AD Therapy Research Articles

Exploring the gut-brain axis in alzheimer’s disease treatment via probiotics: evidence from animal studies-a systematic review and meta-analysis

IntroductionAlzheimer’s disease (AD) is a prevalent neurodegenerative disorder in the elderly, causing cognitive impairment. Its pathogenesis is characterized by amyloid beta deposition, neurofibrillary tangles, and neuroinflammation. Recent research has identified the link between gut dysbiosis, an imbalance of intestinal microorganisms, to this pathogenesis via the gut-brain axis. This study aims to review the probiotics’ therapeutic effect, targeting the gut-brain axis, for AD treatment in animals.MethodsThe method utilized in this study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline. Three reviewers searched articles through PubMed, Scopus, and Embase using advanced search strategy. Articles published between 2010 and 2023 that met the criteria were included.ResultsOf 2,273 articles, 21 animal studies measuring the effects of probiotics genera Lactobacillus and/or Bifidobacterium on AD via at least one of these four outcomes: AD pathology, cognitive function, neuroinflammation, and gut microbiota composition. The results demonstrated that probiotics could repair gut dysbiosis by decreasing pro-inflammatory bacteria and increasing anti-inflammatory bacteria. Repaired dysbiosis was found to be associated with less neuroinflammation as significant reductions in neuroinflammatory markers related to the pathogenesis of AD such as TNF-α (SMD = -2.08, P = 0.005), IL-6 (SMD = -2.98, P < 0.0005), and IL-1β (SMD = -2.49, P = 0.003) were observed. Reduced amyloid beta deposition (SMD = -1.17, P = 0.009) was reported, but reduction in tau hyperphosphorylation was found to be insignificant. For cognitive function, positive results were demonstrated for all three aspects of cognitive function including long-term memory (SMD = 2.55, P < 0.00001), short-term memory (SMD = 1.32, P = 0.003), and spatial recognition (SMD = -1.13, P < 0.00001).ConclusionsParticular formulas of probiotics showed potential effectiveness in AD therapies with demonstrated association with the gut-brain axis. Future studies are required to investigate strain-specific results and optimal dosages and regimens.

Lysosome-Targeting Protein Degradation Through Endocytosis Pathway Triggered by Polyvalent Nano-Chimera for AD Therapy.

The excessive up-regulation of receptor for advanced glycation end products (RAGE), a well-known pathological marker, drives the onset and progression of Alzheimer's disease. Although lysosome-targeting protein degradation has emerged as an effective therapeutic modality, the limited lysosome-sorting efficacy greatly hindered the degradation efficiency of target proteins. Herein, a lysosome-shuttle-like nano-chimera (endoTAC) is proposed based on polyvalent receptor binding mode for enhanced RAGE degradation as well as precise drug delivery. The endoTAC shows a high affinity to RAGE and enhances RAGE degradation due to its polyvalent-interaction with RAGE. Additionally, endoTAC features increased accumulation in diseased brain and shows promise as a precise brain delivery system. After loading with simvastatin, the SV@endoTAC proves to successfully reverse pathological features both in vitro and in vivo. The work proposes that the combination of a lysosome-targeting chimera and an effective drug delivery system can be promising in Alzheimer's disease therapy.

Zebrafish Experimental Animal Models for AD: A Comprehensive Review.

AD disease (AD) is a multifaceted and intricate neurodegenerative disorder characterized by intracellular neurofibrillary tangle (NFT) formation and the excessive production and deposition of Aβ senile plaques. While transgenic AD models have been found instrumental in unravelling AD pathogenesis, they involve cost and time constraints during the preclinical phase. Zebrafish, owing to their simplicity, well-defined behavioural patterns, and relevance to neurodegenerative research, have emerged as a promising complementary model. Zebrafish possess glutaminergic and cholinergic pathways implicated in learning and memory, actively contributing to our understanding of neural transmission processes. This review sheds light on the molecular mechanisms by which various neurotoxic agents, including okadaic acid (OKA), cigarette smoke extract, metals, and transgenic zebrafish models with genetic similarities to AD patients, induce cognitive impairments and neuronal degeneration in mammalian systems. These insights may facilitate the identification of effective neurotoxic agents for replicating AD pathogenesis in the zebrafish brain. In this comprehensive review, the pivotal role of zebrafish models in advancing our comprehension of AD is emphasized. These models hold immense potential for shaping future research directions and clinical interventions, ultimately contributing to the development of novel AD therapies.

