Promoting Alzheimer's disease research and therapy with stem cell technology.

BACKGROUND: Alzheimer's disease (AD) is a prevalent form of dementia leading to memory loss, reduced cognitive and linguistic abilities, and decreased self-care. Current AD treatments aim to relieve symptoms and slow disease progression, but a cure is elusive due to limited understanding of the underlying disease mechanisms. MAIN CONTENT: Stem cell technology has the potential to revolutionize AD research. With the ability to self-renew and differentiate into various cell types, stem cells are valuable tools for disease modeling, drug screening, and cell therapy. Recent advances have broadened our understanding beyond the deposition of amyloidß (Aß) or tau proteins in AD to encompass risk genes, immune system disorders, and neuron-glia mis-communication, relying heavily on stem cell-derived disease models. These stem cell-based models (e.g., organoids and microfluidic chips) simulate in vivo pathological processes with extraordinary spatial and temporal resolution. Stem cell technologies have the potential to alleviate AD pathology through various pathways, including immunomodulation, replacement of damaged neurons, and neurotrophic support. In recent years, transplantation of glial cells like oligodendrocytes and the infusion of exosomes have become hot research topics. CONCLUSION: Although stem cell-based models and therapies for AD face several challenges, such as extended culture time and low differentiation efficiency, they still show considerable potential for AD treatment and are likely to become preferred tools for AD research.

Passive immunotherapy for Alzheimer's disease: challenges & future directions.

Passive immunotherapy with specific antibodies targeting Amyloid ß (Aß) peptide or tubulin-associated unit (tau) protein has emerged as a promising therapeutic approach in Alzheimer's disease (AD). However, in a recent phase III clinical study, Sperling et al. (N Engl J Med 10.1056/NEJMoa2305032, 2023) reported that solanezumab, a monoclonal antibody targeting Aß peptide, failed to slow cognitive decline in AD patients. Previously, three other anti-Aß antibodies, bapineuzumab, crenezumab, and gantenerumab, have also failed to show similar beneficial effects. In addition, three humanized antibodies targeting tau protein failed in their phase II trials. However, other anti-Aß antibodies, such as lecanemab (a humanized mAb binds to soluble Aß protofibrils), donanemab (a humanized mAb binds to insoluble, N-terminal truncated form of Aß peptides) and aducanumab (a human mAb binds to the aggregated form of Aß), have been shown to slow the decline of cognitive functions in early stage AD patients. The specific targets used in passive immunotherapy in these clinical trials may explain the divergent clinical outcomes. There are several challenges and limitations of passive immunotherapy using anti-Aß antibodies and long term longitudinal studies are needed to assess their efficacy, side effects and cost effectiveness in a wider spectrum of subjects, from pre-dementia to more advanced dementia. A combination therapeutic approach using both anti-Aß antibodies and other pharmaceutical agents should also be explored.

Clinical observation on treatment of Alzheimer's disease with Sun's scalp-abdominal acupuncture combined with donepezil hydrochloride. / å­™æ°å¤´é’ˆè ¹é’ˆè”åˆç›é ¸å¤šå¥ˆå“Œé½æ²»ç–—é˜¿å°”èŒ¨æµ·é»˜ç— çš„ä¸´åºŠè§‚å¯Ÿ.

OBJECTIVES: To observe the effect of scalp-abdominal acupuncture combined with donepezil hydrochloride on cognition and life ability of patients with Alzheimer's disease (AD), so as to evaluate its clinical efficacy. METHODS: Sixty AD patients were collected and randomly divided into control group (30 cases) and observation group (30 cases). Patients in the control group were treated with oral donepezil hydrochloride (5 mg, once daily). Patients in the observation group were treated with scalp-abdominal acupuncture at Baihui (GV20), Yintang (GV24+), Sishencong (EX-HN1), "emotional area", Shenting (GV24), "abdominal area 1""abdominal area 8", and bilateral Fengchi (GB20), Taixi (KI3), Xuanzhong (GB39), Zusanli (ST36) on the basis of control group, and electroacupuncture (10 Hz/50 Hz, 0.5 to 5.0 mA) was applied to EX-HN1, "emotional area""abdominal area 1" and "abdominal area 8", once daily, 30 min each time. Four weeks as a course of treatment, both the two groups were treated for two consecutive courses. Before and after treatment, the mini-mental state examination (MMSE), AD assessmennt scale-cognitive subscale (ADAS-Cog) and activity of daily living scale (ADL) were evaluated. The clinical efficacy index was calculated and safety was evaluated. RESULTS: After treatment, the MMSE and ADL scores were higher (P<0.05) and the ADAS-Cog score was lower (P<0.05) than those before treatment in both groups. Compared with the control group, the MMSE and ADL scores were increased (P<0.05) and ADAS-Cog score was decreased (P<0.05) in the observation group. The total effective rate of the observation group (26/30, 86.67%) was higher (P<0.05) than that of the control group (23/30, 76.67%). No adverse reactions occurred in both groups during the treatment. CONCLUSIONS: Scalp-abdominal acupuncture combined with donepezil hydrochloride can effectively improve the cognitive ability and daily living ability of AD patients, and the efficacy is better than that of oral donepezil hydrochloride alone.

