Search Results (1,704)

Background/Objectives: Anti-amyloid immunotherapies reduce amyloid-β (Aβ) plaques but carry a 15–35% risk of amyloid-related imaging abnormalities (ARIA), particularly in APOE ε4/ε4 carriers. This preliminary observational study evaluated blood Aβ oligomer changes following treatment with the multi-component herbal formula Chongnoi-tang (CNT) and contextualized these findings against natural disease trajectories in National Alzheimer’s Coordinating Center (NACC) and Alzheimer’s Disease Neuroimaging Initiative (ADNI) reference cohorts. Methods: This retrospective pilot cohort included 16 patients with Alzheimer’s spectrum conditions treated with CNT. Blood Aβ oligomers were measured using the AlzOn Plus immunoassay. Primary analysis (n = 13) excluded cases with a ceiling-level baseline value, an intercurrent potentially confounding condition, or no true baseline measurement. Results: Mean blood Aβ oligomer levels decreased by 15.8% ± 13.4% at 6 months (median −20.6%; 95% CI −23.9% to −7.8%; Wilcoxon signed-rank test, p < 0.001; paired Cohen’s dz = 1.07). At each participant’s final available follow-up, all 13 primary-analysis patients had values below baseline. High-risk patients (n = 4) showed a mean 25.7% reduction. Baseline Aβ level and 6-month percent biomarker change exhibited an exploratory, non-significant inverse trend in the Pearson correlation (r = −0.489, p = 0.090) that was weaker and non-significant in the Spearman sensitivity analysis (ρ = −0.300, p = 0.320), consistent with regression to the mean and mathematical coupling as plausible contributors. Importantly, all four APOE ε4/ε4 homozygotes showed Aβ reductions without ARIA-like clinical events. Mini-Mental State Examination (MMSE) worsening occurred in 37.5% (3/8) of CNT-treated patients versus 42.9% (15/35) in propensity-matched NACC controls (p = 0.89); given the small sample, this comparison is inconclusive. Conclusions: In this small, uncontrolled pilot study, CNT was associated with blood Aβ reductions, which should be interpreted as a statistical association rather than confirmed evidence of a treatment effect; no treatment discontinuations due to adverse effects were documented in this small cohort, including among APOE ε4/ε4 carriers. These hypothesis-generating findings warrant further confirmation in prospective randomized controlled trials. Full article

Cell-based gene therapy is a promising strategy to promote regeneration in Alzheimer’s disease (AD). Neurotrophin-3 (NT-3) plays a key role in neuroprotection and brain regeneration, providing a strong rationale for its exogenous delivery. Olfactory ensheathing cells (OECs) have high regenerative potential and serve as a vehicle for local gene delivery. We investigated the therapeutic potential of NT-3-expressing OECs in an Aβ1–42-induced AD model in female Wistar rats. Rat OECs were transduced with an Ad5RGD-CAG-NT-3 adenoviral vector, and NT-3 levels were measured in vitro using ELISA. To evaluate the efficacy of NT-3-transduced and non-transduced OECs, we performed behavioral assessments and measured the concentration of NT-3, Aβ1–42, and pTau levels in brain specimens 4 weeks post-transplantation. Transduced OECs exhibited markedly increased NT-3 secretion in vitro compared with non-transduced cells. All OEC-treated groups showed improved cognitive performance following transplantation. However, only NT-3-transduced OECs significantly increased brain NT-3 and reduced Aβ1–42 levels, indicating an enhanced therapeutic effect mediated by NT-3 overexpression. None of the cell grafts affected pTau levels. These findings demonstrate that OEC transplantation improves functional outcomes in experimental AD, while NT-3 overexpression provides biochemical benefits by reducing amyloid accumulation. Taken together, our findings support further investigation of NT-3-expressing OECs as a cell-based gene therapy for AD. Full article

