Management Of Alzheimer's Disease Research Articles

Awareness and Perception Toward Alzheimer's Disease Among Residents Living in the Jazan Province, Saudi Arabia: A Cross-Sectional Study.

Alzheimer's disease (AD) is a growing public health concern, yet misconceptions about the condition are common. This study assessed awareness andsocial perceptionsof AD in Jazan. A cross-sectional survey of 925 adults was conducted. Knowledge was assessed using a 30-item Alzheimer's Disease Knowledge Scale (ADKS). Social perceptions were evaluated using a 10-item questionnaire. Many had misconceptions about AD epidemiology, causes, management, and care. Themean ADKS scorewas 8.89 ± 5.17 out of 30. Knowledge was poorest for symptoms,risk factors, treatment, caregiving, and life impact. Knowledge was highest in those aged >45 years (p = 0.018), in those with income > 15K SR (p = 0.004), in retired individuals (p = 0.023), and in those who learned about AD from books (p = 0.001), healthcare professionals (p = 0.001), or had an affected relative (p = 0.001). However, knowledge was low across all domains, averaging only 29%correct answers. Most respondents held positive social perceptions, yet sizable minorities saw isolation, legal intervention, and institutionalization as appropriate. Additionally, a portion of respondents associated stigma with individuals affected by AD and expressed a sense of burden associated with the condition. There are substantialknowledge gapsand somestigmatizing attitudesabout AD inJazan. Awareness regarding the causes, diagnosis, and management of AD was low. Misconceptions exist that AD only affects older people.Improved public education, especially for higher-risk groups, is needed to address misconceptions and promotesocial inclusionfor those with dementia. Healthcare professionals can play a crucial role.

A New Perspective for the Treatment of Alzheimer's Disease: Exosome-like Liposomes to Deliver Natural Compounds and RNA Therapies.

With the increment of the aging population in recent years, neurodegenerative diseases exert a major global disease burden, essentially as a result of the lack of treatments that stop the disease progression. Alzheimer's Disease (AD) is an example of a neurodegenerative disease that affects millions of people globally, with no effective treatment. Natural compounds have emerged as a viable therapy to fill a huge gap in AD management, and in recent years, mostly fueled by the COVID-19 pandemic, RNA-based therapeutics have become a hot topic in the treatment of several diseases. Treatments of AD face significant limitations due to the complex and interconnected pathways that lead to their hallmarks and also due to the necessity to cross the blood-brain barrier. Nanotechnology has contributed to surpassing this bottleneck in the treatment of AD by promoting safe and enhanced drug delivery to the brain. In particular, exosome-like nanoparticles, a hybrid delivery system combining exosomes and liposomes' advantageous features, are demonstrating great potential in the treatment of central nervous system diseases.

MTOR-Mediated Immunometabolic Reprogramming Nanomodulators Enable Sensitive Switching of Energy Deprivation-Induced Microglial Polarization for Alzheimer's Disease Management.

Metabolic reprogramming that senses brain homeostasis imbalances is necessary to drive detrimental microglial polarization, and specific targeting of this process contributes to the flexible control of pathological inflammatory responses in Alzheimer's disease (AD), displaying distinctive therapeutic benefits. Herein, glutathione-functionalized gold nanocages loaded with the immunosuppressant fingolimod hydrochloride are developed as brain-targeted and microglia-located immunometabolic reprogramming nanomodulators (GAF NPs) for AD management. By virtue of glutathione-mediated transport properties, this nanomodulator can cross the blood-brain barrier and localize to microglia in AD lesions. Through blocking Akt/mTOR/HIF-1α signaling pathways, GAF NPs not only promote the dominated metabolic shift from glycolysis to oxidative phosphorylation under immune activation but also inhibit transporter-mediated glucose overconsumption by microglia. Correlation analysis based on real-time bioenergetic assessment and 18F-labeled fluorodeoxyglucose (FDG) PET reveals that brain glucose utilization and metabolism restored by GAF NP treatment can serve as a sensitive and effective indicator for microglial M1 to M2 polarization switching, ultimately alleviating neuroinflammation and its derived neurodegeneration as well as ameliorating cognitive decline in AD mice. This work highlights a potential nanomedicine aimed at modifying mTOR-mediated immunometabolic reprogramming to halt energy deprivation-induced AD progression.

