Current Alzheimer research最新文献

Introduction: Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by the accumulation of amyloid-beta (Aβ) peptides, especially the toxic Aβ42 isoform, which induces excessive reactive oxygen species (ROS) production leading to oxidative damage, lipid peroxidation, and neuronal loss. Given the critical role of oxidative stress in AD pathogenesis, antioxidants such as ascorbic acid (AA) are being explored for their therapeutic potential.

Objective: This study aimed to investigate the neuroprotective efficacy of ascorbic acid in a transgenic Drosophila melanogaster model expressing human Aβ42 in neuronal tissues.

Methods: Transgenic and wild-type flies were maintained on diets supplemented with optimized, non-toxic concentrations of AA. Biochemical assays were performed to evaluate oxidative stress and antioxidant defense, including glutathione (GSH) levels, glutathione S-transferase (GST), superoxide dismutase (SOD), catalase (CAT), thiobarbituric acid-reactive substances (TBARS), and protein carbonyl content (PCC). Acetylcholinesterase (AChE) activity and locomotor performance were also assessed.

Results: Ascorbic acid supplementation significantly enhanced GSH levels, normalized GST, SOD, and CAT activities, and reduced TBARS and PCC levels, indicating restoration of redox balance. Partial recovery of AChE activity suggested protection of cholinergic neurotransmission. Functionally, AA-fed AD flies exhibited improved locomotor performance, delayed onset of memory impairment, and extended lifespan compared to untreated AD flies.

Conclusion: The findings demonstrate that ascorbic acid provides multifaceted neuroprotection by mitigating oxidative stress, stabilizing cholinergic function, improving behavioural outcomes, and enhancing longevity. AA emerges as a promising, low-cost natural antioxidant for potential use in Alzheimer's disease management.

Alzheimer's Disease (AD) is a neurodegenerative disorder accounting for 60-80% of dementia cases globally. Several risk factors are associated with increased AD onset, including genetics, physical activity, and varying levels of social interaction. Extensive research has explored potential treatments for AD, among which oxytocin (OX) has shown beneficial effects on memory-related neurological processes. OX has been suggested to modulate neuroplasticity within the hippocampus in rat and mouse AD models. Further studies indicate that intranasal administration of OX may lead to significant improvements in memory and cognition. In addition, a non-peptide agonistic analogue, LIT-001, has been investigated. This review aims to provide insight into the potential of OX as a therapeutic target for AD and to explore alternatives that activate similar cellular signaling pathways.

Introduction: Quality of life (QoL) in dementia care can be enhanced through nonpharmacological interventions. This systematic review and meta-analysis aimed to evaluate the effectiveness of such interventions across demographic groups in Saudi Arabia.

Methods: A systematic search identified 11 studies assessing sensory stimulation, mindful walking, functional independence, caregiver support, and public awareness interventions. Data were extracted on study design, population, and outcome measures. Three outcome studies were narratively synthesized.

Results: Sensory stimulation interventions (n = 62) showed the strongest behavioral improvements, with a large effect size (Hedges' g = -2.03). Data from other studies were insufficient for quantitative pooling, and no formal meta-regression or heterogeneity analyses were conducted.

Discussion: Findings suggest that behavioral and psychological interventions tailored to older adults yield the most significant QoL benefits. Caregiver support and awareness programs offer important supplementary benefits, although limited data restrict broader generalizations.

Conclusion: Non-pharmacological interventions, particularly those targeting behavioral and psychological outcomes, improve QoL in dementia care. However, further high-quality studies with comprehensive outcome reporting are needed to strengthen the evidence base and guide populationspecific strategies.

Alzheimer's disease is a neurodegenerative disorder characterized by impairments in cognitive functions such as thinking, behavior, and memory. The major pathological abnormalities associated with the disease include the formation of neurofibrillary tangles and amyloid plaques, which further cause neuroinflammation and nerve cell death. Currently, treatments for the disease focus on symptomatic management rather than addressing the root cause of neurological changes. Therefore, the current status of therapy highlights the need for more effective therapeutic substances that can either prevent abnormal deposition or slow neurodegeneration to preserve nerve cells. In this respect, ATP-sensitive potassium channel openers may have a potential role in prevention and protection. The present article focuses on several cellular mechanisms of this class, including the limitation of neuronal excitability, modulation of neurotransmitter release, prevention of aberrant protein buildup, reduction of excessive calcium influx, reduction of reactive oxygen species levels, and reduction of microglial activation.