Pecan (Carya illinoinensis) is an edible nut rich in phytochemicals with potential health-promoting properties; however, the bioactive constituents responsible for its neuroprotective effects remain insufficiently characterized. This study aimed to identify bioactive constituents from pecan through bioactivity-guided fractionation and to evaluate the protective effects of pecan extract and the identified compound against oxidative stress and amyloid beta (Aβ)_1–42-induced cognitive impairment. Pecan ethanolic extract exhibited antioxidant and cytoprotective activities in PC12 cells exposed to hydrogen peroxide-induced oxidative stress. Sequential liquid–liquid fractionation, silica gel open-column chromatography, and preparative thin-layer chromatography, coupled with repeated bioactivity screening, progressively tracked the active fractions and led to the identification of ethyl gallate as a bioactive constituent of pecan extract by high-performance liquid chromatography and gas chromatography–mass spectrometry. The biological relevance of these findings was further evaluated in Aβ_1–42-injected male mice. Dietary administration of pecan extract significantly improved spontaneous alternation performance in the Y-maze test, whereas ethyl gallate improved Y-maze performance and memory retention in the passive avoidance test, without apparent systemic toxicity under the experimental conditions. Although brain malondialdehyde levels showed a numerical decrease following ethyl gallate administration, the differences were not statistically significant. Collectively, these findings demonstrate the bioactivity-guided linkage of ethyl gallate to an active pecan fraction and provide preclinical evidence supporting further investigation of pecan-derived bioactives as food-derived functional ingredients relevant to cognitive health. Full article

Familial Alzheimer’s disease (FAD) is an accelerated form of dementia affecting cholinergic neurons. Despite several efforts, no single drug or treatment has demonstrated complete efficacy. Therefore, finding effective therapeutic agents is imperative. Previous studies have shown that the PSEN1 I416T variant induces FAD-like neuropathology in cholinergic-like neurons (ChLNs), characterized by the intracellular accumulation of the Aβ (iAβ) peptide, the oxidation of the stress sensor protein DJ-1, the abnormal phosphorylation of the tau protein at serine 202/threonine 205 (pS202/T205), the loss of mitochondrial membrane potential (ΔΨ_m), and activation of the pro-apoptotic proteins tumor protein 53 (TP53), Jun proto-oncogene, AP-1 transcription factor subunit (c-JUN), p53 upregulated modulator of apoptosis (PUMA), and cleaved caspase-3 (CC3). We report for the first time that PSEN1 I416T induces abnormal phosphorylation of Leucine-rich repeat kinase 2 (LRRK2) kinase at residue serine 935 (S935), concomitant with phosphorylated alpha-synuclein (αSYN) at residue serine 129 (S129) and abnormal accumulation of autophagosomes and atypical increase in vesicular lysosomal pH, thereby provoking a profound alteration in autophagy in ChLNs. Here, we also demonstrate for the first time that the potent LRRK2 inhibitor PF-06447475 (hereafter referred to as PF475) almost completely attenuated PSEN1 I416T-induced proteinopathy, oxidative stress (OS), and apoptosis and improve autophagy to an activity comparable to untreated wild-type (WT) ChLNs. Overall, PF475 restored the survival of mutant ChLNs. Taken together, these findings suggest that PF475 is an excellent pharmacological tool with which to investigate the regulation of LRRK2-associated pathological signaling in the PSEN1 I416T familial Alzheimer’s disease (FAD) model. Full article

Alzheimer’s disease (AD) is a complex neurodegenerative disorder with multifaceted pathogenesis. Given the clinical need for multi-target interventions, this study elucidated the neuroprotective mechanisms of walnut (Juglans regia L.) against AD-related cognitive impairment. Methods: We characterized 25 bioactive constituents (fatty acids and ellagitannins) and constructed a protein–protein interaction (PPI) network. GO/KEGG enrichment, integrated with Ingenuity Pathway Analysis (IPA), deciphered pharmacological pathways, followed by molecular docking to evaluate ligand–target binding thermodynamics. Network analysis revealed that walnut phytochemicals synergistically modulate the MAPK-mTORC1-TFEB-mediated endolysosomal homeostasis pathway. Molecular docking indicated that ellagitannins (strictinin, pedunculagin, tellimagrandin I) exhibit robust affinities for upstream RAS/RAF/MEK kinases, suppressing pro-pathogenic signaling. Concurrently, gallic acid targeted ABCA1 and TFEB, promoting TFEB activation and nuclear translocation to enhance beta-amyloid clearance and lysosomal biogenesis. This study provides evidence that walnut attenuates AD pathology through “multi-component” reinforcement of the endolysosomal defense system, establishing a mechanistic foundation for walnut as a promising functional food. Full article