Neuroprotection of Multitargeted Phytochemicals against Alzheimer: A Desperate Need from Nature

Background: Alzheimer’s disease (AD) is an incurable neurodegenerative disorder associated with dementia which leads to the alteration in the psychological and physiological functioning of the individual. From antiquity, medicinal plants serve as important sources of bioactive phytochemicals representing tremendous therapeutic potential. The unavoidable adverse effects associated with synthetic compounds trigger the exploration of new and safer substitutes for the treatment and management of disease conditions. Herbal medication proves to be an emerging and most promising alternative, which is expected to be a revolutionary approach in modern medicine for disease treatment. Objective: Several phytochemicals like resveratrol, curcumin, apigenin, docosahexaenoic acid, epigallocatechin gallate, and α-lipoic acid exhibit great potential in the prevention and management of AD. Their use might be a possible remedy and lead to a safe strategy to delay the onset of AD and slow the progression of this pervasive disorder. To determine the potential of these natural components as anti- AD, this review focuses on the updates on clinical studies and research. Methods: Extensive literature survey was carried out on natural multitargeted bioactive phytochemicals from various scientific databases like PubMed, Science Direct, Scopus, Clinicaltrails.gov, and many reputed foundations. Current prose emphasizes the identified bioactive compounds as anti-AD, which were reviewed with particular emphasis on their scientific impact and novelty. Results: These compounds diminish the pathophysiological aspects of AD; still, further studies are required to prove the safety and efficacy of these compounds in humans. Conclusion: This present review might help the researchers, academicians and industrialists in drug development as a new paradigm of drug discovery.

Triptolide improves Alzheimer's disease by regulating the NF‑κB signaling pathway through the lncRNA NEAT1/microRNA 361‑3p/TRAF2 axis.

Alzheimer's disease (AD) is the most common type of dementia and is a serious social and medical problem threatening human health. The present study investigated the effect and underlying action mechanism of triptolide (Tri) on AD progression. Reverse transcription-quantitative PCR and western blotting analysis were used to determine the changes in RNA expression and levels of NF-κB signaling pathway proteins before and after lipopolysaccharide (LPS) induction. Nucleocytoplasmic separation experiments determined the intracellular localization of long non-coding RNA (lncRNA) nuclear paraspeckle assembly transcript 1 (NEAT1). A dual-luciferase assay was used to analyze the binding between NEAT1 and microRNA (miRNA/miR)-361 or tumor necrosis factor receptor-associated factor 2 (TRAF2) and miR-361-3p and RNA pull-down was used to analyze the binding between NEAT1 and miR-361-3p. Cell Counting Kit-8, flow cytometry and ELISA were used to detect the effects of interaction between Tri and NEAT1/miR-361-3p/TRAF2 on cell viability, apoptosis and inflammatory factor levels, respectively. The results showed that LPS-mediated human microglial clone 3 cell line (HMC3) viability decreased and apoptosis and inflammatory factors (IL-1β, IL-6, IL-18 and TNF-α) increased. Tri inhibited LPS-mediated effects in a dose-dependent manner by downregulating NEAT1 expression. NEAT1 is highly expressed in the cytoplasm and reduces the transcription and translation of downstream TRAF2 by acting as a competitive endogenous RNA that adsorbs miR-361-3p. LPS-mediated HMC3 cell injury, inflammation and activation of NF-κB signaling were partially reversed in presence of Tri. The miR-361-3p mimic promoted the Tri effect and overexpression of (ov)-NEAT1 partially reversed the Tri-miR-361-3p combined effect. The effects of ov-NEAT1 were partially attenuated by small interfering (si)-TRAF2. Overall, Tri inhibited the LPS-induced decrease in viability, increase in apoptosis and inflammation and activation of NF-κB signaling in HMC3 cells. Tri regulation affected the NEAT1/miR-361-3p/TRAF2 axis. These findings suggested a potential therapeutic role for Tri in the clinical management of AD by modulating this molecular axis.