Transcranial Magneto-Acoustic Stimulation Protects Synaptic Rehabilitation from Amyloid-Beta Plaques via Regulation of Microglial Functions.

Transcranial magneto-acoustic stimulation (TMAS), which is characterized by high spatiotemporal resolution and high penetrability, is a non-invasive neuromodulation technology based on the magnetic-acoustic coupling effect. To reveal the effects of TMAS treatment on amyloid-beta (Aß) plaque and synaptic plasticity in Alzheimer's disease, we conducted a comparative analysis of TMAS and transcranial ultrasound stimulation (TUS) based on acoustic effects in 5xFAD mice and BV2 microglia cells. We found that the TMAS-TUS treatment effectively reduced amyloid plaque loads and plaque-associated neurotoxicity. Additionally, TMAS-TUS treatment ameliorated impairments in long-term memory formation and long-term potentiation. Moreover, TMAS-TUS treatment stimulated microglial proliferation and migration while enhancing the phagocytosis and clearance of Aß. In 5xFAD mice with induced microglial exhaustion, TMAS-TUS treatment-mediated Aß plaque reduction, synaptic rehabilitation improvement, and the increase in phospho-AKT levels were diminished. Overall, our study highlights that stimulation of hippocampal microglia by TMAS treatment can induce anti-cognitive impairment effects via PI3K-AKT signaling, providing hope for the development of new strategies for an adjuvant therapy for Alzheimer's disease.

Perceptions and outcomes of an embedded Alzheimer Society First Link Coordinator in rural primary health care memory clinics.

BACKGROUND: Primary health care has a central role in dementia detection, diagnosis, and management, especially in low-resource rural areas. Care navigation is a strategy to improve integration and access to care, but little is known about how navigators can collaborate with rural primary care teams to support dementia care. In Saskatchewan, Canada, the RaDAR (Rural Dementia Action Research) team partnered with rural primary health care teams to implement interprofessional memory clinics that included an Alzheimer Society First Link Coordinator (FLC) in a navigator role. Study objectives were to examine FLC and clinic team member perspectives of the impact of FLC involvement, and analysis of Alzheimer Society data comparing outcomes associated with three types of navigator-client contacts. METHODS: This study used a mixed-method design. Individual semi-structured interviews were conducted with FLC (n = 3) and clinic team members (n = 6) involved in five clinics. Data were analyzed using thematic inductive analysis. A longitudinal retrospective analysis was conducted with previously collected Alzheimer Society First Link database records. Memory clinic clients were compared to self- and direct-referred clients in the geographic area of the clinics on time to first contact, duration, and number of contacts. RESULTS: Three key themes were identified in both FLC and team interviews: perceived benefits to patients and families of FLC involvement, benefits to memory clinic team members, and impact of rural location. Whereas other team members assessed the patient, only FLC focused on caregivers, providing emotional and psychological support, connection to services, and symptom management. Face-to-face contact helped FLC establish a relationship with caregivers that facilitated future contacts. Team members were relieved knowing caregiver needs were addressed and learned about dementia subtypes and available services they could recommend to non-clinic clients with dementia. Although challenges of rural location included fewer available services and travel challenges in winter, the FLC role was even more important because it may be the only support available. CONCLUSIONS: FLC and team members identified perceived benefits of an embedded FLC for patients, caregivers, and themselves, many of which were linked to the FLC being in person.

Photobiomodulation in experimental models of Alzheimer's disease: state-of-the-art and translational perspectives.

