Management Of Alzheimer's Disease Research Articles

Quality of Life in Mild Cognitive Impairment and Mild Dementia Associated with Alzheimer's Disease: A Systematic Review.

Mild cognitive impairment (MCI) and Alzheimer's disease (AD) have a profound impact on patients' quality of life (QoL), with progressive declines occurring as the disease advances. This systematic review aims to summarize the published evidence on patient-reported outcomes (PROs) in individuals with MCI due to AD and mild AD dementia. Comprehensive searches were conducted across five major databases to identify studies reporting on utility values, disutilities, and QoL measures in these patient populations. A total of 23 studies were included that utilized various QoL assessment tools, including EQ-5D (n = 14), SF-36/SF-12 (n = 4), and QOL-AD (n = 11). Reported EQ-5D scores ranged from 0.81 to 0.92 for patients with MCI and from 0.67 to 0.85 for those with mild AD, indicating a noticeable decline in QoL as the disease progresses. QOL-AD scores ranged from 33.8 to 42.5 for MCI and from 32.4 to 38.1 for mild AD, equally reflecting the greater impairment in QoL with disease advancement. Interventions were generally associated with smaller declines in PROs compared to placebo, suggesting a positive impact of treatment in mitigating QoL deterioration. The findings underscore the significant QoL differences between MCI and mild AD, emphasizing the potential benefit of early intervention to preserve QoL and delay disease progression. This review highlights the importance of continued research to better understand QoL in patients with MCI and mild AD dementia, particularly in terms of capturing comprehensive patient-reported outcomes and evaluating the effectiveness of interventions over time. These findings can contribute to a more informed approach in clinical practice and support decision-making in the management of early-stage AD.

A Comprehensive Analysis on Galantamine Based Hybrids for the Management of Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive chronic age-related neurodegenerative brain disorder characterized by the loss of memory and other cognitive functions. The exact etiology of AD is still under investigation, however several factors such as low level of neurotransmitter acetylcholine (ACh), aggregation of amyloid beta (Aβ) in the form of Aβ plaques, hyperphosphorylation of tau protein into neurofibrillary tangles (NFTs), oxidative stress, and metal ion imbalance are the major hallmarks of this disease. Of the multiple hypotheses for AD, the amyloid-β (Aβ) and cholinergic hypothesis are the main targeting hypotheses for AD. Some researchers hypothesized that the primary event associated with the cholinergic neurotransmitter (acetylcholine) is memory loss and cognitive impairment. Due to the disease's complicated pathogenesis, long-term therapy with a single target candidate is futile. As a result, multitargeted and multifunctional therapies have emerged. Various research teams are concentrating on addressing multiple disease factors through hybridization techniques. Consequently, this hybridization approach has been applied to all core scaffolds, including galantamine. In this article, we tried to provide a thorough overview of the most recent developments on galantamine, a prospective AChE inhibitor, and its hybrid analogs as possible therapeutic agents for treating AD. Furthermore, we also provided the design, synthesis, and SAR analysis of the galantamine-based compounds used in the last decades for the management of AD.