Efficient synthesis and molecular docking of new organoselenium and organosulphur compounds as dual inhibitors for the therapy of Alzheimer's disease as well as Diabetes Mellitus

There are several oxidative stress-related pathways interconnecting Alzheimer's disease and type II diabetes, two public health problems worldwide. Therefore, development of potential multifunctional agents for dual therapy of AD and T2D has received much attention. The present study was aimed to synthesize a new selenocarbonyl and thiocarbonyl compounds and evaluating multifunctional ability of them in the AD and T2D dual therapy. [(PhP(Se)(μ-Se)]2, the selenium counterpart of the well-known sulfur transfer Lawesson's reagent, is a useful reagent for the synthesis of selenocarbonyl compounds. For the conversion of various carbonyl compounds into thiocarbonyl derivatives was formulated by its reaction with LR, [(p-MeOC6H4)P(S)(μ-S)]2. The reactions are carried out under mild conditions and afforded the seleno and thio compounds in good yields. By measuring the newly created compounds' overall antioxidant capacity, iron-reducing ability, and scavenging activity against DPPH and ABTS radicals, they were investigated as antioxidant molecules. Additionally, all the compounds were subjected to further investigation by testing their acetylcholinesterase, α-amylase and α-glucosidase inhibiting activity. According to our findings, the amide derivatives exhibited more promising biological inhibitory actions in comparison to the other compounds. With a total antioxidant capacity (TAC) of 75.11 ± 0.04 mg gallic acid/gm, an iron-reducing power (IRP) of 69.86 ± 0.04 µg/mL, a DPPH radical-scavenging activity (%) of 55.89 ± 0.03 (IC50 = 6.19 ± 0.03 µg/ml), and an ABTS radical-scavenging activity (%) of 61.14 ± 0.03 (IC50 = 4.97 ± 0.06 µg/mL), benzoselenoamide derivative 11b in particular showed the highest antioxidant activities when compared to ascorbic acid. It also affected the activity of acetylcholinesterase through competitive inhibition, which was on par with Donepezil as indicated by in vitro percentage of inhibition 57.44 ± 0.07 % (IC50 = 5.13 ± 0.03 µg/mL). Additionally, it exhibited a comparable level of inhibition to Acarbose in the in vitro percentage of inhibition for α-amylase and α-glucosidase activity, 53.17 ± 0.03 (IC50 = 4.32 ± 0.02) and 42.92 ± 0.03 (IC50 = 2.99 ± 0.02) respectively. Furthermore, molecular docking calculations were made to explain the dual inhibitors for the therapy of Alzheimer's as well as Diabetes Mellitus for all synthesized compounds. In silco docking results revealed that compound 11b were the top docked bioactive compounds against the target proteins (AChE as a cholinergic enzyme and 11-Beta-Hydroxysteroid dehydrogenase-1(11β-HSD1)). After these calculations, ADMET analysis was performed to examine the drug properties of all novel compounds. Overall, the results demonstrated that the organoselenium-based compounds might serve as possible drugs for the therapy of Alzheimer's disease as well as Diabetes Mellitus.

Benefits and risks of FDA-approved amyloid-targeting antibodies for treatment of early Alzheimer's disease: Navigating clinician-patient engagement.

The emergence of the United States Food and Drug Administration (FDA)-approved amyloid-targeting therapies for Alzheimer's disease challenges clinicians and healthcare providers with a transformative landscape. Effectively communicating the risks, benefits, burdens, costs, and available support associated with these novel disease-modifying treatments to patients, families, and other healthcare providers is essential but complex. In response, the Alzheimer's Association's Clinical Meaningfulness Workgroup has proposed language surrounding treatment eligibility, benefits, amyloid-related imaging abnormalities (ARIA), apolipoprotein E (APOE) genotyping, and treatment costs, serving as a resource to healthcare professionals in navigating discussions with patients and their families. As the landscape evolves with the approval of new Alzheimer's therapies, this resource stands poised for updates, ensuring its continued relevance in facilitating informed and meaningful patient-provider dialogues. HIGHLIGHTS: Effective communication of risks, benefits, burdens, and costs of FDA-approved amyloid-targeting antibodies is essential to patients, families, and healthcare providers. The Alzheimer's Association's Clinical Meaningfulness Workgroup provides language for physicians and healthcare providers around treatment eligibility, benefits, ARIA, APOE genotyping, and treatment costs. This supplementary resource may be updated as new AD therapies become approved.