Astaxanthin: A Marine Drug That Ameliorates Cerebrovascular-Damage-Associated Alzheimer's Disease in a Zebrafish Model via the Inhibition of Matrix Metalloprotease-13.

Alzheimer's disease (AD) is a major type of dementia disorder. Common cognitive changes occur as a result of cerebrovascular damage (CVD) via the disruption of matrix metalloproteinase-13 (MMP-13). In diabetic cases, the progress of vascular dementia is faster and the AD rate is higher. Patients with type 2 diabetes are known to have a higher risk of the factor for AD progression. Hence, this study is designed to investigate the role of astaxanthin (AST) in CVD-associated AD in zebrafish via the inhibition of MMP-13 activity. CVD was developed through the intraperitoneal and intracerebral injection of streptozotocin (STZ). The AST (10 and 20 mg/L), donepezil (1 mg/L), and MMP-13 inhibitor (i.e., CL-82198; 10 μM) were exposed for 21 consecutive days in CVD animals. The cognitive changes in zebrafish were evaluated through light and dark chamber tests, a color recognition test, and a T-maze test. The biomarkers of AD pathology were assessed via the estimation of the cerebral extravasation of Evans blue, tissue nitrite, amyloid beta-peptide aggregation, MMP-13 activity, and acetylcholinesterase activity. The results revealed that exposure to AST leads to ameliorative behavioral and biochemical changes. Hence, AST can be used for the management of AD due to its multi-targeted actions, including MMP-13 inhibition.

Understanding the multifaceted role of miRNAs in Alzheimer's disease pathology.

Small non-coding RNAs (miRNAs) regulate gene expression by binding to mRNA and mediating its degradation or inhibiting translation. Since miRNAs can regulate the expression of several genes, they have multiple roles to play in biological processes and human diseases. The majority of miRNAs are known to be expressed in the brain and are involved in synaptic functions, thus marking their presence and role in major neurodegenerative disorders, including Alzheimer's disease (AD). In AD, amyloid beta (Aβ) plaques and neurofibrillary tangles (NFTs) are known to be the major hallmarks. The clearance of Aβ and tau is known to be associated with miRNA dysregulation. In addition, the β-site APP cleaving enzyme (BACE 1), which cleaves APP to form Aβ, is also found to be regulated by miRNAs, thus directly affecting Aβ accumulation. Growing evidences suggest that neuroinflammation can be an initial event in AD pathology, and miRNAs have been linked with the regulation of neuroinflammation. Inflammatory disorders have also been associated with AD pathology, and exosomes associated with miRNAs are known to regulate brain inflammation, suggesting for the role of systemic miRNAs in AD pathology. Several miRNAs have been related in AD, years before the clinical symptoms appear, most of which are associated with regulating the cell cycle, immune system, stress responses, cellular senescence, nerve growth factor (NGF)signaling, and synaptic regulation. Phytochemicals, especially polyphenols, alter the expression of various miRNAs by binding to miRNAs or binding to the transcriptional activators of miRNAs, thus control/alter various metabolic pathways. Awing to the sundry biological processes being regulated by miRNAs in the brain and regulation of expression of miRNAs via phytochemicals, miRNAs and the regulatory bioactive phytochemicals can serve as therapeutic agents in the treatment and management of AD.

A task force for diagnosis and treatment of people with Alzheimer's disease in Latin America.

Alzheimer's disease (AD) represents a substantial burden to patients, their caregivers, health systems, and society in Latin America and the Caribbean (LAC). This impact is exacerbated by limited access to diagnosis, specialized care, and therapies for AD within and among nations. The region has varied geographic, ethnic, cultural, and economic conditions, which create unique challenges to AD diagnosis and management. To address these issues, the Americas Health Foundation convened a panel of eight neurologists, geriatricians, and psychiatrists from Argentina, Brazil, Colombia, Ecuador, Guatemala, Mexico, and Peru who are experts in AD for a three-day virtual meeting to discuss best practices for AD diagnosis and treatment in LAC and create a manuscript offering recommendations to address identified barriers. In LAC, several barriers hamper diagnosing and treating people with dementia. These barriers include access to healthcare, fragmented healthcare systems, limited research funding, unstandardized diagnosis and treatment, genetic heterogeneity, and varying social determinants of health. Additional training for physicians and other healthcare workers at the primary care level, region-specific or adequately adapted cognitive tests, increased public healthcare insurance coverage of testing and treatment, and dedicated search strategies to detect populations with gene variants associated with AD are among the recommendations to improve the landscape of AD.

