Alzheimer's Disease Medications 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.

Combining Deep Learning and Structural Modeling to Identify Potential Acetylcholinesterase Inhibitors from Hericium erinaceus.

Alzheimer's disease (AD) is the most common type of dementia, affecting over 50 million people worldwide. Currently, most approved medications for AD inhibit the activity of acetylcholinesterase (AChE), but these treatments often come with harmful side effects. There is growing interest in the use of natural compounds for disease prevention, alleviation, and treatment. This trend is driven by the anticipation that these substances may incur fewer side effects than existing medications. This research presents a computational approach combining machine learning with structural modeling to discover compounds from medicinal mushrooms with a high potential to inhibit the activity of AChE. First, we developed a deep neural network capable of rapidly screening a vast number of compounds to indicate their potential to inhibit AChE activity. Subsequently, we applied deep learning models to screen the compounds in the BACMUSHBASE database, which catalogs the bioactive compounds from cultivated and wild mushroom varieties local to Thailand, resulting in the identification of five promising compounds. Next, the five identified compounds underwent molecular docking techniques to calculate the binding energy between the compounds and AChE. This allowed us to refine the selection to two compounds, erinacerin A and hericenone B. Further analysis of the binding energy patterns between these compounds and the target protein revealed that both compounds displayed binding energy profiles similar to the combined characteristics of donepezil and galanthamine, the prescription drugs for AD. We propose that these two compounds, derived from Hericium erinaceus (also known as lion's mane mushroom), are suitable candidates for further research and development into symptom-alleviating AD medications.

Non-coding RNAs in Regulation of Protein Aggregation and Clearance Pathways: Current Perspectives Towards Alzheimer's Research and Therapy.

Alzheimer's disease (AD) is the leading cause of dementia, affecting approximately 45.0 million people worldwide and ranking as the fifth leading cause of mortality. AD is identified by neurofibrillary tangles (NFTs), which include abnormally phosphorylated tau-protein and amyloid protein (amyloid plaques). Peptide dysregulation is caused by an imbalance between the production and clearance of the amyloid-beta (Aβ) and NFT. AD begins to develop when these peptides are not cleared from the body. As a result, understanding the processes that control both normal and pathological protein recycling in neuronal cells is critical. Insufficient Aβ and NFT clearance are important factors in the development of AD. Autophagy, lysosomal dysfunction, and ubiquitin-proteasome dysfunction have potential roles in the pathogenesis of many neurodegenerative disorders, particularly in AD. Modulation of these pathways may provide a novel treatment strategy for AD. Non-coding RNAs (ncRNAs) have recently emerged as important biological regulators, with particular relevance to the emergence and development of neurodegenerative disorders such as AD. ncRNAs can be used as potential therapeutic targets and diagnostic biomarkers due to their critical regulatory functions in several biological processes involved in disease development, such as the aggregation and accumulation of Aβ and NFT. It is evident that ncRNAs play a role in the pathophysiology of AD. In this communication, we explored the link between ncRNAs and AD and their regulatory mechanisms that may help in finding new therapeutic targets and AD medications.

Association between Incidence of Prescriptions for Alzheimer's Disease and Beta-Adrenoceptor Antagonists: A Prescription Sequence Symmetry Analysis.

Alzheimer's disease (AD) is the most common cause of dementia, with a growing number of patients worldwide. The association between AD and treatment with drugs targeting the beta-adrenergic receptor is controversial. The aim of this study is to assess the association between the initiation of AD medication and beta-adrenoceptor antagonists (beta-blockers) in adults. We conducted a prescription sequence symmetry analysis using the University of Groningen IADB.nl prescription database. We determined the order of the first prescription for treating AD and the first prescription for beta-blockers, with the dispensing date of the first prescription for AD defined as the index date. Participants were adults over 45 years old starting any AD medication and beta-blockers within two years. We calculated adjusted sequence ratios with corresponding 95% confidence intervals. We identified 510 users of both AD and beta-blockers, and 145 participants were eligible. The results were compatible with either a significant decrease in the incidence of AD after using beta-blockers (adjusted sequence ratio (aSR) = 0.52; 95% CI: 0.35-0.72) or, conversely, an increase in beta-blockers after AD medication (aSR = 1.96; 95% CI: 1.61-2.30). There is a relationship between the use of beta-blockers and AD medications. Further research is needed with larger populations to determine whether drug therapy for AD increases the risk of hypertension or whether beta-blockers have potential protective properties against AD development.