A Framework for Best Practices and Readiness in the Advent of Anti-Amyloid Therapy for Early Alzheimer's Disease in Asia.

Advances in biomarker-based diagnostic modalities, recent approval of anti-amyloid monoclonal antibodies for early Alzheimer's disease (AD; mild cognitive impairment or mild dementia due to AD) and late-stage clinical development of other disease-modifying therapies for AD necessitate a significant paradigm shift in the early detection, diagnosis and management of AD. Anti-amyloid monoclonal antibodies target the underlying pathophysiological mechanisms of AD and have demonstrated a significant reduction in the rate of clinical decline in cognitive and functional outcome measures in patients with early AD. With growing recognition of the benefit of early interventions in AD, an increasing number of people may seek diagnosis for their subjective cognitive problems in an already busy medical system. Various factors such as limited examination time, lack of expertise for cognitive assessment and limited access to specialized tests can impact diagnostic accuracy and timely detection of AD. To overcome these challenges, a new model of care will be required. In this paper, we provide practical guidance for institutional readiness for anti-amyloid therapies for early AD in Asia, in terms of best practices for identifying eligible patients and diagnosing them appropriately, safe administration of anti-amyloid monoclonal antibodies and monitoring of treatment, managing potential adverse events such as infusion reactions and amyloid-related imaging abnormalities, and cross-disciplinary collaboration. Education and training will be the cornerstone for the establishment of new pathways of care for the identification of patients with early AD and delivery of anti-amyloid therapies in a safe and efficient manner to eligible patients.

Immune rejuvenation - a potential AD therapy.

Immune rejuvenation - a potential AD therapy.

Inflammation, Autoimmunity and Neurodegenerative Diseases, Therapeutics and Beyond.

Neurodegenerative disease (ND) incidence has recently increased due to improved life expectancy. Alzheimer's (AD) or Parkinson's disease (PD) are the most prevalent NDs. Both diseases are poly genetic, multifactorial and heterogenous. Preventive medicine, a healthy diet, exercise, and controlling comorbidities may delay the onset. After the diseases are diagnosed, therapy is needed to slow progression. Recent studies show that local, peripheral and age-related inflammation accelerates NDs' onset and progression. Patients with autoimmune disorders like inflammatory bowel disease (IBD) could be at higher risk of developing AD or PD. However, no increase in ND incidence has been reported if the patients are adequately diagnosed and treated. Autoantibodies against abnormal tau, β amyloid and α- synuclein have been encountered in AD and PD and may be protective. This discovery led to the proposal of immune-based therapies for AD and PD involving monoclonal antibodies, immunization/ vaccines, pro-inflammatory cytokine inhibition and anti-inflammatory cytokine addition. All the different approaches have been analysed here. Future perspectives on new therapeutic strategies for both disorders are concisely examined.

SSK1-Loaded Neurotransmitter-Derived Nanoparticles for Alzheimer's Disease Therapy via Clearance of Senescent Cells.

Age is a significant contributor to the onset of AD. Senolysis has been recently demonstrated to ameliorate aging-associated diseases that showing a great potential in AD therapy. However, due to the presence of BBB, the anti-AD activity of senolytics are significantly diminished. SSK1 is a prodrug that can be activated by β-gal, a lysosomal enzyme commonly upregulated in senescent cells, and thus selectively eliminates senescent cells. Furthermore, the level of β-gal is significantly correlated with conventional AD genes from clinical sequencing data. SSK1-loaded neurotransmitter -derived lipid nanoparticles are herein developed (SSK1-NPs) that revealing good BBB penetration and bioavailability of in the body. At the brain lesion, SSK1-NP treatment significantly reduces the expression of genes associated with senescence, induced senescent cells elimination, decreased amyloid-beta accumulation, and eventually improve cognitive function of aged AD mice. SSK1-NPs, a novel nanomedicine displaying potent anti-AD activity and excellent safety profile, provides a promising strategy for AD therapy.