Assessing the Role of the Generative Pretrained Transformer (GPT) in Alzheimer's Disease Management: Comparative Study of Neurologist- and Artificial Intelligence-Generated Responses.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder posing challenges to patients, caregivers, and society. Accessible and accurate information is crucial for effective AD management. This study aimed to evaluate the accuracy, comprehensibility, clarity, and usefulness of the Generative Pretrained Transformer's (GPT) answers concerning the management and caregiving of patients with AD. In total, 14 questions related to the prevention, treatment, and care of AD were identified and posed to GPT-3.5 and GPT-4 in Chinese and English, respectively, and 4 respondent neurologists were asked to answer them. We generated 8 sets of responses (total 112) and randomly coded them in answer sheets. Next, 5 evaluator neurologists and 5 family members of patients were asked to rate the 112 responses using separate 5-point Likert scales. We evaluated the quality of the responses using a set of 8 questions rated on a 5-point Likert scale. To gauge comprehensibility and participant satisfaction, we included 3 questions dedicated to each aspect within the same set of 8 questions. As of April 10, 2023, the 5 evaluator neurologists and 5 family members of patients with AD rated the 112 responses: GPT-3.5: n=28, 25%, responses; GPT-4: n=28, 25%, responses; respondent neurologists: 56 (50%) responses. The top 5 (4.5%) responses rated by evaluator neurologists had 4 (80%) GPT (GPT-3.5+GPT-4) responses and 1 (20%) respondent neurologist's response. For the top 5 (4.5%) responses rated by patients' family members, all but the third response were GPT responses. Based on the evaluation by neurologists, the neurologist-generated responses achieved a mean score of 3.9 (SD 0.7), while the GPT-generated responses scored significantly higher (mean 4.4, SD 0.6; P<.001). Language and model analyses revealed no significant differences in response quality between the GPT-3.5 and GPT-4 models (GPT-3.5: mean 4.3, SD 0.7; GPT-4: mean 4.4, SD 0.5; P=.51). However, English responses outperformed Chinese responses in terms of comprehensibility (Chinese responses: mean 4.1, SD 0.7; English responses: mean 4.6, SD 0.5; P=.005) and participant satisfaction (Chinese responses: mean 4.2, SD 0.8; English responses: mean 4.5, SD 0.5; P=.04). According to the evaluator neurologists' review, Chinese responses had a mean score of 4.4 (SD 0.6), whereas English responses had a mean score of 4.5 (SD 0.5; P=.002). As for the family members of patients with AD, no significant differences were observed between GPT and neurologists, GPT-3.5 and GPT-4, or Chinese and English responses. GPT can provide patient education materials on AD for patients, their families and caregivers, nurses, and neurologists. This capability can contribute to the effective health care management of patients with AD, leading to enhanced patient outcomes.

Different physical exercise in the treatment of Alzheimer's disease.

Alzheimer's disease (AD) is rapidly becoming one of the most expensive, burdening, and deadly diseases of this century. Up to now, there is still a lack of pharmacotherapy with substantial efficacy, and physical exercise is a promising and low-cost way to aid in delaying the process of AD. The aim of this review is to summarise the efficacy of different physical exercise approaches and doses in the management of AD, including aerobic exercise, resistance exercise and multicomponent exercise. A literature search using MeSH terms for each topic is undertaken using PubMed and the Web of Science Core Collection database, supplemented by hand searching for additional references. Retrieved articles were reviewed, synthesised, and summarised. This review shows that aerobic exercise has been almost unanimously recognised for the improvement of cognition, neuropsychiatric symptoms and activities of daily living. Resistance exercise also shows a good prospect in the above aspects and has a unique advantage in enhancing muscle strength, while multicomponent physical activity does not seen to significantly improve cognitive function. Each type of exercise has a dose effect, but for individuals with AD, the most appropriate exercise dose is still controversial.

The relationship between micronutrients and cognitive ability in an elderly population with mild cognitive impairment and Alzheimer’s disease: a cross-sectional study

BackgroundMild cognitive impairment (MCI) and Alzheimer’s disease (AD) are significant neurodegenerative disorders with increasing prevalence worldwide. Lifestyle and dietary factors, including micronutrients, have been suggested as modifiable risk factors for disease development. This study aims to investigate the association between micronutrients and cognitive ability in these diseases.MethodsA cross-sectional study involving 105 participants with MCI and AD was conducted. Dietary assessments were performed using a validated food frequency questionnaire (FFQ), and micronutrient intake was calculated based on nutrient content. Disease severity was evaluated using the Functional Assessment Staging Tool (FAST). Statistical analyses, including correlation coefficients and multiple regression models, were employed to examine the association between micronutrients and disease progression.ResultsThe results revealed significant correlations between disease severity and several micronutrients, including omega-3 fatty acids (B = -0.2, P = 0.01), carotenoids (B = -0.19, P = 0.02), dietary antioxidant compounds, including vitamins A, C, D, E (B = -0.19, P = 0.02), selenium (B = -0.17, P = 0.03), alpha-carotene (B = -0.16, P = 0.04), beta-carotene (B = -0.17, P = 0.03), and lycopene (B = -0.16, P = 0.04). Multivariate regression analysis showed that higher intake of omega-3 fatty acids was associated with slower disease progression. Furthermore, the levels of these micronutrients declined in advanced stages of the disease.ConclusionOmega-3 fatty acids and carotenoids may affect the cognitive ability and disease progression. Further longitudinal studies are warranted to establish causality and explore the therapeutic implications of these findings for the prevention and management of MCI and AD.