Alzheimer's disease (AD) poses a significant public health problem, affecting millions of people across the world. Despite decades of research into therapeutic strategies for AD, effective prevention or treatment for this devastating disorder remains elusive. In this review, we discuss the potential of photobiomodulation (PBM) for preventing and alleviating AD-associated pathologies, with a focus on the biological mechanisms underlying this therapy. Future research directions and guidance for clinical practice for this non-invasive and non-pharmacological therapy are also highlighted. The available evidence indicates that different treatment paradigms, including transcranial and systemic PBM, along with the recently proposed remote PBM, all could be promising for AD. PBM exerts diverse biological effects, such as enhancing mitochondrial function, mitigating the neuroinflammation caused by activated glial cells, increasing cerebral perfusion, improving glymphatic drainage, regulating the gut microbiome, boosting myokine production, and modulating the immune system. We suggest that PBM may serve as a powerful therapeutic intervention for AD.

Slovenian Memory Clinic Organization with the Introduction of Potential New Alzheimer's Disease Treatment.

Slovenia, situated in Central Europe with a population of 2.1 million, has an estimated 44,278 individuals with mild cognitive impairment due to Alzheimer's disease or mild Alzheimer's dementia, rendering them potential candidates for disease-modifying treatment (DMT), such as lecanemab. We identified 114 potential candidates whose real-life expenses for diagnostic process surmount to more than €80,000. Treating all potential candidates nationwide would amount to €1.06 billion, surpassing Slovenia's entire annual medication expenditure for 2022 (€743 million). The introduction of DMTs and the associated logistics, along with potential complications, will significantly change societal, professional, and patient approach to treatment of Alzheimer's disease.

Who Benefited Most from the Internet-Based Conversational Engagement RCT (I-CONECT)? Application of the Personalized Medicine Approach to a Behavioral Intervention Study.

BACKGROUND: Many Alzheimer's Disease (AD) clinical trials have failed to demonstrate treatment efficacy on cognition. It is conceivable that a complex disease like AD may not have the same treatment effect due to many heterogeneities of disease processes and individual traits. OBJECTIVES: We employed an individual-level treatment response (ITR) approach to determine the characteristics of treatment responders and estimated time saved in cognitive decline using the Internet-based Conversational Engagement Clinical Trial (I-CONECT) behavioral intervention study as a model. DESIGN AND SETTING: I-CONECT is a multi-site, single-blind, randomized controlled trial aimed to improve cognitive functions through frequent conversational interactions via internet/webcam. The experimental group engaged in video chats with study staff 4 times/week for 6 months; the control group received weekly 10-minute check-in phone calls. PARTICIPANTS: Out of 186 randomized participants, current study used 139 participants with complete information on both baseline and 6-month follow-up (73 with mild cognitive impairment (MCI), 66 with normal cognition; 64 in the experimental group, and 75 in the control group). MEASUREMENTS: ITR scores were generated for the Montreal Cognitive Assessment (MoCA) (global cognition, primary outcome) and Category Fluency Animals (CFA) (semantic fluency, secondary outcome) that showed significant efficacy in the trial. ITR scores were generated through 300 iterations of 3-fold cross-validated random forest models. The average treatment difference (ATD) curve and the area between the curves (ABC) were estimated to measure the heterogeneity of treatment responses. Responder traits were identified using SHapley Additive exPlanations (SHAP) and decision tree models. The time saved in cognitive decline was explored to gauge clinical meaningfulness. RESULTS: ABC statistics showed substantial heterogeneity in treatment response with MoCA but modest heterogeneity in treatment response with CFA. Age, cognitive status, time spent with family and friends, education, and personality were important characteristics that influenced treatment responses. Intervention group participants in the upper 30% of ITR scores demonstrated potential delays of 3 months in semantic fluency (CFA) and 6 months in global cognition (MoCA), assuming a 5-fold faster natural cognitive decline compared to the control group during the post-treatment period. CONCLUSIONS: ITR-based analyses are valuable in profiling treatment responders for features that can inform future trial design and clinical practice. Reliably measuring time saved in cognitive decline is an area of ongoing research to gain insight into the clinical meaningfulness of treatment.

Effectiveness of Personalized Hippocampal Network-Targeted Stimulation in Alzheimer Disease: A Randomized Clinical Trial.