Neuroprotective effects of repetitive transcranial magnetic stimulation on Alzheimer's disease: Undetermined therapeutic protocols and mechanisms

AbstractAlzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by gradual deterioration of cognitive functions, for which an effective treatment is currently unavailable. Repetitive transcranial magnetic stimulation (rTMS), a well‐established noninvasive brain stimulation method, is utilized in clinical settings to address various neuropsychiatric conditions, such as depression, neuropathic pain, and poststroke dysfunction. Increasing evidence suggests that rTMS may enhance cognitive abilities in individuals with AD. However, its optimal therapeutic protocols and precise mechanisms are currently unknown, impeding its clinical implementation. In the present review, we aimed to summarize and discuss the efficacy‐related parameters in rTMS treatment, encompassing stimulus frequency, stimulus pattern, stimulus intensity, and the configuration of the stimulus coil. Furthermore, we reviewed promising rTMS therapeutic protocols involving various combinations of these factors, that were examined in clinical studies. Based on our analysis, we propose that a multisite high‐frequency rTMS (HF‐rTMS) regimen has value in AD therapy, and that promising single‐site protocols, such as HF‐rTMS, applied over the left dorsolateral prefrontal cortex, precuneus, or cerebellum are required to be validated in larger clinical studies. Lastly, we provide a comprehensive review of the potential mechanisms underlying the neuroprotective effects of rTMS on cognition in AD in terms of brain network modulation as well as cellular and molecular reactions. In conclusion, the interaction of diverse mechanisms may be responsible for the total therapeutic effect of rTMS on AD. This review provides theoretical and practical evidence for the future clinical application and scientific research of rTMS in AD.

A recent update on huprine and its hybrids as a potential multifunctional agent for the treatment of Alzheimer's disease

AbstractAlzheimer's disease (AD) is a common age‐related neurodegenerative brain disorder characterized by the impairment in memory and other cognitive functions. Although there is currently no successful pharmacotherapy for AD, researchers are continuously exploring the various pathogenesis of AD to develop potential therapeutic drugs. Of the multiple hypotheses for AD, the cholinergic and amyloid‐β (Aβ) hypothesis are the main targeting hypothesis for AD. Some researchers proposed that the symptoms involved in AD (loss of memory, cognitive impairment, and amnesia) are the main event linked to the cholinergic neurotransmitter (acetylcholine). Therefore, the development of AChE inhibitors to increase the level of ACh in the synaptic cleft can improve learning and memory in AD patients. Huprine X is a synthetic ChE inhibitor developed by the hybridization of Huperzine A and the synthetic drug tacrine. This review focuses on the last 10 year's literature search on huprine and its analogues for the treatment of AD. We expect that this review can be helpful for medicinal chemists, and neuro‐chemists to provide new ideas for the development of new drugs therapy for AD.

A nonhuman primate model with Alzheimer’s disease-like pathology induced by hippocampal overexpression of human tau

BackgroundAlzheimer’s disease (AD) is one of the most burdening diseases of the century with no disease-modifying treatment at this time. Nonhuman primates (NHPs) share genetic, anatomical, and physiological similarities with humans, making them ideal model animals for investigating the pathogenesis of AD and potential therapies. However, the use of NHPs in AD research has been hindered by the paucity of AD monkey models due to their long generation time, ethical considerations, and technical challenges in genetically modifying monkeys.MethodsHere, we developed an AD-like NHP model by overexpressing human tau in the bilateral hippocampi of adult rhesus macaque monkeys. We evaluated the pathological features of these monkeys with immunostaining, Nissl staining, cerebrospinal fluid (CSF) analysis, magnetic resonance imaging (MRI), positron emission tomography (PET), and behavioural tests.ResultsWe demonstrated that after hippocampal overexpression of tau protein, these monkeys displayed multiple pathological features of AD, including 3-repeat (3R)/4-repeat (4R) tau accumulation, tau hyperphosphorylation, tau propagation, neuronal loss, hippocampal atrophy, neuroinflammation, Aβ clearance deficits, blood vessel damage, and cognitive decline. More interestingly, the accumulation of both 3R and 4R tau is specific to NHPs but not found in adult rodents.ConclusionsThis work establishes a tau-induced AD-like NHP model with many key pathological and behavioural features of AD. In addition, our model may potentially become one of the AD NHP models adopted by researchers worldwide since it can be generated within 2 ~ 3 months through a single injection of AAVs into the monkey brains. Hence, our model NHPs may facilitate mechanistic studies and therapeutic treatments for AD.