Future Therapeutic Strategies for Alzheimer's Disease: Focus on Behavioral and Psychological Symptoms.

Alzheimer's disease (AD) is a progressive, degenerative brain disorder that impairs memory and thinking skills, leading to significant economic and humanistic burdens. It is associated with various neuropsychiatric symptoms (NPS) such as anxiety, agitation, depression, aggression, apathy, and psychosis. NPSs are common in patients with AD, affecting up to 97% of individuals diagnosed with AD. The severity of NPS is linked to disease progression and cognitive decline. NPS in Alzheimer's disease leads to increased morbidity, mortality, caregiver burden, earlier nursing home placement, and higher healthcare costs. Despite their significant impact, clinical research on NPS in AD is limited. In clinical settings, accurately distinguishing and diagnosing NPS related to AD remains a challenge. Additionally, conventional treatments for NPS in AD are often ineffective, highlighting the need for new therapies that target these specific symptoms. Understanding these comorbidities can aid in early diagnosis and better management of AD. In this review, we provide a summary of the various neurological and psychiatric symptoms (NPS) associated with AD and new candidates under development for the treatment of NPS based on their therapeutic targets and mechanisms. On top of the conventional NPS studied so far, this review adds recent advancements in the understanding of social functional impairment in AD. This review also provides information that can contribute to the advancement of studies and translational research in this field by emphasizing therapeutic targets and mechanisms of action focused on AD-related NPS rather than conventional mechanisms targeted in AD drug development. Above all, considering the relative lack of research in this new field despite the importance of clinical, medical, and translational research, it may increase interest in NPS in AD, its pathophysiological mechanisms, and potential therapeutic candidates such as molecules with antioxidant potential.

The Therapeutic Potential of Yoga for Alzheimer's Disease: A Critical Review.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory impairment, and behavioral changes, significantly impacting the quality of life of affected individuals and their caregivers. While pharmacological treatments offer limited relief, nonpharmacological interventions, like yoga, have gained attention for their potential therapeutic benefits. This critical review synthesizes findings from various studies on the feasibility, adherence, physical function, cognitive improvements, inflammatory markers, neuroprotection, and mood and behavioral changes associated with yoga interventions for older adults with AD. Despite these promising results, further research with randomized controlled trials, larger sample sizes, control groups, longitudinal follow-ups, standardized protocols, and diverse populations is necessary to confirm these benefits and understand the long-term effects of yoga on AD progression. This critical review highlights yoga's potential as a valuable nonpharmacological intervention in the holistic management of AD.

A Review on Phytochemical Constituents Used as Current Treatment Strategies for Neurodegenerative Disease.

In today's time, a diversity of neurodegenerative diseases that widely affect the CNS causing insufficiency in particular brain processes such as memory, mobility, and cognition due to the moderate loss of CNS neurons. This review emphasizes different phytochemical constituents used widely for the prevention or treatment of various neurodegenerative diseases such as Alzheimer's disease (AD) and Parkin-son's disease (PD). Berberin (BBR), which is an isoquinoline class of alkaloid and isolated from the plant Hydrastis condenses and Berberis aaristata, has both acetylcholine esterase (AChE) inhibiting properties as well as monoamine oxidase (MAO) inhibiting properties involved in the betterment of AD by decreasing the production of reactive oxygen species (ROS). Like BBR, Physostigmine, isolated from the Physostigma venenosum / Calabar bean and belongs to the family Leguminosae, and Morphine, isolated from the plant Papaver somniferum / Opium poppy or Breadseed poppy, also has a significant impact on the management and treatment of AD and PD by reducing both neuroinflammation and pro-inflammatory cytokines production. Morphine bineurodegenerative diseases with μ-opioid receptor (MOR) in CNS elevate GABA levels in the synaptic cleft of the brain and reduces the neurotoxicity via stimulation of MOR. It has been discovered that physostigmine improves cognitive function in AD patients and reduces α-synu-clein expression in PD neural cell lines. Isorhyncophylline (IRN) is a Chinese herbal medicine isolated from the plant Uncaria rhyncophylla which provides neuroprotective efficiency against neurotoxicity that occurs by amyloid β (the main component of amyloid plaques) found in the brain of people with AD.