Heavy metals and metalloids are persistent environmental contaminants that accumulate in the central nervous system and interact with endogenous essential metals, yet most neurotoxicological research continues to treat metals as independent agents rather than as co-occurring mixtures. This review systematically compares the evidence for cumulative and interactive effects of heavy metal mixtures across four major neurodegenerative diseases—Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS)—asking which metal combinations have been directly documented for each disease, and whether these patterns are disease-specific or shared. Following a PubMed search (January 2016–June 2026), 93 unique studies were included (AD: 49; PD: 38; ALS: 19; MS: 18; 31 shared across diseases). Combined exposure to lead, cadmium, arsenic, and mercury is linked to amyloid-beta accumulation and dementia risk in AD; manganese–vanadium co-exposure produces more severe dopaminergic damage in PD than either metal alone, with manganese activating the familial PD gene LRRK2; a multi-metal mixture in ALS was associated with a three-fold higher disease risk independent of genetic susceptibility; and MS showed almost no designed mixture studies despite considerable single-metal data, with conflicting findings across cohorts. Three general mechanisms were identified: competition at shared membrane transporters (notably DMT1), sequestration by metal-binding proteins, and direct synergistic or antagonistic interactions, in which essential elements can modulate toxic-metal handling. Mixture-statistics approaches (WQS, BKMR), already established for AD and PD, should be extended to MS to close this evidence gap. Full article

The escalating global burden of neurodegenerative and neuropsychiatric disorders is deeply intertwined with cumulative environmental toxicant exposure. To accurately capture the prodromal and subclinical impacts of this multi-chemical “pollutome”, research is shifting from symptom-based assessments toward the use of objective, quantifiable biological indicators. Guided by the PRISMA-ScR framework, this scoping review systematically analyzed literature across PubMed, Scopus, Web of Science, and Embase databases without temporal restrictions. The final selection included 52 human observational studies that evaluated the relationship between environmental stressors and objective neurobiological markers across diverse geographical populations and life stages. The synthesized evidence reveals that varied environmental insults—including ambient air pollution (e.g., fine particulate matter, PM_2.5), heavy metals, agrochemicals, and persistent organic contaminants—frequently correlate with measurable alterations in fluid biomarkers. These exposures are primarily associated with variations in markers of axonal damage (neurofilament light chain), astrocytic reactivity (glial fibrillary acidic protein), potential microglial dysfunction (soluble triggering receptor expressed on myeloid cells 2), and cytostructural alterations (Tau proteins and amyloid-beta). The literature highlights distinct windows of vulnerability, spanning from early-life epigenetic modifications (DNA methylation) to adult neurovascular injury. Mechanistically, despite their chemical heterogeneity, the available evidence suggests that these pollutants may converge on shared pathophysiological pathways defined by blood–brain barrier disruption and chronic, self-perpetuating neuroinflammation. Understanding environmental neurotoxicity may benefit from moving beyond traditional single-pollutant approaches toward a broader exposome framework. Future epidemiological research should integrate high-dimensional human biomonitoring with artificial intelligence and machine learning architectures. This computational integration would be essential to decode non-linear multi-pollutant interactions and accelerate the deployment of targeted, early-stage public health interventions. Full article

Alzheimer’s disease (AD) is associated with both mild and moderate to severe traumatic brain injury (TBI). This narrative review gives an account of the association of TBI and AD and highlights possible cellular and molecular pathways linking these pathologies. Following TBI, the immune system of the brain is rapidly activated and gives rise to acute neuroinflammation. While neuroinflammation is protective in nature, it may persist chronically in the case of less-controlled prolonged responses, triggering neuroprotective loss and neurotoxicity. Moreover, reduced clearance of amyloid-beta may occur, along with its overproduction and aggregation. Tau protein regulation is also altered by kinase and phosphatase enzymes, resulting in the accumulation of hyperphosphorylated tau protein in neurons and glial cells and the emergence of intracellular tau neurofibrillary tangles. More to the point, vascular impairment following TBI has been reported to contribute to cognitive decline and AD. Blood–brain barrier breakdown following TBI allows for infiltration of peripheral immune cells and blood-derived proteins into the brain, which exacerbates neuroinflammation, interrupts synaptic signaling, and promotes oxidative stress. The neuroinflammatory response, dynamic alterations in amyloid and tau biology, and vascular impairment are thought to interact within a broader network of processes associated with AD neurodegeneration, rather than acting as isolated mechanisms. Full article