Nanotechnology for microglial targeting and inhibition of neuroinflammation underlying Alzheimer’s pathology

BackgroundAlzheimer's disease (AD) is considered to have a multifactorial etiology. The hallmark of AD is progressive neurodegeneration, which is characterized by the deepening loss of memory and a high mortality rate in the elderly. The neurodegeneration in AD is believed to be exacerbated following the intercoupled cascades of extracellular amyloid beta (Aβ) plaques, uncontrolled microglial activation, and neuroinflammation. Current therapies for AD are mostly designed to target the symptoms, with limited ability to address the mechanistic triggers for the disease. In this study, we report a novel nanotechnology based on microglial scavenger receptor (SR)-targeting amphiphilic nanoparticles (NPs) for the convergent alleviation of fibril Aβ (fAβ) burden, microglial modulation, and neuroprotection.MethodsWe designed a nanotechnology approach to regulate the SR-mediated intracellular fAβ trafficking within microglia. We synthesized SR-targeting sugar-based amphiphilic macromolecules (AM) and used them as a bioactive shell to fabricate serum-stable AM–NPs via flash nanoprecipitation. Using electron microscopy, in vitro approaches, ELISA, and confocal microscopy, we investigated the effect of AM–NPs on Aβ fibrilization, fAβ-mediated microglial inflammation, and neurotoxicity in BV2 microglia and SH-SY5Y neuroblastoma cell lines.ResultsAM–NPs interrupted Aβ fibrilization, attenuated fAβ microglial internalization via targeting the fAβ-specific SRs, arrested the fAβ-mediated microglial activation and pro-inflammatory response, and accelerated lysosomal degradation of intracellular fAβ. Moreover, AM–NPs counteracted the microglial-mediated neurotoxicity after exposure to fAβ.ConclusionsThe AM–NP nanotechnology presents a multifactorial strategy to target pathological Aβ aggregation and arrest the fAβ-mediated pathological progression in microglia and neurons.Graphical

Bioinformatic identification and experiment validation reveal 6 hub genes, promising diagnostic and therapeutic targets for Alzheimer’s disease

BackgroundAlzheimer’s disease (AD) is a progressive neurodegenerative disease that can cause dementia. We aim to screen out the hub genes involved in AD based on microarray datasets.MethodsGene expression profiles GSE5281 and GSE28146 were retrieved from Gene Expression Omnibus database to acquire differentially expressed genes (DEGs). Gene Ontology and pathway enrichment were conducted using DAVID online tool. The STRING database and Cytoscape tools were employed to analyze protein-protein interactions and identify hub genes. The predictive value of hub genes was assessed by principal component analysis and receiver operating characteristic curves. AD mice model was constructed, and histology was then observed by hematoxylin-eosin staining. Gene expression levels were finally determined by real-time quantitative PCR.ResultsWe obtained 197 overlapping DEGs from GSE5281 and GSE28146 datasets. After constructing protein-protein interaction network, three highly interconnected clusters were identified and 6 hub genes (RBL1, BUB1, HDAC7, KAT5, SIRT2, and ITGB1) were selected. The hub genes could be used as basis to predict AD. Histological abnormalities of brain were observed, suggesting successful AD model was constructed. Compared with the control group, the mRNA expression levels of RBL1, BUB1, HDAC7, KAT5 and SIRT2 were significantly increased, while the mRNA expression level of ITGB1 was significantly decreased in AD groups.ConclusionRBL1, BUB1, HDAC7, KAT5, SIRT2 and ITGB1 are promising gene signatures for diagnosis and therapy of AD.