Demystifying the Role of Neuroinflammatory Mediators as Biomarkers for Diagnosis, Prognosis, and Treatment of Alzheimer's Disease: A Review.

Neuroinflammatory mediators play a pivotal role in the pathogenesis of Alzheimer's Disease (AD), influencing its onset, progression, and severity. The precise mechanisms behind AD are still not fully understood, leading current treatments to focus mainly on managing symptoms rather than preventing or curing the condition. The amyloid and tau hypotheses are the most widely accepted explanations for AD pathology; however, they do not completely account for the neuronal degeneration observed in AD. Growing evidence underscores the crucial role of neuroinflammation in the pathology of AD. The neuroinflammatory hypothesis presents a promising new approach to understanding the mechanisms driving AD. This review examines the importance of neuroinflammatory biomarkers in the diagnosis, prognosis, and treatment of AD. It delves into the mechanisms underlying neuroinflammation in AD, highlighting the involvement of various mediators such as cytokines, chemokines, and ROS. Additionally, this review discusses the potential of neuroinflammatory biomarkers as diagnostic tools, prognostic indicators, and therapeutic targets for AD management. By understanding the intricate interplay between neuroinflammation and AD pathology, this review aims to help in the development of efficient diagnostic and treatment plans to fight this debilitating neurological condition. Furthermore, it elaborates recent advancements in neuroimaging techniques and biofluid analysis for the identification and monitoring of neuroinflammatory biomarkers in AD patients.

JNK inhibitor and ferroptosis modulator as possible therapeutic modalities in Alzheimer disease (AD)

Alzheimer disease (AD) is among the most prevalent neurodegenerative diseases globally, marked by cognitive and behavioral disruptions. Ferroptosis is a form of controlled cell death characterized by intracellular iron accumulation associated with lipid peroxide formation, which subsequently promotes AD initiation and progression. We hypothesized that targeting the ferroptosis pathway may help in AD management. Therefore, our study aimed to evaluate the potential neuroprotective effect of the antifungal Ciclopirox olamine (CPX-O) that acts through iron chelation. We employed CPX-O separately or in combination with the JNK inhibitor (SP600125) in a mice model of AlCl3-induced AD. Animals underwent examination for behavioral, biochemical, histological, and immunohistochemical findings. Our results revealed that AlCl3 was associated with disruptions in learning and memory parameters, neuronal degeneration in the hippocampus, increased immunoreactivity of amyloid-β and tau proteins, a significant rise in iron, nitric oxide (NO), malondialdehyde (MDA), JNK, and P53 levels, along with the significant decrease in glutathione peroxidase activity. Interestingly, the administration of CPX-O alone or in combination with SP600125 in the AlCl3-induced AD model caused an improvement in the previously described examination findings. Therefore, CPX-O may be a promising candidate for AD treatment, and future clinical trials will be required to confirm these preclinical findings.

Orexin Receptor Antagonists for the Prevention and Treatment of Alzheimer's Disease and Associated Sleep Disorders.