Ethyl caffeate attefnuates Aβ-induced toxicity in Caenorhabditis elegans AD models via the insulin/insulin-like growth factor-1 signaling pathway

The pathogenesis of Alzheimer's disease (AD), a multifactorial progressive neurodegenerative disease associated with aging, is unclear. Ethyl caffeate is a plant polyphenol that has been reported to have neuroprotective effects, but the mechanisms by which it acts are unclear. In this study, for the first time, we investigated the molecular mechanism of its anti-AD properties using the Caernorhabditis elegans model. The results of our experiments showed that ethyl caffeate delayed the paralysis symptoms of CL4176 to a different extent and reduced the exogenous 5-hydroxytryptophan-induced paralysis phenotype. Further studies revealed that ethyl caffeate lowered Aβ plaques and depressed the expression of Aβ monomers and oligomers, but did not influence the mRNA levels of Aβ. Moreover, it was able to bring paraquat-induced ROS levels down to near-standard conditions. Real-time quantitative PCR experiment showed a significant upregulation of the transcript abundance of daf-16, skn-1 and hsf-1, key factors associated with the insulin/insulin-like growth factor 1 (IGF-1) signaling pathway (IIS), and their downstream genes sod-3, gst-4 and hsp-16.2. It was further shown that ethyl caffeate activated the translocation of DAF-16 and SKN-1 from the cytoplasm to the nucleus and enhanced the expression of sod-3::GFP, gst-4::GFP and hsp-16.2::GFP in transgenic nematodes. This meant that the protection against Aβ toxicity by ethyl caffeate may be partly through the IIS signaling pathway. In addition, ethyl caffeate suppressed the aggregation of polyglutamine proteins in AM141, which indicated a potential protective effect against neurodegenerative diseases based on abnormal folding and aggregation of amyloid proteins. Taken together, ethyl caffeate is expected to develop as a potential drug for the management of AD.

Ameliorating the Role of Aripiprazole in Memory Deficits Induced by Intracerebroventricular Streptozotocin-Induced Dementia of Alzheimer's Type.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder causing immense suffering for the patients. Dopamine D2 and 5-hydroxytryptamine receptor 1A (5-HT1A) receptors' activation has been reported to play a crucial role in managing neurological outcomes in the brain and other health disorders. This study aimed to investigate the role of aripiprazole, a dopamine D2 and 5-HT1A selective receptors' activator, in the restoration of memory deficit induced by streptozotocin in mice. The cognitive functions of animals were determined using the Morris water maze. Brain sections were stained with hematoxylin and eosin and Congo red to examine the structural deviations. Brain oxidative stress (thiobarbituric acid reactive substance and glutathione), acetylcholinesterase activity, IL-6, and IL-10 were measured to assess biochemical alterations. Activation of D2 and 5-HT1A with aripiprazole attenuated STZ-induced cognitive deficit, increased brain GSH levels, reduced TBARS levels, AChE activity, IL-6 levels, and IL-10 levels and prevented STZ-induced brain anomalies in mice. Hence, the present study concluded that aripiprazole mitigated STZ-induced memory impairment and can be used as an efficacious therapeutic target for the management of AD.

Combined Donepezil with Astaxanthin via Nanostructured Lipid Carriers Effective Delivery to Brain for Alzheimer's Disease in Rat Model.