The evolution of Alzheimer’s disease therapies: A comprehensive review

Abstract Alzheimer`s disease (AD) is a progressive neurodegenerative disease which accounts for most of the cases of dementia. The progression of the disease cannot be fully controlled by current medications, nor do they produce adequate therapeutic results. Understanding the molecular and cellular alterations linked to AD pathogenesis has advanced significantly in recent decades. Amyloid-peptide-containing cerebral plaques and thread-like neuronal structures made of the microtubule-associated protein TAU are two pathogenic features of the condition. Therefore, inhibiting amyloid formation, aggregation, or subsequent neurotoxic events is the primary goal of therapeutic drug development. Here, some newer therapeutic modalities are described, including anti-amyloid therapy, anti-tau therapy, antineuroinflammatory therapy, neuroprotective agents including N-methyl- d -aspartate (NMDA) receptor modulators, and brain stimulation. Drug repositioning may speed up the development of pharmaceuticals, but non-pharmacological therapies, particularly repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), also have the potential to be used in therapeutic settings. Here we discussed current symptomatic therapy for AD as well as novel prospective disease-modifying medicines that are presently being investigated in phase I–III trials in this review. The study emphasizes how taking into account the intricate nature of AD pathogenesis and investigating drug repurposing strategies which can open the door to the creation of innovative AD therapies.

Nano-based Cell therapy for AD and PD

Nano-based Cell therapy for AD and PD

Diagnostic and prognostic value of biomarkers in atopic dermatitis for assessing its endotypes, phenotypes, and treatment efficacy

Atopic dermatitis is a highly heterogeneous disease that usually requires a tailored approach to therapy. Recent studies have described a variety of biomarkers linked to diverse pathophysiological aspects of atopic dermatitis. Furthermore, they have provided encouraging evidence supporting high clinical importance of these biomarkers as promising tools for personalized diagnosis, assessment of disease severity, and monitoring of treatment efficacy. This review aims to provide a comprehensive summary of research progress on atopic dermatitis biomarkers, their diagnostic and prognostic value, as well as the benefits they might potentially offer not only for determining the disease endotype, but also for developing novel management strategies. The implementation of easily accessible and simple methods to measure atopic dermatitis biomarkers into clinical practice is an ambitious task for allergologists and dermatologists. A detailed overview of currently available data will allow us to identify the most important trajectories for future research in this area that will promote the concept of personalized atopic dermatitis therapy, reduce the disease burden, and improve the quality of life of patients.

The European Platform for Neurodegenerative Diseases (EPND)

AbstractBackgroundBiomarker discovery, development, and validation are reliant on large‐scale analyses of high‐quality samples and data. However, discovery, access, and sharing of data and samples are hindered both by silos that limit collaboration, and by complex requirements for secure, legal, and ethical sharing. The European Platform for Neurodegenerative Diseases (EPND) project aims to address these challenges and accelerate biomarker discovery, development and validation, by building a scalable, sustainable platform for collaboration, data and sample sharing. In this presentation we will give an overview of the design of EPND and the achievements in the first year of this 5‐year project.MethodEPND is a multidisciplinary consortium of 29 public and private partners with expertise on data discovery, ethical, legal and regulatory aspects of data sharing, biomarker studies, stakeholder engagement and sustainability. EPND will leverage existing data and research infrastructures, including the Alzheimer’s Disease Data Initiative (ADDI) AD Workbench, which will allow the platform to connect to a global research network. EPND was launched in November 2021 and is funded by the Innovative Medicines Initiative (IMI, grant agreement number 101034344, epnd.org).ResultIn this first year of the project, the design of the data platform has been finalised. EPND has launched its Cohort Catalogue, which features information on participants, samples and data from 60+ neurodegeneration cohorts, spanning 17 countries and 13 disease areas, and involving over 155,000 patients. In addition to standardised operational procedures on sample selection, biobanking, and data harmonisation, we have also developed a white paper on legal, ethical and regulatory aspects of data and sample sharing. Finally, we have performed case studies on ATN biomarkers in plasma and blood in 350 patients with Alzheimer’s disease, Parkinson’s disease and Lewy body dementia.ConclusionWe initiated a multidisciplinary consortium with the goal to accelerate collaborative research into the discovery and validation of biomarkers, to support development of diagnostics and disease‐modifying therapies for AD and other neurodegenerative diseases.