Orexins/hypocretins are neuropeptides produced by the hypothalamic neurons, binding two G-protein coupled receptors (orexin 1 and orexin 2 receptors) and playing a critical role in regulating arousal, wakefulness, and various physiological functions. Given the high prevalence of sleep disturbances in Alzheimer's disease (AD) and their reported involvement in AD pathophysiology, the orexin system is hypothesized to contribute to the disease pathogenesis. Specifically, recent evidence suggests that orexin's influence may extend beyond sleep regulation, potentially affecting amyloid-β and tau pathologies. Dual orexin receptor antagonists (DORAs), namely suvorexant, lemborexant, and daridorexant, demonstrated efficacy in treating chronic insomnia disorder across diverse clinical populations. Considering their stabilizing effects on sleep parameters and emerging evidence of a possible neuroprotective role, these agents represent a promising strategy for AD management. This leading article reviews the potential use of orexin receptor antagonists in AD, particularly focusing on their effect in modulating disease-associated sleep disturbances and clinical outcomes. Overall, clinical studies support the use of DORAs to enhance sleep quality in patients with AD with comorbid sleep and circadian sleep-wake rhythm disorders. Preliminary results also suggest that these compounds might influence AD pathology, potentially affecting disease progression. Conversely, research on selective orexin receptor antagonists in AD is currently limited. Further investigation is needed to explore orexin antagonism not only as a symptomatic treatment for sleep disturbances, but also for its broader implications in modifying AD neurodegeneration, emphasizing mechanisms of action and long-term outcomes.

Revolutionizing Alzheimer's Diagnosis and Management: The Dawn of Biomarker-Based Precision Medicine.

Alzheimer's disease (AD), a leading cause of dementia, presents a formidable global health challenge intensified by the aging population. This review encapsulates the evolving landscape of AD diagnosis and treatment with a special focus on the innovative role of fluid biomarkers. Pathologically, AD is marked by amyloid beta (Aβ) plaques and neurofibrillary tangles of hyperphosphorylated tau, which lead to synaptic dysfunction, neuronal loss, and cognitive decline. These pathological changes, commencing decades before symptom onset, underscore the need for early detection and intervention. Diagnosis traditionally relies on clinical assessment, neuropsychological testing, and neuroimaging techniques. However, fluid biomarkers in cerebrospinal fluid and blood, such as various forms of Aβ, total tau, phosphorylated tau, and neurofilament light chain, are emerging as less invasive, cost-effective diagnostic tools. These biomarkers are pivotal for early diagnosis, differential diagnosis, disease progression monitoring, and treatment response evaluation. The treatment landscape is shifting toward personalized medicine, highlighted by advancements in Aβ immunotherapies, such as lecanemab and donanemab. Demonstrating efficacy in phase III clinical trials, these therapies hold promise as tailored treatment strategies based on individual biomarker profiles. The integration of fluid biomarkers into clinical practice represents a significant advance in AD management, providing the potential for early and precise diagnosis, coupled with personalized therapeutic approaches. This heralds a new era in combating this debilitating disease.

Green synthesis of Tacrine modified Schiff bases as anti-Alzheimer Agents: An effective strategy validated through in-silico and in-vitro analysis

A variety of Tacrine-modified Schiff base analogues were developed via solvent free (green) method and structurally elucidated using 1HNMR, FTIR and UV–Vis analysis. High product yield was obtained from the synthesised molecules, which were produced efficiently at room temperature without the need of a solvent. The developed molecules were subsequently assessed for their potential to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). These molecules revealed effective inhibition of AChE and BChE enzymes with IC50 values varying from 0.1 ± 0.02 to 0.3 ± 0.03 μM and 0.065 ± 0.01 to 0.3 ± 0.03 μM respectively. Compared to the standard Tacrine which has IC50 values of 0.35 ± 0.02 μM for AChE and 0.1 ± 0.01 μM for BChE. Notably, compound 3f showed strong inhibition among others for both the enzymes. The structure–activity relationship of derivatives synthesized were verified and established through molecular docking studies. Theoretical ADME studies also predicted excellent drug-likeness for all the synthesized molecules. Antioxidant activities were also assessed because elevated oxidative stress levels are linked with cognitive loss in Alzheimer's disease (AD). These findings suggest that the lead compound is potentially an effective inhibitor for the therapeutic management of AD.

The Potential Related Genes and Mechanisms Involved in Improving the Treadmill Exercise Ability of APP/PS1 Mice.