Donepezil (DPL), a specific acetylcholinesterase inhibitor, is used as a first-line treatment to improve cognitive deficits in Alzheimer's disease (AD) and it might have a disease modifying effect. Astaxanthin (AST) is a natural potent antioxidant with neuroprotective, anti-amyloidogenic, anti-apoptotic, and anti-inflammatory effects. This study aimed to prepare nanostructured lipid carriers (NLCs) co-loaded with donepezil and astaxanthin (DPL/AST-NLCs) and evaluate their in vivo efficacy in an AD-like rat model 30 days after daily intranasal administration. DPL/AST-NLCs were prepared using a hot high-shear homogenization technique, in vitro examined for their physicochemical parameters and in vivo evaluated. AD induction in rats was performed by aluminum chloride. The cortex and hippocampus were isolated from the brain of rats for biochemical testing and histopathological examination. DPL/AST-NLCs showed z-average diameter 149.9 ± 3.21 nm, polydispersity index 0.224 ± 0.017, zeta potential -33.7 ± 4.71 mV, entrapment efficiency 81.25 ±1.98% (donepezil) and 93.85 ±1.75% (astaxanthin), in vitro sustained release of both donepezil and astaxanthin for 24 h, spherical morphology by transmission electron microscopy, and they were stable at 4-8 ± 2°C for six months. Differential scanning calorimetry revealed that donepezil and astaxanthin were molecularly dispersed in the NLC matrix in an amorphous state. The DPL/AST-NLC-treated rats showed significantly lower levels of nuclear factor-kappa B, malondialdehyde, β-site amyloid precursor protein cleaving enzyme-1, caspase-3, amyloid beta (Aβ1‑42), and acetylcholinesterase, and significantly higher levels of glutathione and acetylcholine in the cortex and hippocampus than the AD-like untreated rats and that treated with donepezil-NLCs. DPL/AST-NLCs showed significantly higher anti-amyloidogenic, antioxidant, anti-acetylcholinesterase, anti-inflammatory, and anti-apoptotic effects, resulting in significant improvement in the cortical and hippocampal histopathology. Nose-to-brain delivery of DPL/AST-NLCs is a promising strategy for the management of AD.

Antioxidant evaluation and computational prediction of prospective drug-like compounds from polyphenolic-rich extract of Hibiscus cannabinus L. seed as antidiabetic and neuroprotective targets: assessment through in vitro and in silico studies

BackgroundReports have implicated diabetes mellitus (DM) and Alzheimer’s disease (AD) as some of the global persistent health challenges with no lasting solutions, despite of significant inputs of modern-day pharmaceutical firms. This study therefore, aimed to appraise the in vitro antioxidant potential, enzymes inhibitory activities, and as well carry out in silico study on bioactive compounds from polyphenolic-rich extract of Hibiscus cannabinus seed (PEHc).MethodsIn vitro antioxidant assays were performed on PEHc using standard methods while the identification of phytoconstituents was carried out with high performance liquid chromatography (HPLC). For the in silico molecular docking using Schrodinger’s Grid-based ligand docking with energetics software, seven target proteins were retrieved from the database (https://www.rcsb.org/).ResultsHPLC technique identified twelve chemical compounds in PEHc, while antioxidant quantification revealed higher total phenolic contents (243.5 ± 0.71 mg GAE/g) than total flavonoid contents (54.06 ± 0.09 mg QE/g) with a significant (p < 0.05) inhibition of ABTS (IC50 = 218.30 ± 0.87 µg/ml) and 1, 1-diphenyl-2-picrylhydrazyl free radicals (IC50 = 227.79 ± 0.74 µg/ml). In a similar manner, the extract demonstrated a significant (p < 0.05) inhibitory activity against α-amylase (IC50 = 256.88 ± 6.15 µg/ml) and α-glucosidase (IC50 = 183.19 ± 0.23 µg/ml) as well as acetylcholinesterase (IC50 = 262.95 ± 1.47 µg/ml) and butyrylcholinesterase (IC50 = 189.97 ± 0.82 µg/ml), respectively. Furthermore, In silico study showed that hibiscetin (a lead) revealed a very strong binding affinity energies for DPP-4, (PDB ID: 1RWQ) and α-amylase (PDB ID: 1SMD), gamma-tocopherol ( for peptide-1 receptor; PDB ID: 3C59, AChE; PDB ID: 4EY7 and BChE; PDB ID: 7B04), cianidanol for α-glucosidase; PDB ID: 7KBJ and kaempferol for Poly [ADP-ribose] polymerase 1 (PARP-1); PDB ID: 6BHV, respectively. More so, ADMET scores revealed drug-like potentials of the lead compounds identified in PEHc.ConclusionAs a result, the findings of this study point to potential drug-able compounds in PEHc that could be useful for the management of DM and AD.