Domestic abuse (DA) and Alzheimer's disease (AD) and related dementias) are two of humankind's most significant societal healthcare issues. DA is widespread, with one in three women and one in four men experiencing physical, psychological, emotional, sexual, and financial abuse in their lifetime. AD is the most common form of dementia and is expected to affect more than 152 million people worldwide by 2050. Given the incidence and prevalence of these two problems, any causal relationship between them carries profound societal consequences. Herein, we describe five types of overlapping relationships between DA and AD: 1. intimate partner violence (IPV) as a risk factor for AD; 2. AD as a risk factor for worsening ongoing DA; 3. abuse of caregivers by people with AD; 4. abuse of people with AD by caregivers; and 5. reactivation of previous DA behavior in a person with AD. Chronologically, these five types cover the spectrum from occurring decades before the onset of AD symptoms to emerging only after AD symptoms have manifested. Mechanistically, these five subtypes reflect the paradoxical fact that DA and AD may be causes or consequences of each other. Phenomenologically, they encompass the full spectrum of DA, including physical, psychological, emotional, sexual, and financial abuse. Given the challenges in recognizing, managing, and treating both DA and AD, society's need to recognize the DA/AD Problem and to identify and prevent the five subtypes of DA and AD overlap is an emerging healthcare priority.

Introduction: The locus coeruleus is the primary site of norepinephrine (NE) synthesis in the brain. Its dysfunction has been implicated in the pathogenesis of Alzheimer's disease. Vascular risk factors, thyroid dysfunction, and vitamin deficiencies have also been associated with an increased risk of dementia. This study aimed to evaluate the relationship between the catecholaminergic system-by measuring cerebrospinal fluid (CSF) levels of L-3,4-dihydroxyphenylalanine (L-DOPA), dopamine (DA), and NE-and vascular risk factors, thyroid dysfunction, and vitamin deficiencies.

Methods: We conducted a cross-sectional observational study in which CSF levels of L-DOPA, DA and NE were measured in 117 participants. Data on Blood Pressure (BP), heart rate, glycaemic and lipid profiles, smoking history, thyroid function and vitamin B12 and folic acid levels were collected for each participant.

Results: We found significant correlations between NE and CSF glucose levels (r = 0.308, p = 0.003) in participants without diabetes mellitus, between L-DOPA and orthostatic variation of diastolic BP (r = -0.288, p = 0.014) and high-density lipoprotein (r = 0.404, p = 0.001) and between NE and triglycerides (r = 0.271, p = 0.030) and folic acid (r = 0.298, p = 0.009).

Discussion: This is the first study to demonstrate correlations between CSF NE levels and CSF glucose, probably due to the effect of NE on astrocytes, and between CSF NE levels and folic acid, possibly related to its role in catecholamine synthesis. CSF L-DOPA levels were correlated with cardiovascular risk factors such as the orthostatic regulation of diastolic BP.

Conclusion: These findings may contribute to a better understanding of the pathophysiology of neurodegenerative diseases.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-beta (Aβ) plaque deposition, neurofibrillary tangles of hyperphosphorylated tau protein, and chronic neuroinflammation, leading to synaptic dysfunction and cognitive decline. Current diagnostic methods rely on clinical symptoms and limited biomarkers, while available treatments only provide symptomatic relief without halting disease progression. MicroRNAs (miRNAs), small non-coding RNAs of 19-22 nucleotides, have emerged as crucial regulators of gene expression through post-transcriptional mechanisms and show distinct dysregulation patterns in AD patients' blood, cerebrospinal fluid (CSF), and brain tissues. Key miRNAs such as miR-132, miR-146a, miR-34a, and miR-125b demonstrate consistent alterations in expression levels, correlating with disease progression and offering potential as non-invasive diagnostic tools. This review comprehensively examines the dual role of miRNAs as diagnostic biomarkers and therapeutic targets for AD. We also provide an analysis of specific miRNA signatures in different biofluids (plasma, serum, CSF) and brain regions that correlate with disease stages, highlighting their potential for early and non-invasive diagnosis. Therapeutically, miRNAs modulate multiple AD-related pathways, including neuroinflammation via NF-κB signaling, Aβ production through BACE1 inhibition, and tau phosphorylation via GSK3β regulation. miRNAs also influence synaptic plasticity, mitochondrial function, and autophagy, presenting multifaceted opportunities for intervention. However, challenges, including miRNA heterogeneity, stability, and targeted delivery, remain critical impediments. Advances in nanocarriers, exosomal miRNAs, and viral vectors show promise in overcoming these obstacles, enabling precise miRNA modulation. In addition, we underscore the need for standardized protocols, further validation in clinical cohorts, and the development of cost-effective detection methods to translate miRNA-based approaches into practical diagnostics and therapies. By integrating miRNA biomarkers with existing diagnostic tools and exploring combinatorial therapeutic strategies, researchers can harness the potential of miRNAs to revolutionize AD intervention, paving the way for early detection and effective treatment of this devastating disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by abnormalities in protein metabolism leading to the accumulation of extracellular amyloid-beta (Aβ) plaques and intracellular neurofibrillary tangles (hyperphosphorylated tau protein). While these pathological constructs have held significant attention for decades, emerging evidence highlights the understanding of neuroinflammation (notably involving microglia, and cytokine signaling) as a critical initial event with respect to the inception and progression of AD. This review discusses the dynamic and dualistic effects of immune response in AD based on the relationship between neuroinflammatory processes and classical neuropathological characteristics. Microglia are ubiquitous immune cells in the central nervous system responsible for maintaining homeostasis as the brain's "housekeepers" by removing cellular debris, pruning synapses, and monitoring cell interactions. However, microglia in AD function produce a chronically activated phenotype that elicits neurotoxicity, impairs synaptic functioning, and is are protracted source of neuroinflammation. The appearance of disease-associated microglia (DAM) may illustrate complexities of TREM2 signaling for the anabolism of Aβ clearance and the modulation of inflammatory systems. Cytokine imbalance - higher expression of pro-inflammatory (e.g., IL-1β, TNF-α) and lower expression of antiinflammatory (e.g., IL-10, TGF-β) - adds to a self-perpetuating inflammatory loop that exacerbates Aβ and tau pathology, brain-blood barrier permeability, and peripheral-CNS immune communications. The mechanisms of an inflammatory event may drive brain tau hyperphosphorylation, tau propagation, along with other pathophysiological neurodegenerative features of traumatic brain injury and Alzheimer's disease. While examples of therapies targeting microglia and their cytokine activity are actively being explored, clinical efforts have been mixed. Neuroimaging development (e.g., TSPO-PET), cytokine collection and compositional approaches, and application of single-cell transcriptomics are providing new ways of thinking about complex neuroimmunology. Exploring, informing, and defining the timing, context, and variations of neuroinflammatory responses will be ultimately needed to create effective, targeted therapies for Alzheimer's disease (AD).