Brexpiprazole for the Treatment of Agitation in Alzheimer Dementia

Agitation is a prevalent, distressing, and burdensome manifestation of Alzheimer dementia in need of an efficacious, safe, and well-tolerated treatment. To confirm the efficacy, safety, and tolerability of brexpiprazole in patients with agitation in Alzheimer dementia. This randomized clinical trial was a 12-week, double-blind, placebo-controlled, fixed-dose, parallel-arm trial that ran from May 2018 to June 2022 at 123 clinical trial sites in Europe and the United States. Participants included patients with agitation in Alzheimer dementia in a care facility or community-based setting. Stable Alzheimer disease medications were permitted. In this 2-arm trial, patients were randomized to receive oral brexpiprazole or placebo (2:1 ratio) for 12 weeks. Within the brexpiprazole arm, patients were further randomized to receive fixed doses of 2 mg/d or 3 mg/d in a 1:2 ratio. The primary end point was change in Cohen-Mansfield Agitation Inventory total score (which measures the frequency of 29 agitated behaviors) from baseline to week 12 for brexpiprazole, 2 or 3 mg, vs placebo. Safety was assessed by standard measures, including treatment-emergent adverse events. A total of 345 patients were randomized to receive brexpiprazole (n = 228) or placebo (n = 117); completion rates were 198 (86.8%) for brexpiprazole and 104 (88.9%) for placebo. Mean (SD) age was 74.0 (7.5) years, and 195 of 345 patients were female (56.5%). Patients receiving brexpiprazole, 2 or 3 mg (n = 225), demonstrated statistically significantly greater improvement than those taking placebo (n = 116) in Cohen-Mansfield Agitation Inventory total score from baseline to week 12 (brexpiprazole baseline, 80.6, mean change, -22.6; placebo baseline, 79.2, mean change, -17.3; least-squares mean difference, -5.32; 95% CI, -8.77 to -1.87; P = .003; Cohen d effect size, 0.35). No treatment-emergent adverse events had an incidence of 5% or more with brexpiprazole and greater incidence than placebo. The proportion of patients who discontinued because of adverse events was 12 of 226 (5.3%) for brexpiprazole and 5 of 116 (4.3%) for placebo. In this study, patients with Alzheimer dementia who took brexpiprazole, 2 or 3 mg, showed a statistically significant improvement vs placebo in agitation over 12 weeks. Brexpiprazole was generally well tolerated over 12 weeks in this vulnerable patient population. ClinicalTrials.gov Identifier: NCT03548584.

Pathophysiological Aspects and Therapeutic Armamentarium of Alzheimer's Disease: Recent Trends and Future Development.

Alzheimer's disease (AD) is the primary cause of dementia and is characterized by the death of brain cells due to the accumulation of insoluble amyloid plaques, hyperphosphorylation of tau protein, and the formation of neurofibrillary tangles within the cells. AD is also associated with other pathologies such as neuroinflammation, dysfunction of synaptic connections and circuits, disorders in mitochondrial function and energy production, epigenetic changes, and abnormalities in the vascular system. Despite extensive research conducted over the last hundred years, little is established about what causes AD or how to effectively treat it. Given the severity of the disease and the increasing number of affected individuals, there is a critical need to discover effective medications for AD. The US Food and Drug Administration (FDA) has approved several new drug molecules for AD management since 2003, but these drugs only provide temporary relief of symptoms and do not address the underlying causes of the disease. Currently, available medications focus on correcting the neurotransmitter disruption observed in AD, including cholinesterase inhibitors and an antagonist of the N-methyl-D-aspartate (NMDA) receptor, which temporarily alleviates the signs of dementia but does not prevent or reverse the course of AD. Research towards disease-modifying AD treatments is currently underway, including gene therapy, lipid nanoparticles, and dendrimer-based therapy. These innovative approaches aim to target the underlying pathological processes of AD rather than just managing the symptoms. This review discusses the novel aspects of pathogenesis involved in the causation of AD of AD and in recent developments in the therapeutic armamentarium for the treatment of AD such as gene therapy, lipid nanoparticles, and dendrimer-based therapy, and many more.