Nanomedicine in the Management of Alzheimer's Disease: State-of-the-Art.

Alzheimer's disease (AD) is a deadly, progressive, and irreversible brain condition that impairs cognitive abilities. Globally, it affects 32.6 million individuals, and if no viable therapies are available by 2050, that figure might rise to 139 million. The current course of treatment enhances cognitive abilities and temporarily relieves symptoms, but it does not halt or slow the disease's development. Additionally, treatments are primarily offered in conventional oral dosage forms, and conventional oral treatments lack brain specialization and cause adverse effects, resulting in poor patient compliance. A potential nanotechnology-based strategy can improve the bioavailability and specificity of the drug targeting in the brain. Furthermore, this review extensively summarizes the applications of nanomedicines for the effective delivery of drugs used in the management of AD. In addition, the clinical progress of nanomedicines in AD is also discussed, and the challenges facing the clinical development of nanomedicines are addressed in this article.

Adipose tissue-derived mesenchymal stem cells ameliorate cognitive impairment in Alzheimer's disease rat model: Emerging role of SIRT1.

Alzheimer's disease (AD) is a complex form of neurodegenerative dementia. Growing body of evidence supports the cardinal role of sirtuin1 (SIRT1) in neurodegeneration and AD development. Recently, adipose tissue-derived mesenchymal stem cells (Ad-MSCs) have made their mark for a wide array of regenerative medicine applications, including neurodegenerative disorders. Therefore, the present study aimed to investigate the therapeutic potential of Ad-MSCs in AD rat model, and to explore the possible implication of SIRT1. Ad-MSCs were isolated from rat epididymal fat pads and properly characterized. Aluminum chloride was used to induce AD in rats, and afterward, a group of AD-induced rats received a single dose of Ad-MSCs (2 × 106 cell, I.V per rat). One month after Ad-MSCs transplantation, behavioral tests were done, brain tissues were collected, then histopathological and biochemical assessments were performed. Amyloid beta and SIRT1 levels were determined by enzyme-linked immunosorbent assay. Whereas expression levels of neprilysin, BCL2 associated X protein, B-cell lymphoma-2, interleukin-1β, interleukin-6, and nerve growth factor in hippocampus and frontal cortex brain tissues were assessed using reverse transcriptase quantitative polymerase chain reaction. Our data demonstrated that transplantation of Ad-MSCs alleviated cognitive impairment in AD rats. Additionally, they exhibited anti-amyloidogenic, antiapoptotic, anti-inflammatory, as well as neurogenic effects. Furthermore, Ad-MSCs were found to possibly mediate their therapeutic effects, at least partially, via modulating both central and systemic SIRT1 levels. Hence, the current study portrays Ad-MSCs as an effective therapeutic approach for AD management and opens the door for future investigations to further elucidate the role of SIRT1 and its interrelated molecular mediators in AD.

Exploring the Link between Chronic Kidney Disease and Alzheimer's Disease: A Longitudinal Follow-Up Study Using the Korean National Health Screening Cohort.

Chronic kidney disease (CKD) and Alzheimer's disease (AD) are common chronic diseases in the elderly population. Although a relationship between CKD and the occurrence of AD has been proposed, previous research results have been disputed, and further investigation is necessary to confirm this relationship. In this longitudinal follow-up study, we examined data from the Korean National Health Insurance Service-Health Screening Cohort, consisting of 15,756 individuals with CKD and 63,024 matched controls aged ≥40 years who received health check-ups between 2002 and 2019. Overlap-weighted Cox proportional hazard regression models were exploited to calculate hazard ratios (HRs) for the association between CKD and AD. During the monitoring period, individuals with CKD had a greater incidence of AD than those without CKD (15.80 versus 12.40 per 1000 person years). After accounting for various factors, CKD was significantly associated with a 1.14-fold increased likelihood of developing AD, with a 95% confidence interval ranging from 1.08 to 1.20. In subgroup analysis, this relationship persisted irrespective of age (≥70 or <70), sex, income, smoking status, alcohol consumption, place of residence, or fasting blood glucose level. Additionally, the association between CKD and AD was still evident among patients who were overweight or obese, those with normal blood pressure or cholesterol levels, and those without any other health conditions or with a CCI score of ≥2. These results suggest that CKD could increase the probability of developing AD in the Korean adult population irrespective of demographic or lifestyle conditions. This may make it challenging to predict AD in patients with CKD, emphasizing the importance of frequent AD screening and management.