Background: Previous research explores the relationship between the cognitive status of people with dementia (PwD) and their performance in complex, domain-specific interaction tasks. However, these activities and their sophisticated instructions are challenging for PwD, potentially biasing performance metrics. This study aims to answer whether the cognitive status of PwD is related to their performance in simple touch and tangible tasks disassociated from a domain.

Methods: This study involved 7 formal caregivers and data from 21 PwD corresponding to completion times of interaction tasks. Relationships between completion times and the cognitive status of PwD were explored using Spearman's rank correlation, mutual information, gini importance, permutation importance, and a principal component analysis (PCA) visualization.

Results: Completion times of drag & drop, grasp, and tap interaction tasks have a strong negative monotonic association with the MMSE score (Bonferroni-corrected p-value < 0.05). The most relevant gestures were drag & drop, tap, and grasp. The PCA visualization allowed formal caregivers to detect relationships between patients' performance and their MMSE scores (p-value < 0.05).

Discussion: The cognitive status of PwD is related to their performance in simple interaction tasks disassociated from a domain. As the MMSE score decreases, task completion times increase. In addition, the PCA visualization was considered useful to inform decision-making.

Conclusion: This work provides the foundation for technology-enhanced cognitive activities supported by touch and tangible gestures that can be used to determine the cognitive status of PwD.

Introduction: Alzheimer's Disease (AD) is the commonest pathology underlying dementia, but it frequently coexists with cerebrovascular disease (CVD). Existing literature supports a possible role for vascular risk factors (VRFs), including hypertension, diabetes and dyslipidaemia in AD pathogenesis. This study aims to determine whether VRFs contribute to typical AD pathogenesis or co-morbid CVD in mixed AD.

Methods: Well-characterised probable AD subjects participating in two large clinical trials of Hydromethylthionine were classified into "typical AD" and "mixed" patterns based on FDG-PET images. VRFs, including hypertension, diabetes and dyslipidaemia, and MRI-derived White Matter Hyperintensities (WMHs) and brain fraction (as a measure of brain atrophy) were analysed to investigate the relationship between VRFs and AD subtypes.

Results: Of 794 participants, 533 (67.1%) were classified as typical AD and 261 (32.8%) were classified as mixed. Among VRFs, cardiovascular risks were significantly more frequent in typical AD (59%) than in mixed subtype (47%) (p = 0.002).

Discussion: We found that it was mainly hypertension that differed according to subtypes. Although brain atrophy is the main driver of cognitive impairment in patients with AD subtype, the microvascular pathology in the form of WMHs was significantly higher in patients with hypertension, irrespective of subtype.

Conclusion: Although hypertension is the main risk factor for cerebrovascular disease, contrary to our expectation, hypertension is common in typical AD than the mixed subtype, and this association is driven by the hitherto unsuspected contribution of microvascular pathology to cognitive impairment in typical AD.