Importance: Repetitive transcranial magnetic stimulation (rTMS) has emerged as a safe and promising intervention for Alzheimer disease (AD). Objective: To investigate the effect of a 4-week personalized hippocampal network-targeted rTMS on cognitive and functional performance, as well as functional connectivity in AD. Design, Setting, and Participants: This randomized clinical trial, which was sham-controlled and masked to participants and evaluators, was conducted between May 2020 and April 2022 at a single Korean memory clinic. Eligible participants were between ages 55 and 90 years and had confirmed early AD with evidence of an amyloid biomarker. Participants who met the inclusion criteria were randomly assigned to receive hippocampal network-targeted rTMS or sham stimulation. Participants received 4-week rTMS treatment, with assessment conducted at weeks 4 and 8. Data were analyzed between April 2022 and January 2024. Interventions: Each patient received 20 sessions of personalized rTMS targeting the left parietal area, functionally connected to the hippocampus, based on fMRI connectivity analysis over 4 weeks. The sham group underwent the same procedure, excluding actual magnetic stimulation. A personalized 3-dimensional printed frame to fix the TMS coil to the optimal target site was produced. Main Outcomes and Measures: The primary outcome was the change in the AD Assessment Scale-Cognitive Subscale test (ADAS-Cog) after 8 weeks from baseline. Secondary outcomes included changes in the Clinical Dementia Rating-Sum of Boxes (CDR-SOB) and Seoul-Instrumental Activity Daily Living (S-IADL) scales, as well as resting-state fMRI connectivity between the hippocampus and cortical areas. Results: Among 30 participants (18 in the rTMS group; 12 in the sham group) who completed the 8-week trial, the mean (SD) age was 69.8 (9.1) years; 18 (60%) were female. As the primary outcome, the change in ADAS-Cog at the eighth week was significantly different between the rTMS and sham groups (coefficient [SE], -5.2 [1.6]; P = .002). The change in CDR-SOB (-4.5 [1.4]; P = .007) and S-IADL (1.7 [0.7]; P = .004) were significantly different between the groups favoring rTMS groups. The fMRI connectivity analysis revealed that rTMS increased the functional connectivity between the hippocampus and precuneus, with its changes associated with improvements in ADAS-Cog (r = -0.57; P = .005). Conclusions and Relevance: This randomized clinical trial demonstrated the positive effects of rTMS on cognitive and functional performance, and the plastic changes in the hippocampal-cortical network. Our results support the consideration of rTMS as a potential treatment for AD. Trial Registration: ClinicalTrials.gov Identifier: NCT04260724.

Human dental pulp stem cells mitigate the neuropathology and cognitive decline via AKT-GSK3ß-Nrf2 pathways in Alzheimer's disease.

Oxidative stress is increasingly recognized as a major contributor to the pathophysiology of Alzheimer's disease (AD), particularly in the early stages of the disease. The multiplicity advantages of stem cell transplantation make it fascinating therapeutic strategy for many neurodegenerative diseases. We herein demonstrated that human dental pulp stem cells (hDPSCs) mediated oxidative stress improvement and neuroreparative effects in in vitro AD models, playing critical roles in regulating the polarization of hyperreactive microglia cells and the recovery of damaged neurons. Importantly, these therapeutic effects were reflected in 10-month-old 3xTg-AD mice after a single transplantation of hDPSCs, with the treated mice showing significant improvement in cognitive function and neuropathological features. Mechanistically, antioxidant and neuroprotective effects, as well as cognitive enhancements elicited by hDPSCs, were at least partially mediated by Nrf2 nuclear accumulation and downstream antioxidant enzymes expression through the activation of the AKT-GSK3ß-Nrf2 signaling pathway. In conclusion, our findings corroborated the neuroprotective capacity of hDPSCs to reshape the neuropathological microenvironment in both in vitro and in vivo AD models, which may be a tremendous potential therapeutic candidate for Alzheimer's disease.

Effects of Exercise Training on Immune-Related Genes and Pathways in the Cortex of Animal Models of Alzheimer's Disease: A Systematic Review.