Establishing glial responses to anti‐Aβ immunotherapy through single‐cell RNAseq to gain insights into mechanisms of ARIA

AbstractBackgroundWhile anti‐Aβ immunotherapies effectively clear Aβ plaques, mouse and human data show consistent and significant cerebrovascular adverse events of this treatment approach. Anti‐Aβ immunotherapies have been plagued in clinical trials by the occurrence of amyloid‐related imaging abnormalities (ARIA), signifying cerebrovascular disruptions of the edema (ARIA‐E) or hemorrhagic (ARIA‐H) type in the brain. Despite these cerebrovascular adverse effects, the FDA granted accelerated approval to aducanumab and lecanemab. However, our mechanistic understanding underlying ARIA remains minimal. Elucidating the mechanism(s) by which anti‐Aβ antibodies cause ARIA is critical towards improving safety of these therapies for AD. MethodIn the current study, we aimed to determine the glial responses to anti‐Ab antibodies with the hypothesis that astrocytes and microglia have temporal cellular shifts that contribute to cerebrovascular dysfunction after acute anti‐Aβ antibody administration. To identify changes in glial gene expression in response to acute anti‐Aβ antibody we performed a single cell sequencing and digital spatial profiling (DSP) on 14mo Tg2576 APP mice (Fig. 1). We observed differences in size of clusters between anti‐Aβ (6E10) and IgG control (IgG1) intracranial injections after 24hr and 3days, suggesting some clusters of cells respond to anti‐Aβ in a time‐dependent or antibody manner (Fig. 2).ResultPreliminary data identified some of the clusters as microglia (Cx3cr1) and astrocytes (Aldoc), as well as oligodendrocytes (Plp). Apoe was increased in multiple cell types. DSP on these mice is ongoing, however we aim to further characterize the transcriptional profile of glia at the vasculature, and in the vicinity of Aβ plaques and cerebral amyloid angiopathy (CAA). Contralateral hemispheres are utilized for downstream validation studies.ConclusionOur work will elucidate the mechanisms of anti‐Aβ antibody‐induced glial response and establish the role of astrocytes and microglia in cerebrovascular dysfunction and ARIA. This work is critical to improve safety and increase generalizability of these therapies.

Cerebral microbleeds and amyloid pathology

AbstractBackgroundCerebral microbleeds (CMBs) are common in the elderly population and are associated with cognitive decline. The aim of the current study was to examine the association between CMBs and cerebral amyloid pathology in cognitively unimpaired (CU) and cognitively impaired (CI) individuals included in the Amyloid Biomarker Study.MethodWe included 2550 CU and 1002 CI participants from 12 cohorts of the Amyloid Biomarker Study. Presence of amyloid pathology was determined based on Aß42 levels in CSF (n = 2873) or amyloid‐PET (n = 679) using data‐driven or center‐specific cutoffs. CMBs were assessed on in vivo MRI and were classified as present (≥1) or absent. The association of amyloid pathology with CMBs and its dependency on age, sex, APOE‐e4 carriership and hypertension was assessed using generalized‐estimating‐equations.ResultThirty‐seven percent of participants were amyloid positive, 38% were APOE‐e4 carrier, 54% were female, 30% had hypertension and 17% had CMBs (20% of the amyloid positive and 16% of the amyloid negative group, respectively). The mean age was 66.7 years (SD9.2). In CU participants, there was no association between amyloid pathology and CMBs. In CI individuals, CMB prevalence was associated with amyloid pathology depending on age (p = 0.044). At younger ages (&lt;75 years), CMBs were more common in amyloid positive rather than amyloid negative participants while at older ages, amyloid negative participants had CMBs more often. However, the interaction between amyloid status and age became insignificant when hypertension was considered. CMB prevalence was associated with amyloid pathology depending on hypertension (p = 0.006). In CI participants without hypertension, CMBs were more common in those that were amyloid positive rather than amyloid negative. In CI participants with hypertension, there was no significant difference in CMB prevalence between the amyloid positive and negative groups (Figure 1). Sex and APOE‐e4 status did not affect the observed associations between amyloid pathology and CMBs in participants with CI.ConclusionCMB prevalence is associated with amyloid pathology and this association is dependent on hypertension. Knowledge on the background prevalence of CMBs considering AD biomarker and vascular risk factor status is needed to inform clinical trial design and safety evaluation of AD therapies.