an in-lab version using a different controller (Xbox 360 controller joystick for in-lab sample versus keyboard arrow keys for online sample). Results: Data indicated that the rate of skill acquisition among MindCrowd users were not significantly different from those of the in-lab cohort. Furthermore, the contact-to-consent rate observed in this study (although low) was similar to that of other online AD cohorts. Conclusion: Overall, this study demonstrates that implementing online games designed to study and measure motor practice effects into online research cohorts is feasible and valid. Future research will explore how online game performance is associated with age and dementia risk factors that may help further an understanding of AD.