Background: Alzheimer's disease (AD) is a chronic neurodegenerative disease that affects the immune system due to the accumulation of amyloid-ß (Aß) and tau associated molecular pathology and other pathogenic processes. To address AD pathogenesis, various approaches had been conducted from drug development to lifestyle modification to reduce the prevalence of AD. Exercise is considered a prominent lifestyle modification to combat AD. Objective: This observation prompted us to review the literature on exercise related to immune genes in the cortex of animal models of AD. We focused on animal model studies due to their prevalence in this domain. Methods: The systematic review was conducted according to PRISMA standards using Web of Science (WoS) and PubMed databases. Any kind of genes, proteins, and molecular molecules were included in this systematic review. The list of these immune-related molecules was analyzed in the STRING database for functional enrichment analysis. Results: We found that 17 research studies discussed immune-related molecules and 30 immune proteins. These studies showed that exercise had the ability to ameliorate dysfunction in AD-related pathways, which led to decreasing the expression of microglia-related pathways and Th17-related immune pathways. As a result of decreasing the expression of immune-related pathways, the expression of apoptosis-related pathways was also decreasing, and neuronal survival was increased by exercise activity. Conclusions: Based on functional enrichment analysis, exercise not only could reduce apoptotic factors and immune components but also could increase cell survival and Aß clearance in cortex samples. PROSPERO ID: CRD42022326093.

Do microbes play a role in Alzheimer's disease?

Alzheimer's disease is a complex and progressive condition that affects essential neurological functions such as memory and reasoning. In the brain, neuronal loss, synaptic dysfunction, proteinopathy, neurofibrillary tangles, and neuroinflammation are the hallmarks of Alzheimer's disease pathophysiology. In addition, recent evidence has highlighted that microbes, whether commensal or pathogenic, also have the ability to interact with their host and to regulate its immune system, therefore participating in the exchanges that lead to peripheral inflammation and neuropathology. Because of this intimate relationship, bacteria, viruses, fungi, and protozoa have been implicated in the development of Alzheimer's disease. Here, we bring together current and most recent evidence of the role of microbes in Alzheimer's disease, raising burning questions that need to be addressed to guide therapeutic approaches and potential prophylactic strategies.

Biomarkers for Managing Neurodegenerative Diseases.

Neurological disorders are the leading cause of cognitive and physical disability worldwide, affecting 15% of the global population. Due to the demographics of aging, the prevalence of neurological disorders, including neurodegenerative diseases, will double over the next two decades. Unfortunately, while available therapies provide symptomatic relief for cognitive and motor impairment, there is an urgent unmet need to develop disease-modifying therapies that slow the rate of pathological progression. In that context, biomarkers could identify at-risk and prodromal patients, monitor disease progression, track responses to therapy, and parse the causality of molecular events to identify novel targets for further clinical investigation. Thus, identifying biomarkers that discriminate between diseases and reflect specific stages of pathology would catalyze the discovery and development of therapeutic targets. This review will describe the prevalence, known mechanisms, ongoing or recently concluded therapeutic clinical trials, and biomarkers of three of the most prevalent neurodegenerative diseases, including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD).

Mechanistic insights and emerging therapeutic stratagems for Alzheimer's disease.

Alzheimer's disease (AD), a multi-factorial neurodegenerative disorder has affected over 30 million individuals globally and these numbers are expected to increase in the coming decades. Current therapeutic interventions are largely ineffective as they focus on a single target. Development of an effective drug therapy requires a deep understanding of the various factors influencing the onset and progression of the disease. Aging and genetic factors exert a major influence on the development of AD. Other factors like post-viral infections, iron overload, gut dysbiosis, and vascular dysfunction also exacerbate the onset and progression of AD. Further, post-translational modifications in tau, DRP1, CREB, and p65 proteins increase the disease severity through triggering mitochondrial dysfunction, synaptic loss, and differential interaction of amyloid beta with different receptors leading to impaired intracellular signalling. With advancements in neuroscience tools, new inter-relations that aggravate AD are being discovered including pre-existing diseases and exposure to other pathogens. Simultaneously, new therapeutic strategies involving modulation of gene expression through targeted delivery or modulation with light, harnessing the immune response to promote clearance of amyloid deposits, introduction of stem cells and extracellular vesicles to replace the destroyed neurons, exploring new therapeutic molecules from plant, marine and biological sources delivered in the free state or through nanoparticles and use of non-pharmacological interventions like music, transcranial stimulation and yoga. Polypharmacology approaches involving combination of therapeutic agents are also under active investigation for superior therapeutic outcomes. This review elaborates on various disease-causing factors, their underlying mechanisms, the inter-play between different disease-causing players, and emerging therapeutic options including those under clinical trials, for treatment of AD. The challenges involved in AD therapy and the way forward have also been discussed.

Impact of mechanical ventilation on clinical outcomes in ICU-admitted Alzheimer's disease patients: a retrospective cohort study.