Alzheimer's disease (AD) causes a decline in skeletal muscle function, which can further exacerbate the cognitive dysfunction of patients with AD. It has been widely established that exercise improves AD brain pathology, but the role of skeletal muscle in AD is still poorly understood. In this study, we investigated the effects of treadmill exercise on the exercise ability of APP/PS1 transgenic AD mice and explored potential gene expression changes in their skeletal muscle. The APP/PS1 mice were subjected to a treadmill exercise for 12 weeks, followed by the Morris water maze and the open field test. After behavioral experiments, the changes in morphology, area, collagen fiber deposition, and ultrastructure of the skeletal muscle were determined; the balance of skeletal muscle protein synthesis and decomposition was analyzed; and changes in gene expression were investigated using RNA-Seq. We found that this exercise strategy can promote the learning and memory abilities of AD mice, reduce their anxiety-like behavior, improve their exercise ability, alleviate skeletal muscle atrophy, and optimize the microstructure. It can also enhance skeletal muscle protein synthesis and decomposition and improve several signaling pathways, such as the JAK-STAT, Wnt, and NOD-like receptors while decreasing calcium, cAMP, cGMP-PKG, and other signaling pathways. Six KEGG enrichment signaling pathways were downregulated and five signaling pathways were upregulated in the AD mice compared with wild-type mice, and these pathways were precisely reversed after the treadmill exercise. The expression of transcription factors such as Fosb and Egr1 in the skeletal muscle of AD mice decreased, followed by a decrease in the regulated target genes Socs1, Srrm4, and Il1b, a trend that was reversed following the exercise intervention. After exercise, AD mice exhibited a similar gene expression to that of wild-type mice, indicating enhanced exercise ability. The potential regulatory pathways and related genes identified in this study provide valuable insights for the clinical management and treatment of AD.

Harmonizing Insights: LR-FFT Feature Extraction for Alzheimer’s and Autism Spectrum Disorder Detection in EEG Signals

Alzheimer’s Disease (AD) and Autism Spectrum Disorder (ASD) represent two distinct but equally impactful challenges in the field of neurology and cognitive health. AD is a degenerative neurological condition characterized by its progressive nature, typically affecting individuals in later stages of life. The hallmark features include cognitive impairment, mem- ory deterioration, and alterations in behavior. In contrast, ASD is a developmental disorder typically diagnosed in childhood, marked by difficulties in social interaction, communication, and repetitive behaviors. This paper explores the potential of the time-frequency feature extraction model known as the Left-Right Fast Fourier Transform (LR-FFT) in the context of these two disorders. While AD and ASD differ significantly in their onset, presentation, and demographic affected, both necessitate early and accurate diagnosis to enable timely intervention and tailored treatment strategies. Our research yields promising results, with classification accuracies reaching 88.26% for AD and 99.86% for ASD, demonstrating the LR-FFT’s potential to enhance diagnostic accuracy. By contributing to improved differentiation between these complex neurological conditions, this work aims to advance our understanding and management of AD and ASD, ultimately benefiting patients, their families, and healthcare practitioners.

The Potential of Emerging Medicinal Plants and their Phytoconstituents in Treating Alzheimer's Disease

Backgrounds: Alzheimer's disease (AD) impacts a total of 30 million individuals worldwide, resulting in the impairment of brain cells. Despite the approval of medications, there are still poor results and adverse effects that continue to exist, which has led to continued research for more effective treatments. Objectives: We prioritize the study of medicinal plants and their bioactive chemicals to attract researchers and pharmaceutical companies interested in producing powerful herbal medicines and semi-synthetic drugs for the treatment of Alzheimer's disease, although minimizing any potential adverse effects. Methods: This review investigate the effective use of medicinal plants and their phytochemicals in the treatment of AD to manage its growth and relieve symptoms via improving cognitive deficits. Result: These medicinal plants and their phytochemicals contribute to the treatment of AD by protecting against cell damage induced by beta amyloid, improving memory and learning abilities, functioning as nerve tonics, and exhibiting strong antioxidant and anti-inflammatory activities. Furthermore, they have demonstrated therapeutic benefits in the management of AD. The finding suggests that several phytoconstituents/ plant metabolites are present in numerous anti-Alzheimer's plants known for their anti-Alzheimer's properties such as rosmarinic acid, quercetin, kaempferol, gallic acid, β-sitosterol, oleic acid and linalool. In addition, this article emphasizes the anti- Alzheimer's disease significance of various important phytochemicals. Conclusions: The review proposes that medicinal plants and their bioactive phytochemicals hold potential as a viable alternative treatment for AD. The utilization of these medicinal plants can improve memory and decrease the likelihood of developing Alzheimer's disease in the future.