Background/Objectives: Alzheimer disease (AD) causes progressive cognitive and functional loss and substantial caregiver and healthcare burden. Anti-amyloid monoclonal antibodies represent a shift toward biology-directed treatment in biomarker-confirmed early symptomatic AD, but modest clinical effects must be balanced against amyloid-related imaging abnormalities (ARIA), intensive monitoring, and implementation burden. Heterogeneity in trial populations, endpoints, dosing, stopping rules, and follow-up complicates interpretation. This narrative review critically integrates efficacy, safety, durability, biomarker, and implementation evidence for lecanemab and donanemab while preserving study-family relationships and avoiding unsupported cross-trial superiority claims. Methods: For this revised narrative review, a targeted PubMed/MEDLINE search covering the period from database inception was initially conducted before manuscript submission and was subsequently updated through 21 August 2026, supplemented by reference-list and citation tracking. Search terms combined Alzheimer disease with lecanemab, donanemab, anti-amyloid monoclonal antibody, ARIA, APOE, amyloid PET, open-label extension, real-world, clinical meaningfulness, implementation, and access. Sixty-two sources were purposively selected for a comprehensive narrative synthesis; no meta-analysis or formal certainty grading was performed. Results: Pivotal trials demonstrated statistically significant but modest average slowing of decline: Clarity AD showed a 0.45-point between-group difference in CDR-SB worsening at 18 months, and TRAILBLAZER-ALZ 2 showed a 3.25-point iADRS difference in the low/medium-tau population at 76 weeks. ARIA-E occurred in 12.6% of lecanemab-treated and 24.0% of donanemab-treated participants in the pivotal trials, with higher risk in APOE ε4 carriers. Extensions and biomarker analyses suggest persistent biological effects but are less secure for causal inference, and real-world evidence is currently more mature for lecanemab. Conclusions: Both antibodies substantially reduce amyloid and modestly slow average clinical decline in selected patients, but neither restores lost function, greater amyloid clearance does not establish greater individual benefit, and cross-trial superiority cannot be inferred. Treatment requires biomarker-guided selection, APOE-informed risk counseling, serial MRI, infusion and ARIA-management capacity, and shared decision-making that incorporates cost, access, and patient/caregiver burden. Full article

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-beta (Aβ) deposition and cognitive decline. Clinical evidence indicates that Hericium erinaceus whole fruiting body powder offers limited therapeutic efficacy, which is suggested to be constrained by whole-food matrix interference and uncertainties in central nervous system (CNS) exposure. Therefore, we hypothesized that erinacine C (EC)—a purified active component from Hericium erinaceus mycelia—could resolve these limitations and potentially exhibit favorable neuroprotective effects owing to its low molecular weight and lipophilicity. In this study, we investigated the neuroprotective potential and associated signaling alterations of EC using APP/PS1 transgenic mice and Aβ_25-35-induced PC12 cells. In vivo, oral administration of EC alleviated deficits in activities of daily living, as evidenced by improvements in nesting and burrowing behaviors, along with enhanced short-term spatial memory in the Y-maze test. EC treatment was associated with a reduction in hippocampal Aβ plaque accumulation, suppression of glial activation (GFAP and IBA1), and decreased IL-6 levels in both serum and hippocampal tissues. In vitro, EC intervention counteracted Aβ_25-35-induced cytotoxicity in PC12 cells. Analysis of signaling markers revealed that EC treatment was accompanied by a restoration of p-Akt/Akt levels and a suppression of p-GSK3β (Tyr216) activation. Consequently, EC treatment was correlated with reduced tau hyperphosphorylation, the up-regulation of the anti-apoptotic protein Bcl-2, and the down-regulation of pro-apoptotic markers including Bax and cleaved-caspase-3, thereby lowering the total apoptotic rate. Taken together, these findings suggest that EC may mitigate cognitive impairment and neurodegeneration in parallel with alterations in the Akt/GSK3β/tau/caspase-3 signaling response, thereby representing a potentially promising therapeutic candidate for the intervention of AD. Full article