Atrophy patterns in subjects at increased risk of Alzheimer’s Disease

AbstractBackgroundCognitively impaired individuals have multiple contributing conditions leading to heterogeneous atrophy patterns. Unfortunately, neuroimaging data is usually contaminated by noise, which can lead to spurious non‐clinically relevant clusters. Identification of true disease specific clusters requires techniques robust against noise.MethodWe developed an unsupervised approach named COllaborative Clustering based on Adaptive Laplace modeling (CoCAL) to simultaneously cluster individuals and features while removing noise. We derived the distributions of the coefficients produced by non‐negative matrix tri‐factorization (Fig. 1). We applied CoCAL to the PREVENT‐AD dataset, a cohort of cognitively unimpaired participants with a family history of Alzheimer’s Disease (AD). The groups clustered by CoCAL were compared by student’s t‐test with FDR correction, and each cluster is evaluated by Alzheimer’s Progression Score (APS).ResultExperimental results on a synthetic dataset demonstrated superior clustering performance of CoCAL over several benchmark clustering methods including k‐means and conventional matrix factorization based clustering methods. On the PREVENT‐AD dataset, two clusters (G1 and G2) were identified by CoCAL (Table 1). The corresponding t‐test statistic values of regions with p‐values &lt; 0.05 are plotted in Fig. 2. Cluster G1 showed higher APS compared to G2 (APS scores: 0.197 ± 0.0562 [G1] vs ‐0.080 ± 0.0539 [G2], p &lt; 0.001). There were no significant differences in sex, age and APOE ε4 status between the groups.ConclusionWhen applying CoCAL to the PREVENT‐AD cohort, two distinctive atrophy patterns emerge: a parietotemporal cluster (G1) and a fronto‐occipital cluster (G2). G1 corresponds well with classic patterns of cortical atrophy in AD, and participants in this group demonstrate higher APS than G2 participants. In contrast, the greater atrophy in the frontal and occipital lobes in the G2 cluster may reflect either gray matter atrophy from vascular contributions, or the frontal variant of AD. Further investigations into the progression of these different clusters and sub‐networks within the cluster could yield insight for more targeted management of AD.

A Mobile Application to Assist Alzheimer's Caregivers During COVID-19 Pandemic: Development and Evaluation.

Access to healthcare services for patients with Alzheimer's disease (AD) was limited during the COVID-19 pandemic. A mobile application (app) can help overcome this limitation for patients and caregivers. Our study aims to develop and evaluate an app to help caregivers of patients with AD during COVID-19. The study was performed in three steps. First, a questionnaire of features required for the app design was prepared based on the interviews with caregivers of AD patients and neurologists. Then, questionnaire was provided to neurologists, medical informatics, and health information management specialists to identify the final features. Second, the app was designed using the information obtained from the previous phase. Third, the quality of the app and the level of user satisfaction were evaluated using the mobile app rating scale (MARS) and the questionnaire for user interface satisfaction (QUIS), respectively. The number of 41 data elements in four groups (patient's profile, COVID-19 management and control, AD management and control, and program functions) were identified for designing the app. The quality evaluation of the app based on MARS and user satisfaction evaluation based on QUIS showed the app was good. This is the first study that focused on developing and evaluating a mobile app for assisting Alzheimer's caregivers during the COVID-19 pandemic. As the app was designed based on users' needs and covered both information about AD and COVID-19, it can help caregivers perform their tasks more efficiently.