Highly sensitive blood-based biomarkers detection of beta-amyloid and phosphorylated-tau181 for Alzheimer's disease.

Plasma biomarker has the potential to be the reliable and propagable approach in the early stage diagnosis of Alzheimer's disease (AD). However, conventional methods appear powerless in the detection of these biomarkers at low concentrations in plasma. Here, we determined plasma biomarker concentrations of patients across the AD spectrum by an improved digital enzyme-linked immunosorbent assay (ELISA) technique. Confirms the predictive and diagnostic value of this method for AD patients and study the relationships between these biomarkers and cognitive status. Plasma concentrations of amyloid-beta 40 (Aβ40), amyloid-beta 42 (Aβ42) and plasma phosphorylated tau at threonine 181 (p-tau181) were determined in 43 AD patients, 33 mild cognitive impairment (MCI) patients and 40 normal cognition (NC) subjects as healthy controls using the improved digital ELISA technique. In addition, all subjects were required to receive neuropsychological assessments. Plasma p-tau181 level showed certain discrepancies between NC and MCI (p < 0.05), AD (p < 0.01) groups. The level of plasma Aβ42 (p < 0.05) and Aβ40 (p < 0.01) was significantly different between AD and NC group. The p-tau181 level was able to distinguish AD (AUC = 0.8768) and MCI (AUC = 0.7932) from NC with higher accuracy than Aβ42/Aβ40 ratio (AUC = 0.8343, AUC = 0.6569). Both p-tau181 (CDR: r = 0.388 p < 0.001; MMSE: r = -0.394 p < 0.001) and Aβ42/Aβ40 ratio (CDR: r = -0.413 p < 0.001; MMSE: r = 0.358 p < 0.001) showed stronger positive correlation with clinical dementia rating (CDR) and mini mental state examination (MMSE) scores than Aβ42 (CDR: r = -0.280 p = 0.003; MMSE: r = 0.266 p = 0.005) or Aβ40 (CDR: r = 0.373 p < 0.001; MMSE: r = -0.288 p = 0.002) alone. Plasma p-tau181 level and Aβ42/Aβ40 ratio showed promising values in diagnosis of AD and MCI. Our results indicate that this improved digital ELISA diagnosis approach can facilitate early recognition and management of AD and pre-AD patients.

The Endocannabinoid System in Alzheimer's Disease: ANetwork Meta-Analysis.

The findings concerning the association between endocannabinoid system (ECS) and Alzheimer's disease (AD) exhibited inconsistencies when examining the expression levels of endocannabinoids. This study aimed to provide a comprehensive summary of the studies regarding alterations of the ECS in AD. Six databases were thoroughly searched for literature to select relevant studies investigating the ECS in AD, including changes in cannabinoid receptors (CB1R and CB2R), endocannabinoids (2-AG and AEA), and their associated enzymes (FAAH and MAGL). Traditional meta-analysis evaluated the expression levels of the ECS in AD, and the results showed no significant differences in ECS components between healthy controls and AD patients. However, subgroup analysis revealed significantly lower expression levels of CB1R in AD than in controls, particularly in studies using western blot (SMD = -0.88, p < 0.01) and in studies testing CB1R of frontal cortex (SMD = -1.09, p < 0.01). For studies using HPLC, the subgroup analysis indicated significantly higher 2-AG levels in AD than in controls (SMD = 0.46, p = 0.02). Network meta-analysis examined the rank of ECS alterations in AD compared to controls, and the findings revealed that 2-AG and MAGL exhibited the largest increase and CB1R showed the largest decrease relative to the control group. Based on the findings of traditional meta-analysis and network meta-analysis, we proposed that AD patients may present decreased expression levels of CB1R and increased expression levels of 2-AG and its degrading enzyme MAGL. Our results may contribute to the growing body of research supporting the therapeutic potential of ECS modulation in the management of AD.