Introduction: Vitamin D status has been investigated as a modifiable risk factor with cognitive decline. However, studies pertaining to this remain inconsistent across populations, and there are fewer studies associating vitamin D status, cognitive decline, amyloid markers and oxidative stress markers in older adults. Therefore, this study was conducted to analyze the association between these parameters. Methodology: This cross-sectional study included 145 older adults aged between 51 and 80 years. Participants were categorized based on serum vitamin D levels into sufficient (n = 53), insufficient (n = 61), and deficient (n = 31) groups. Cognitive performance was assessed using the Modified Mini Mental State (3MS) test. Plasma levels of Aβ 1-40 and Aβ 1-42 and oxidative stress markers (TBARS, GPx, SOD) were measured. Statistical analysis was performed using ANOVA and Spearman’s correlation. Results: Results showed that the vitamin D concentrations did not differ significantly between cognitively impaired and normal individuals within vitamin D strata (vitamin D sufficient, insufficient and deficient groups). Plasma Aβ 1-40 levels were significantly elevated in cognitively impaired participants across all vitamin D groups. A reduced Aβ 1-42/Aβ 1-40 ratio was observed in sufficient and insufficient Vitamin D groups. Additionally, GPx levels were significantly higher in the vitamin D-deficient group. Correlation analysis showed that 3MS scores were negatively associated with age (r = −0.2607, p = 0.0015), Aβ 1-40 (r = −0.4016, p = 0.0001), and Aβ 1-42 (r = −0.3025, p = 0.0002), and positively correlated with Aβ 1-42/Aβ 1-40 ratio (r = 0.2176, p = 0.0086). Conclusions: These findings suggest that cognitive impairment in older adults is strongly associated with amyloid burden, oxidative stress, and age, whereas vitamin D status was not directly correlated with cognitive performance in this cohort. Full article

Alzheimer’s disease (AD) pathology is increasingly recognized to manifest in the retina, offering a non-invasive window for early biomarker discovery. This proof-of-concept study investigated whether multimodal retinal imaging—hyperspectral imaging (HSI), optical coherence tomography (OCT), and color fundus photography (CFP)—can differentiate individuals with and without cerebral amyloid-beta (Aβ) pathology in 40 participants with PET-confirmed Aβ status (17 Aβ+, cognitively normal or with mild cognitive impairment; 23 Aβ− cognitively normal controls). HSI-derived gray-level co-occurrence matrix (GLCM) texture, OCT-derived ganglion cell–inner plexiform layer (GC-IPL) thickness, and CFP-derived vascular biomarkers (VBMs) were extracted, and logistic regression with leave-one-out cross-validation assessed classification performance per modality, alone and combined; the cohort was supplemented with AD dementia patients for an exploratory cross-sectional comparison across disease-stage groups. HSI showed nominally lower GLCM correlation at 466 nm in Aβ+ participants, most pronounced in the inferior macula (AUC = 0.72). GC-IPL thickness showed a similar inferior-predominant regional pattern. Combining HSI and GC-IPL features yielded the best performance (AUC = 0.84; sensitivity = 0.82; specificity = 0.78), although this improvement over the unimodal models did not reach statistical significance, whereas vascular biomarkers contributed minimally. In an exploratory cross-sectional comparison across AD stage groups drawn from two cohorts, HSI features showed a non-monotonic pattern, decreasing in early Aβ+ stages and rising again in dementia. These findings provide preliminary evidence of complementary information between HSI and OCT for detecting retinal biomarkers of early-stage AD, supporting multimodal retinal imaging as a scalable screening approach warranting validation in larger, longitudinal cohorts. Full article