Auvelity: A New Era in Medicine - Unraveling the Multifaceted Benefits of Dextromethorphan/Bupropion Combination

Background: Depression is a prevalent global illness, impacting 280 million people worldwide, and Major Depressive Disorder (MDD) is ranked as the third leading cause of disease burden globally. People previously diagnosed with depression are more likely to develop Alzheimer's disease (AD). The recent approval of Auvelity by the FDA has made a remarkable breakthrough in drug development, offering a multi-dimensional approach for managing multiple diseases. Objective: The main objective of this study is to investigate the role of Auvelity, a new drug, in treating MDD and its potential to manage agitation in individuals with Alzheimer's disease (AD). Methodology: Data on Auvelity was collected from various sources, including accessdata.fda.gov, PubMed, and Scopus, and compiled for analysis. Discussion: Auvelity is the first oral medication to demonstrate the rapid onset of action, with statistically significant antidepressant efficacy observed as early as one week compared to a placebo. It contains a combination of dextromethorphan (45 mg) and bupropion (105 mg). The drug's mechanism of action involves a combination of NMDA receptor blockade and agonism of the sigma-1 receptor, resulting in the antagonization of the glutamatergic neurotransmitter pathway. Due to the similarity in the mechanism of action with AD medications like Memantine, there is a hypothesis that Auvelity could effectively reduce symptoms of AD. Conclusion: The approval of Auvelity marks a significant advancement in depression treatment with its unique NMDA antagonist mechanism, rapid onset of action, and low-risk profile.

Disparity in the use of Alzheimer's disease treatment in Southern Brazil

Alzheimer's disease (AD) treatment is freely available in the Brazilian public health system. However, the prescription pattern and its associated factors have been poorly studied in our country. We reviewed all granted requests for AD treatment in the public health system in October 2021 in the Rio Grande do Sul (RS) state, Southern Brazil. We performed a spatial autocorrelation analysis with the population-adjusted patients receiving any AD medication as the outcome and correlated it with several socioeconomic variables. 2382 patients with AD were being treated during the period analyzed. The distribution of the outcome variable was not random (Moran's I 0.17562, P <.0001), with the most developed regions having a higher number of patients/100,000 receiving any AD medication. We show that although AD medications are available through the public health system, there is a clear disparity between regions of RS state. Factors related to socioeconomic development partly explain this finding.

Review of Alzheimer's disease drugs and their relationship with neuron-glia interaction.

Alzheimer's disease (AD) is the most common cause of dementia worldwide. Because Alzheimer's disease has no known treatment, sufferers and their caregivers must concentrate on symptom management. Astrocytes and microglia are now known to play distinct physiological roles in synaptic function, the blood-brain barrier, and neurovascular coupling. Consequently, the search for drugs that can slow the degenerative process in dementia sufferers continues because existing drugs are designed to alleviate the symptoms of Alzheimer's disease. Drugs that address pathological changes without interfering with the normal function of glia, such as eliminating amyloid-beta deposits, are prospective treatments for neuroinflammatory illnesses. Because neuron-astrocytes-microglia interactions are so complex, developing effective, preventive, and therapeutic medications for AD will necessitate novel methodologies and strategic targets. This review focused on existing medications used in treating AD amongst which include Donepezil, Choline Alphoscerate, Galantamine, Dextromethorphan, palmitoylethanolamide, citalopram, resveratrol, and solanezumab. This review summarizes the effects of these drugs on neurons, astrocytes, and microglia interactions based on their pharmacokinetic properties, mechanism of action, dosing, and clinical presentations.

The Effect of Ethanol Extract from Mesua ferrea Linn Flower on Alzheimer's Disease and Its Underlying Mechanism.

The effects of Mesua ferrea Linn flower (MFE) extract on the pathogenic cascade of Alzheimer's disease (AD) were determined by an in vitro and cell culture model in the search for a potential candidate for the treatment of AD. The 2,2'-azino-bis-3-ethylbenzthiazoline-6-sulphonic acid (ABTS) and 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay exhibited that the MFE extract had antioxidant activities. According to the Ellman and the thioflavin T method's result, the extracts could inhibit acetylcholinesterase and β-amyloid (Aβ) aggregation. Studies on neuroprotection in cell culture found that the MFE extract could reduce the death of human neuroblastoma cells (SH-SY5Y) caused by H2O2 and Aβ. Western blot analysis exhibited that the MFE extract alleviated H2O2-induced neuronal cell damage by downregulating the pro-apoptotic proteins, including cleaved caspase-3, Bax, and by enhancing the expression of anti-apoptotic markers including MCl1, BClxl, and survivin. Moreover, MFE extract inhibited the expression of APP, presenilin 1, and BACE, and increased the expression of neprilysin. In addition, the MFE extract could enhance scopolamine-induced memory deficit in mice. Overall, results showed that the MFE extract had several modes of action related to the AD pathogenesis cascade, including antioxidants, anti-acetylcholinesterase, anti-Aβ aggregation, and neuroprotection against oxidative stress and Aβ. Therefore, the M. ferrea L. flower might be a possibility for further development as a medication for AD.