Background: Alzheimer's disease (AD) is increasingly recognized as a pressing global public health issue, demanding urgent development of scientific AD management strategies. In recent years, the proportion of AD patients in Intensive Care Units (ICU) has been on the rise. Simultaneously, the use of mechanical ventilation (MV) is becoming more prevalent among this specific patient group. Considering the pathophysiological characteristics of AD, the application of MV in AD patients may lead to different outcomes. However, due to insufficient research data, the significant impact of MV on the prognosis of AD patients in the ICU remains unclear. Therefore, we conducted this study to comprehensively evaluate the potential influence of MV on the survival rate of AD patients in the ICU. Methods: We obtained data from the MIMIC-IV database for patients diagnosed with AD. Using propensity score matching (PSM), we paired patients who received MV treatment with those who did not receive treatment. Next, we conducted Cox regression analysis to evaluate the association between MV and in-hospital mortality, 7-day mortality, 28-day mortality, 90-day mortality, 4-year mortality, length of hospital stay, and ICU stay. Results: The data analysis involved a cohort of 641 AD patients spanning from 2008 to 2019, inclusive. Following a 1:2 propensity score matching (PSM) procedure, 300 patients were successfully paired, comprising 123 individuals who underwent MV treatment and 177 who did not. MV demonstrated an association with an elevated risk of in-hospital mortality (HR 5.782; 95% CI 2.981-11.216; p < 0.001), 7-day mortality (HR 6.353; 95% CI 3.014-13.392; p < 0.001), 28-day mortality (HR 3.210; 95% CI 1.977-5.210; p < 0.001), 90-day mortality (HR 2.334; 95% CI 1.537-3.544; p < 0.001), and 4-year mortality (HR 1.861; 95% CI 1.370-2.527; p < 0.001). Furthermore, it was associated with a prolonged length of ICU stay [3.6(2.2,5.8) vs. 2.2(1.6,3.7); p = 0.001]. In the subgroup analysis, we further confirmed the robustness of the results obtained from the overall population. Additionally, we observed a significant interaction (p-interaction <0.05) between age, admission type, aspirin use, statin use, and the use of MV. Conclusion: In patients with AD who are receiving treatment in the ICU, the use of MV has been linked to higher short-term, medium-term, and long-term mortality rates, as well as prolong ICU stays. Therefore, it is crucial to break away from conventional thinking and meticulously consider both the medical condition and personal preferences of these vulnerable patients. Personalized treatment decisions, comprehensive communication between healthcare providers and patients, formulation of comprehensive treatment plans, and a focus on collaboration between the ICU and community organizations become imperative.

Physical activity improves the visual-spatial working memory of individuals with mild cognitive impairment or Alzheimer's disease: a systematic review and network meta-analysis.

Objective: Our network meta-analysis aimed to ascertain the effect of physical activity on the visual-spatial working memory of individuals with mild cognitive impairment and Alzheimer's disease as well as to propose tailored exercise interventions for each group. Methods: Employing a frequentist approach, we performed a network meta-analysis to compare the effectiveness of different exercise interventions in improving the visual-spatial working memory of individuals with mild cognitive impairment and Alzheimer's disease. Subsequently, we explored the moderating variables influencing the effectiveness of the exercise interventions through a subgroup analysis. Results: We included 34 articles involving 3,074 participants in the meta-analysis, comprised of 1,537 participants from studies on mild cognitive impairment and 1,537 participants from studies on Alzheimer's disease. The articles included exhibited an average quality score of 6.6 (score studies) and 6.75 (reaction time [RT] studies), all passing the inconsistency test (p > 0.05). In the mild cognitive impairment literature, mind-body exercise emerged as the most effective exercise intervention (SMD = 0.61, 95% CI: 0.07-1.14). In Alzheimer's disease research, aerobic exercise was identified as the optimal exercise intervention (SMD = 0.39, 95% CI: 0.06-0.71). Conclusion: The results of the subgroup analysis suggest that the most effective approach to enhancing the visual-spatial working memory of individuals with mild cognitive impairment entails exercising at a frequency of three or more times per week for over 60 min each time and at a moderate intensity for more than 3 months. Suitable exercise options include mind-body exercise, multicomponent exercise, resistance exercise, and aerobic exercise. For individuals with Alzheimer's disease, we recommend moderately intense exercise twice per week for over 90 min per session and for a duration of 3 months or longer, with exercise options encompassing aerobic exercise and resistance exercise.