Misfolded proteins, including islet amyloid polypeptide (hIAPP), serum amyloid A (SAA), and amyloid-betas (Aβs) such as Aβ1-40 and Aβ1-42 oligomers, collectively referred to in our work as amyloid oligomers, have been implicated in the development of both metabolic and cardiovascular diseases. However, their potential role as early biomarkers of myocardial damage remains insufficiently explored. We conducted a systematic review following PRISMA guidelines and epistemic meta-analysis to investigate the association between misfolded protein oligomers and early myocardial injury. All English- and Spanish-language articles with titles, abstracts, or keywords relevant to the research topic and indexed in at least one of the following databases—PubMed, BIREME, or Web of Science—were included. A comprehensive search across major databases identified 30 eligible studies. Thirty studies met inclusion criteria, in humans and animals, and in vitro. Amyloid oligomers were consistently elevated in patients with acute myocardial infarction, type 2 diabetes, or coronary artery disease compared with controls. In specific individual cohorts, a higher SAA concentration correlated with major adverse cardiovascular events, where it acted as an independent predictor of mortality in reperfused AMI (RR 5.8; 95% CI: 1.3–27.7) and cardiac rupture (OR 8.8; 95% CI: 1.7–25.6). Our findings support the hypothesis that protein misfolding contributes to early myocardial injury and highlight its potential as a novel source of cardiometabolic biomarkers. Full article

Background: This study aims to develop an amyloid-beta-induced three-dimensional (3D) Alzheimer’s disease model using the Magnetic Levitation (MagLev) technique and rat pheochromocytoma (PC-12) (rat pheochromocytoma) cells. Methods: Initially, optimization studies were performed to determine the appropriate paramagnetic agent concentration and cell number required for the formation of 3D cellular structures. The formation of these structures was monitored by light microscopy, and cell viability was evaluated using a live/dead assay. Filamentous actin (F-actin) expression was assessed by immunostaining. Subsequently, amyloid beta 1–42 (Aβ1–42) aggregates were introduced into the 3D cellular structures to establish a 3D Alzheimer’s disease model. The 3D disease model was characterized by immunostaining of Choline Acetyltransferase (ChAT). Finally, the applicability of the developed model for therapeutic evaluation was demonstrated using curcumin as a representative neuroprotective compound. Results: The optimization studies successfully enabled the formation of 3D cellular structures using the magnetic levitation technique. Immunostaining analysis showed an increase in F-actin expression in 3D structures. Following the introduction of Aβ1–42 aggregates, a significant decline in cell viability was observed by day 21. ChAT immunostaining revealed a decrease in fluorescence intensity (F.I.) to 28% of the control level, corresponding to an approximately 72% reduction in ChAT expression. Curcumin treatment increased cell viability by 22%, 23%, and 13% on days 7, 15, and 21, respectively. Conclusion: Overall, the findings showed that the 3D Aβ 1–42 induced 3D Alzheimer’s disease model can provide a valuable experimental platform for investigating neurodegenerative diseases and evaluating potential therapeutic interventions. Full article

Background/Objectives: Alzheimer’s disease (AD) is a multifactorial neurodegenerative condition characterised by cognitive impairment, cholinergic deficiency and neuroinflammation. Carvacrol and thymol are two related natural monoterpenes with reported antioxidant, anti-inflammatory, anti-apoptotic and cholinesterase-inhibiting properties. This scoping review aims to map the current evidence regarding the effects of carvacrol and thymol on AD-related pathologies and identify their mechanisms of action. Methods: A systematic literature search was conducted in February 2026 across PubMed, Scopus and Web of Science. This review included original, English-language primary research articles investigating the effects of carvacrol and thymol on AD using in vitro, in vivo, or in silico models. Results: From an initial pool of 87 unique records, 30 primary studies met the inclusion criteria, encompassing direct AD pathology models (e.g., amyloid-beta), AD-associated risk models (e.g., metabolic or hypertensive impairment), and general cognitive impairment models. Both carvacrol and thymol reduced escape latency during spatial learning acquisition training and increased time spent in the target quadrant during probe trials, indicating improvements in both learning and memory retention, although several studies reported non-linear relationships. At the cellular level, carvacrol and thymol modulated distinct redox and inflammatory pathways, including nuclear factor erythroid 2-related factor 2 upregulation and tumour necrosis factor-alpha suppression. Synthetic derivatives and nanocarrier formulations (e.g., liposomes, nanoemulsions) demonstrated enhanced acetylcholinesterase inhibition and biological stability relative to parent monoterpenes. No clinical trials were identified, and formal critical appraisal was not performed. Conclusions: Preclinical evidence indicates that carvacrol and thymol show potential multi-targeted neuroprotective activity across diverse models of cognitive dysfunction. However, clinical translation remains unproven due to heterogeneous experimental designs, pharmacokinetic limitations, a lack of human trials, and unassessed study quality. Full article