Amyloid-beta aggregation implicates multiple pathways in Alzheimer's disease: Understanding the mechanisms.

Alzheimer's disease (AD) is a progressive neurodegenerative condition characterized by tau pathology and accumulations of neurofibrillary tangles (NFTs) along with amyloid-beta (Aβ). It has been associated with neuronal damage, synaptic dysfunction, and cognitive deficits. The current review explained the molecular mechanisms behind the implications of Aβ aggregation in AD via multiple events. Beta (β) and gamma (γ) secretases hydrolyzed amyloid precursor protein (APP) to produce Aβ, which then clumps together to form Aβ fibrils. The fibrils increase oxidative stress, inflammatory cascade, and caspase activation to cause hyperphosphorylation of tau protein into neurofibrillary tangles (NFTs), which ultimately lead to neuronal damage. Acetylcholine (Ach) degradation is accelerated by upstream regulation of the acetylcholinesterase (AChE) enzyme, which leads to a deficiency in neurotransmitters and cognitive impairment. There are presently no efficient or disease-modifying medications for AD. It is necessary to advance AD research to suggest novel compounds for treatment and prevention. Prospectively, it might be reasonable to conduct clinical trials with unclean medicines that have a range of effects, including anti-amyloid and anti-tau, neurotransmitter modulation, anti-neuroinflammatory, neuroprotective, and cognitive enhancement.

Disease progression model using the integrated Alzheimer's Disease Rating Scale.

An Alzheimer's disease (AD) dementia disease progression model was developed based on the integrated Alzheimer's Disease Rating Scale (iADRS). Data from 3483 placebo participants in six AD trials were used to develop the disease progression model with NONMEM (version 7.4.2) and examined for mild cognitive impairment, and mild and moderate dementia due to AD. Baseline iADRS score was significantly influenced by AD symptomatic medication use, EXPEDITION2 enrollment (included moderate AD participants), age, and baseline Mini-Mental State Examination (MMSE) score. Rate of disease progression increased across disease stage and was significantly influenced by AD medication use, age, and baseline MMSE score. Apolipoprotein E ε4 carrier status did not influence baseline iADRS score or disease progression. These results demonstrate a disease progression model describing the time course of the iADRS across the AD severity spectrum. This model can assist future clinical trials in study design optimization and treatment effect interpretation. A disease progression model described the integrated Alzheimer's Disease Rating Scale (iADRS) time course in mild cognitive impairment to moderate Alzheimer's disease. Using the linear regression model, iADRS scores can be calculated for Mini-Mental State Examination scores. Results can help optimize future clinical trial design and aid in understanding treatment effects.

Early start of anti-dementia medication is associated with lower health and social care costs in Alzheimer´s patients: a Finnish nationwide register study.

To evaluate the association between health and social care costs and early start of anti-dementia medication in a nationwide cohort of Finnish Alzheimer's disease (AD) patients. The cohort included 7454 Finnish AD patients who had their first AD diagnosis in 2012 and lived at home at the time of diagnosis. Data were collected retrospectively from the Finnish national health and social care registers. The primary outcome was 2-year cumulative direct costs after the incident AD diagnosis. The exploratory variable was early anti-dementia medication start (anti-dementia medication started within 3 months of the incident AD diagnosis). Sociodemographic variables, admission to 24-h care and care intensity level, as well as comorbidities were considered as adjusting variables. Of all patients, 88.9% started AD medication within 3months of diagnosis. The 2-year cumulative costs were €30,787 and €40,484 per patient for early and late starters, respectively. When adjusted for possible confounders, early start of anti-dementia medication was associated with 26.5% lower 2-year cumulative costs compared to late starters (relative cost 0.735; p < 0.001). Early diagnosis and start of anti-dementia medication is important for managing the costs of increasing number of AD patients.