Molecular mechanisms and therapeutic potential of icariin in the treatment of Alzheimer's disease

BackgroundIcariin (ICA) is the main active component of Epimedium, a traditional Chinese medicine (TCM), known to enhance cognitive function in Alzheimer's disease (AD). This study aims to investigate and summarize the mechanisms through which ICA treats AD. MethodsThe PubMed and CNKI databases were utilized to review the advancements in ICA's role in AD prevention and treatment by analyzing literature published between January 2005 and April 2023. To further illustrate ICA's impact on AD development, tables, and images are included to summarize the relationships between various mechanisms. ResultsThe study reveals that ICA ameliorates cognitive deficits in AD model mice by modulating Aβ via multiple pathways, including BACE-1, NO/cGMP, Wnt/Ca2+, and PI3K/Akt signaling. ICA exhibits neuroprotective properties by inhibiting neuronal apoptosis through the suppression of ER stress in AD mice, potentially linked to NF-κB, MAPK, ERK, and PERK/Eif2α signaling pathways. Moreover, ICA may safeguard neurons by attenuating mitochondrial oxidative stress injury. ICA can also enhance learning, memory, and cognition by improving synaptic structure via regulation of the PSD-95 protein. Furthermore, ICA can mitigate neuroinflammation by inactivating microglial activity through the upregulation of PPARγ, TAK1/IKK/NF-κB, and JNK/p38 MAPK signaling pathways. ConclusionThis study indicates that ICA possesses multiple beneficial effects in AD treatment. Through the integration of pharmacological and molecular biological research, ICA may emerge as a promising candidate to expedite the advancement of TCM in the clinical management of AD.

Transferrin functionalized nanostructured lipid carriers for targeting Rivastigmine and Resveratrol to Alzheimer's disease: Synthesis, in vitro characterization and brain uptake analysis

The management of Alzheimer's disease (AD) remains challenging owing to its complex pathophysiology and blood-brain barrier (BBB) restrictions. A rationally designed combination drug multi-target strategy has emerged as a promising approach for AD management. Considering the lipophilic nature of BBB and the need to embed dual drugs- Rivastigmine hydrogen tartrate and Resveratrol, nanostructured lipid carriers (NLCs) were used as drug delivery vehicle. NLCs were formulated by water/oil/water (w/o/w) double emulsion method and optimized using central composite design. HPLC method for simultaneous determination of drugs was developed and validated. To target the overexpressed Transferrin (TF) receptors, NLCs were surface functionalized with TF by covalent coupling employing carbodiimide chemistry. The success of conjugation was ascertained by Zeta potential, FTIR and TEM and the Bradford assay which estimated the conjugation efficiency of 47.52 ± 3.2%. A particle size of <100 nm was obtained which is favourable for brain delivery. Sustained release of drugs from nanoparticles was obtained, where TF-NLCs demonstrated a significantly slow release compared to NLCs. The functional stability and biocompatibility of the nanosystems was ensured by DPPH assay and hemolysis test, respectively. The confocal laser scanning microscopy (CLSM) revealed significantly higher (∼1.7 folds) brain uptake of TF-NLCs compared to NLCs in vivo following intraperitoneal administration. Dual drugs loaded TF functionalized NLCs demonstrated favourable in vitro and in vivo attributes for efficient brain targeting and hence AD management.

An ongoing journey of chalcone analogues as single and multi-target ligands in the field of Alzheimer's disease: A review with structural aspects.

Alzheimer's disease (AD) is a chronic and irreversible neurodegenerative disorder with progressive dementia and cognitive impairment. AD poses severe health challenge in elderly people and become one of the leading causes of death worldwide. It possesses complex pathophysiology with several hypotheses (cholinergic hypothesis, amyloid hypothesis, tau hypothesis, oxidative stress, mitochondrial dysfunction etc.). Several attempts have been made for the management of multifactorial AD. Acetylcholinesterase is the only target has been widely explored in the management of AD to the date. The current review set forth the chalcone based natural, semi-synthetic and synthetic compounds in the search of potential anti-Alzheimer's agents. The main highlights of current review emphasizes on chalcone target different enzymes and pathways like Acetylcholinesterase, β-secretase (BACE1), tau proteins, MAO, free radicals, Advanced glycation end Products (AGEs) etc. and their structure activity relationships contributing in the inhibition of above mentioned various targets of AD.