Effect of transcranial direct current stimulation and transcranial magnetic stimulation on the cognitive function of individuals with Alzheimer's disease: a systematic review with meta-analysis and meta-regression.

OBJECTIVE: To analyze the effects of transcranial direct current stimulation (tDCS) and transcranial magnetic stimulation (TMS) on the cognitive function of individuals with Alzheimer's disease (AD). METHODS: This systematic review with meta-analysis and meta-regression included randomized clinical trials published until 05/2022. We included studies conducted with individuals with AD of both sexes, aged between 55 and 85 years, treated with tDCS, TMS, or both. RESULTS: Twenty-one studies were included in the systematic review and sixteen in the meta-analysis. Meta-regression suggested a significant influence of anodic tDCS with current intensity of 1.5 mA on cognitive function. Significant results were found with treatment frequencies of three and five days a week for two weeks. Subgroup analysis found that anodic tDCS influences cognitive function, regardless of AD stage. Similar was observed for TMS using a frequency of 20 Hz and current intensity of 90% of the resting motor threshold. DISCUSSION: Anodal tDCS and 20 Hz TMS have demonstrated the ability to improve cognitive function in AD by modulating neural activity. These therapies are safe and well-tolerated, offering promise as adjuncts to available pharmacological treatments. Studies with greater methodological rigor and parameter standardization are warranted. Comprehensive investigations involving neuroimaging techniques may provide a better understanding of the interaction between induced electrical fields and the complex neural networks affected in AD, paving the way for more personalized and effective neurostimulation approaches.

Deciphering the intricate linkage between the gut microbiota and Alzheimer's disease: Elucidating mechanistic pathways promising therapeutic strategies.

BACKGROUND: The gut microbiome is composed of various microorganisms such as bacteria, fungi, and protozoa, and constitutes an important part of the human gut. Its composition is closely related to human health and disease. Alzheimer's disease (AD) is a neurodegenerative disease whose underlying mechanism has not been fully elucidated. Recent research has shown that there are significant differences in the gut microbiota between AD patients and healthy individuals. Changes in the composition of gut microbiota may lead to the development of harmful factors associated with AD. In addition, the gut microbiota may play a role in the development and progression of AD through the gut-brain axis. However, the exact nature of this relationship has not been fully understood. AIMS: This review will elucidate the types and functions of gut microbiota and their relationship with AD and explore in depth the potential mechanisms of gut microbiota in the occurrence of AD and the prospects for treatment strategies. METHODS: Reviewed literature from PubMed and Web of Science using key terminologies related to AD and the gut microbiome. RESULTS: Research indicates that the gut microbiota can directly or indirectly influence the occurrence and progression of AD through metabolites, endotoxins, and the vagus nerve. DISCUSSION: This review discusses the future challenges and research directions regarding the gut microbiota in AD. CONCLUSION: While many unresolved issues remain regarding the gut microbiota and AD, the feasibility and immense potential of treating AD by modulating the gut microbiota are evident.

In-situ growth of CeO2 on biofilms: Innovative nanoparticles for photothermal therapy & multi-pronged attack on Alzheimer's disease.

Alzheimer's disease (AD) is complex and multifactorial, and its pathogenesis involves multiple factors and processes. This study pioneered the in situ growth of cerium oxide nanoparticles on macrophage membranes (Ce-RAW). Further, carbon quantum dots (CQD) were biomimetically modified by Ce-RAW, leading to the synthesis of a multifunctional nanocomposite (CQD-Ce-RAW). Within the framework of this research, CQD-Ce-RAW was strategically combined with photothermal therapy (PTT), aiming to achieve a more significant therapeutic effect. The macrophage membrane confers the system with anti-phagocytic and anti-inflammatory biological functions. More importantly, the ultra-small size of cerium oxide grown on the membrane acts as a reactive oxygen species (ROS) scavenger and alleviates the degree of oxidative stress. Meanwhile, CQD as a photosensitizer helps dissociate amyloid-ß (Aß) aggregates and chelates excess copper ions, thus further inhibiting Aß aggregation. Cell experiments showed that CQD-Ce-RAW combined with PTT could effectively degrade and inhibit the aggregation of Aß, remove ROS, and improve cell survival rate. The results of in vivo photothermal experiments demonstrated that near-infrared light enhanced the efficiency of drug penetration through the blood-brain barrier and facilitated its accumulation in brain tissue. This comprehensive therapeutic approach can intervene in the disease progression from multiple pathways, providing a new prospect for treating AD.