A deep learning based convolutional neural network model with VGG16 feature extractor for the detection of Alzheimer Disease using MRI scans

Alzheimer's disease (AD) is one of the most prevalent types of dementia, which primarily affects people over age 60. In clinical practice, it is a challenging task to identify AD in its early stages, and there are currently very few reliable diagnostic systems available for the identification. Additionally, clinical studies for AD medications have a high risk of failure, and currently, there is no confirmed cure. There are various stages of AD: very mild demented, mild, and moderate. It is challenging to identify these stages, due to which the very mild demented case worsens and results in a complete health loss along with weak memory and makes it unable to perform daily tasks without the assistance of others. Early identification of mild cases can help patients to guide additional medical care to stop the disease's progression and avoid brain damage. Recently, there has been a substantial amount of interest in applying deep learning (DL) for early AD recognition. The limitations of these algorithms are that they cannot detect changes in the brain networks in patients with mild demented functional working brain networks. However, to stop AD growth, various scientists and researchers are striving to build methods for early identification by using MRI images. In this article, for early diagnoses of AD, two MRI datasets containing 6400 and 6330 images have been used, and the DL algorithm is utilized by applying a neural network classifier with a VGG16 feature extractor for the early diagnosis of AD, which results in the outcome in the form of accuracy, precision, recall, AUC and F1-score as (90.4%, 0.905, 0.904, 0.969, and 0.904), and (71.1%, 0.71, 0.711, 0.85, and 0.71) for dataset 1 and dataset 2, respectively. Furthermore, the results are compared with previous studies, which concluded the proposed model performs better. Lastly, this article is applicable to identify various machine learning (ML) and DL approaches that can be utilized to study AD stage identification.

Aduhelm, the Newly Approved Medication for Alzheimer Disease: What Epidemiologists Can Learn and What Epidemiology Can Offer.

Alzheimer disease (AD) is a progressive disorder common among older adults and culminating in profound cognitive impairments and high mortality risk. The US Food and Drug Administration (FDA) recently provided accelerated approval for Aduhelm, a medication for AD treatment. Aduhelm (Biogen Inc., Cambridge, Massachusetts) has been described as the first disease-modifying treatment for AD but has not been demonstrated to improve patients' cognitive or functional outcomes. In this commentary, we describe why Aduhelm approval was controversial and aspects of the current evidence of special pertinence to epidemiologists. The FDA decision was based primarily on 2 randomized controlled trials (RCTs), both terminated early, with conflicting findings about the cognitive benefits of Aduhelm. Both RCTs showed important adverse effects of the medication. The FDA cited the documented reduction in brain amyloid, an AD biomarker hypothesized as a surrogate outcome, to justify accelerated approval. Despite lack of racial/ethnic diversity in the RCT participants, concerns about health disparities have been invoked to argue for public funding of this expensive medication. The Centers for Medicare and Medicaid Services recently made a "Coverage with Evidence Development" determination for Aduhelm and similar medications. We end by describing how innovative study designs could accelerate postapproval research and evaluate the proposed surrogate outcomes.

Theranostic F-SLOH mitigates Alzheimer's disease pathology involving TFEB and ameliorates cognitive functions in Alzheimer's disease models

Accumulation of amyloid-β (Aβ) oligomers and phosphorylated Tau aggregates are crucial pathological events or factors that cause progressive neuronal loss, and cognitive impairments in Alzheimer's disease (AD). Current medications for AD have failed to halt, much less reverse this neurodegenerative disorder; therefore, there is an urgent need for the development of effective and safe drugs for AD therapy. In the present study, the in vivo therapeutic efficacy of an Aβ-oligomer-targeted fluorescent probe, F-SLOH, was extensively investigated in 5XFAD and 3XTg-AD mouse models. We have shown that F-SLOH exhibits an efficient inhibitory activity against Aβ aggregation in vivo, and acts as an effective theranostic agent for the treatment of multiple neuropathological changes in AD mouse models. F-SLOH has been found to significantly reduce not only the levels of Aβ oligomers, Tau aggregates and plaques but also the levels of amyloid precursor protein (APP) and its metabolites via autophagy lysosomal degradation pathway (ALP) in the brains of 5XFAD and 3XTg-AD mice. It also reduces astrocyte activation and microgliosis ultimately alleviating neuro-inflammation. Furthermore, F-SLOH mitigates hyperphosphorylated Tau aggregates, synaptic deficits and ameliorates synaptic memory function, and cognitive impairment in AD mouse models. The mechanistic studies have shown that F-SLOH promotes the clearance of C-terminal fragment 15 (CTF15) of APP and Paired helical filaments of Tau (PHF1) in stable cell models via the activation of transcription factor EB (TFEB). Moreover, F-SLOH promotes ALP and lysosomal biogenesis for the clearance of soluble, insoluble Aβ, and phospho Tau. Our results unambiguously reveal effective etiological capabilities of theranostic F-SLOH to target and intervene multiple neuropathological changes in AD mouse models. Therefore, F-SLOH demonstrates tremendous therapeutic potential for treating AD in its early stage.