Lacticaseibacillus rhamnosus HA-114 and Bacillus subtilis R0179 Prolong Lifespan and Mitigate Amyloid-β Toxicity in C.elegans via Distinct Mechanisms.

Recent advances linking gut dysbiosis with neurocognitive disorders such as Alzheimer's disease (AD) suggest that the microbiota-gut-brain axis could be targeted for AD prevention, management, or treatment. We sought to identify probiotics that can delay Aβ-induced paralysis. Using C. elegans expressing human amyloid-β (Aβ)1-42 in body wall muscles (GMC101), we assessed the effects of several probiotic strains on paralysis. We found that Lacticaseibacillus rhamnosus HA-114 and Bacillus subtilis R0179, but not their supernatants or heat-treated forms, delayed paralysis and prolonged lifespan without affecting the levels of amyloid-β aggregates. To uncover the mechanism involved, we explored the role of two known pathways involved in neurogenerative diseases, namely mitophagy, via deletion of the mitophagy factor PINK-1, and fatty acid desaturation, via deletion of the Δ9 desaturase FAT-5. Pink-1 deletion in GMC101 worms did not modify the life-prolonging and anti-paralysis effects of HA-114 but reduced the protective effect of R0179 against paralysis without affecting its life-prolonging effect. Upon fat5 deletion in GMC101 worms, the monounsaturated C14:1 and C16:1 FAs conserved their beneficial effect while the saturated C14:0 and C16:0 FAs did not. The beneficial effects of R0179 on both lifespan and paralysis remained unaffected by fat-5 deletion, while the beneficial effect of HA-114 on paralysis and lifespan was significantly reduced. Collectively with clinical and preclinical evidence in other models, our results suggest that HA-114 or R0179 could be studied as potential therapeutical adjuncts in neurodegenerative diseases such as AD.

Dietary interventions for Alzheimer's in Pakistan: The MIND diet perspective.

Dear Editor, Alzheimer’s disease (AD) stands as the prevalent type of dementia, making up 50–75% of total cases, and showing a higher incidence among elderly patients. (1). Pakistan is a lower-middle-income country with an estimated 150,000–200,000 patients affected by dementia (2). Nevertheless, the patient population faces inadequate healthcare resources, with only one neurosurgeon for every 1,000,000 patients (3). The Alzheimer's Association Facts and Figures Guidelines (2014) have highlighted diet as a modifiable risk factor in progression of AD (4). Thus, investigating lifestyle modifications in the early stages of AD to potentially alleviate the disease progression becomes imperative, considering the significant burden the disease imposes on the healthcare system. The MIND diet is a composite dietary approach, derived from both the Mediterranean and DASH diets. It underscores the consumption of leafy greens, berries, nuts, whole grains, fish, legumes, and poultry while advocating for the use of olive oil. Conversely, it discourages the intake of red meat, butter, cheese, pastries, and fried or fast-food items (5). Agarwal et al. investigated the impact of the MIND diet on AD pathology in 581 autopsied participants from the Rush Memory and Aging Project. Their research demonstrated a significant correlation between adherence to the MIND diet and a decline in overall disease pathology, particularly in the reduction of Beta-amyloid plaques (6). Furthermore, another study illustrated that increased compliance with the MIND diet was associated with a reduced risk of hippocampal sclerosis (HS), a neurodegenerative condition linked to AD, even after accounting for other factors, such as APOE-4 status and AD pathology (7). Moreover, Morris et al.'s longitudinal study on US participants found a 53% lower risk for AD among individuals who adhered closely to the MIND diet and a 35% lower risk for those with moderate adherence after a follow-up of approximately 4.5 years (8). These findings indicate a potential role for the MIND diet in reducing the risk of AD and slowing cognitive decline. A comprehensive literature search on PubMed and PakMediNet revealed a lack of research, evaluating the efficacy of the MIND diet in the management of AD in Pakistan. This underscores the inadequacy in the implementation of the MIND diet among the patients. Consequently, it is recommended that researchers submit research grant proposals about the efficacy of the MIND diet in AD to different funding organizations. ---Continue