Amyloid-Related Imaging Abnormalities in 2 Phase 3 Studies Evaluating Aducanumab in Patients With Early Alzheimer Disease

The EMERGE and ENGAGE phase 3 randomized clinical trials of aducanumab provide a robust data set to characterize amyloid-related imaging abnormalities (ARIA) that occur with treatment with aducanumab, an amyloid-β (Aβ)-targeting monoclonal antibody, in patients with mild cognitive impairment due to Alzheimer disease or mild Alzheimer disease dementia. To describe the radiographic and clinical characteristics of ARIA that occurred in EMERGE and ENGAGE. Secondary analysis of data from the EMERGE and ENGAGE trials, which were 2 double-blind, placebo-controlled, parallel-group, phase 3 randomized clinical trials that compared low-dose and high-dose aducanumab treatment with placebo among participants at 348 sites across 20 countries. Enrollment occurred from August 2015 to July 2018, and the trials were terminated early (March 21, 2019) based on a futility analysis. The combined studies consisted of a total of 3285 participants with Alzheimer disease who received 1 or more doses of placebo (n = 1087) or aducanumab (n = 2198; 2752 total person-years of exposure) during the placebo-controlled period. Primary data analyses were performed from November 2019 to July 2020, with additional analyses performed through July 2021. Participants were randomly assigned 1:1:1 to high-dose or low-dose intravenous aducanumab or placebo once every 4 weeks. Dose titration was used as a risk-minimization strategy. Brain magnetic resonance imaging was used to monitor patients for ARIA; associated symptoms were reported as adverse events. Of 3285 included participants, the mean (SD) age was 70.4 (7.45) years; 1706 participants (52%) were female, 2661 (81%) had mild cognitive impairment due to Alzheimer disease, and 1777 (54%) used symptomatic medications for Alzheimer disease. A total of 764 participants from EMERGE and 709 participants from ENGAGE were categorized as withdrawn before study completion, most often owing to early termination of the study by the sponsor. Unless otherwise specified, all results represent analyses from the 10-mg/kg group. During the placebo-controlled period, 425 of 1029 patients (41.3%) experienced ARIA, with serious cases occurring in 14 patients (1.4%). ARIA-edema (ARIA-E) was the most common adverse event (362 of 1029 [35.2%]), and 263 initial events (72.7%) occurred within the first 8 doses of aducanumab; 94 participants (26.0%) with an event exhibited symptoms. Common associated symptoms among 103 patients with symptomatic ARIA-E or ARIA-H were headache (48 [46.6%]), confusion (15 [14.6%]), dizziness (11 [10.7%]), and nausea (8 [7.8%]). Incidence of ARIA-E was highest in aducanumab-treated participants who were apolipoprotein E ε4 allele carriers. Most events (479 of 488 [98.2%]) among those with ARIA-E resolved radiographically; 404 of 488 (82.8%) resolved within 16 weeks. In the placebo group, 29 of 1076 participants (2.7%) had ARIA-E (apolipoprotein E ε4 carriers: 16 of 742 [2.2%]; noncarriers, 13 of 334 [3.9%]). ARIA-microhemorrhage and ARIA-superficial siderosis occurred in 197 participants (19.1%) and 151 participants (14.7%), respectively. In this integrated safety data set from EMERGE and ENGAGE, the most common adverse event in the 10-mg/kg group was ARIA-E, which occurred in 362 of the 1029 patients (35.2%) in the 10-mg/kg group with at least 1 postbaseline MRI scan, with 94 patients (26.0%) experiencing associated symptoms. The most common associated symptom was headache. ClinicalTrials.gov Identifiers: NCT02484547, NCT02477800.

Effect of electroacupuncture on learning-memory ability and expression of IL-1β, IL-6 and TNF-α in hippocampus and spleen in mice with Alzheimer's disease

To explore the effect of electroacupuncture (EA) on the ability of spatial learning-memory and the expression of IL-1β, IL-6 and TNF-α in the hippocampus and spleen tissues and the number of hippocampal neurons and spleen lymphocytes in Alzheimer's disease (AD) mice, so as to study its mechanisms underlying improvement of AD. Twenty-four SAMP8 mice were randomly and equally divided into AD model, EA and medication groups, and 8 SAMR1 mice were used as the control group. EA (2 Hz, 0.1 mA) was applied to "Baihui"(GV20) and "Yintang"(EX-HN3) for 20 min in the EA group, and intragastric administration of donepezil hydrochloride (0.92 mg/kg) was applied in the medication group, once daily for 15 d. The learning-memory ability was determined by Morris water maze task, and the histopathological changes of hippocampus were observed after H.E. staining, followed by determining neurons and the number of splenic lymphocytes. The expression levels of IL-1β, IL-6 and TNF-α in the hippocampus and spleen were detected by immunohistochemistry and Western blot, respectively. After mode-ling, the escape latency of place navigation test in the Morris water maze, the spleen index, immunoactivity and expression levels of IL-1β, IL-6 and TNF-α proteins in the hippocampus and spleen tissues were significantly increased (P<0.05, P<0.01). Compared with the model group, the escape latency, spleen index, immunoactivity and expression levels of IL-1β, IL-6 and TNF-α proteins in both hippocampus and spleen were significantly down-regulated in the medication (except the escape latency) and EA groups (P<0.01, P<0.05). The effect of EA was evidently superior to that of medication in shortening the escape latency, lowering the spleen index, and immunoactivity of hippocampal IL-6 and splenic TNF-α immunoactivity (P<0.01, P<0.05). Outcomes of H.E. staining showed disordered arrangement of neurons with nuclear pyknosis or apoptosis in partial neurons in the hippocampus, and thickened and swollen spleen capsule tissue with loose structure and an increased number of lymphocytes in the model group, which was relatively milder in the EA and medication groups. EA can improve the learning-memory ability of AD mice, which may be associated with its effect in relieving the inflammation reaction in the hippocampus and spleen tissues.

Can Emerging Therapies Resolve Unmet Needs With Current Treatment in Early-Stage Alzheimer Disease?

While no current medications for Alzheimer disease (AD) can modify the disease, the agents do slow symptom progression. The earlier the medications are started for patients diagnosed with AD, the greater the potential benefit. Clinical trials are in progress on drugs with a variety of mechanisms that may modulate the disease course: neuronal protection; protein synthesis or aggregation inhibition; immunologic priming with antibodies; vaccines; and secretase inhibition. Early diagnosis, whether in the primary care setting or the specialty setting, continues to be critical to give patients their best chance at managing their illness. Although current treatments cannot give patients back what they have already lost, in the near future, drugs may be able to slow or even halt their cognitive and functional decline if clinicians identify AD early enough in the disease process.

Personalizing the Care and Treatment of Alzheimer's Disease: An Overview.

Alzheimer’s disease (AD) is a progressive, complex, and multifactorial neurodegenerative disorder, still without effective and stable therapeutic strategies. Currently, available medications for AD are based on symptomatic therapy, which include acetylcholinesterase (AChE) inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonist. Additionally, medications such as antipsychotic drugs, antidepressants, sedative, and hypnotic agents, and mood stabilizers are used for the management of behavioral and psychological symptoms of dementia (BPSD). Clinical research has been extensively investigated treatments focusing on the hallmark pathology of AD, including the amyloid deposition, tau hyperphosphorylation, neuroinflammation, and vascular changes; however, so far without success, as all new potential drugs failed to show significant clinical benefit. The underlying heterogeneous etiology and diverse symptoms of AD suggest that a precision medicine strategy is required, which would take into account the complex genetic, epigenetic, and environmental landscape of each AD patient. The article provides a comprehensive overview of the literature on AD, the current and potential therapy of both cognitive symptoms as well as BPSD, with a special focus on gut microbiota and epigenetic modifications as new emerging drug targets. Their specific patterns could represent the basis for novel individually tailored approaches aimed to optimize precision medicine strategies for AD prevention and treatment. However, the successful application of precision medicine to AD demands a further extensive research of underlying pathological processes, as well as clinical and biological complexity of this multifactorial neurodegenerative disorder.