Alzheimer's disease (AD) is a debilitating neurodegenerative condition characterized by progressive cognitive impairment, memory deterioration, and neuronal dysfunction. Its complex pathophysiology involves multiple interlinked processes, including amyloid-β (Aβ) aggregation, tau hyperphosphorylation, oxidative stress, neuroinflammation, synaptic dysfunction, and cholinergic deficits. Current FDA-approved therapies provide only symptomatic relief and fail to halt disease progression, highlighting the urgent need for more effective treatment strategies. This review provides a comprehensive overview of the pathological mechanisms underlying AD and the emerging therapeutic targets for the design of tractable anti-AD scaffolds, namely, acetylcholinesterase, beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), glycogen synthase kinase-3β (GSK3β), dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A), histone deacetylases (HDACs), and soluble epoxide hydrolase (sEH). Emphasis is placed on the paradigm shift from single-target therapies to multitarget-directed ligands (MTDLs), which are increasingly recognized as promising tools to tackle AD's multifactorial pathology. We also discuss recent advances in medicinal chemistry and structure-guided drug discovery campaigns aimed at developing pharmacologically optimized, BBB-penetrant MTDLs. By consolidating mechanistic insights with therapeutic innovation, this review aims to facilitate the development of next-generation therapeutics with enhanced efficacy and disease-modifying potential in AD.

Vascular cognitive impairment (VCI) affects 20% to 40% of cardiovascular patients, yet early identification remains challenging. This retrospective study evaluated the predictive value of carotid ultrasound parameters for VCI in 412 patients with cardiovascular risk factors who underwent carotid ultrasound and cognitive assessment between January 2019 and December 2023. Patients were categorized into normal cognition (n = 156), mild cognitive impairment (n = 184), and vascular dementia (n = 72) based on Montreal Cognitive Assessment scores. Carotid intima-media thickness (cIMT) progressively increased from normal cognition (0.89 ± 0.15 mm) to vascular dementia (1.18 ± 0.24 mm,  < .001). After multivariable adjustment, cIMT >1.0 mm (Odds Ratio [OR]: 2.84, 95% CI: 1.76-4.58), carotid stenosis ≥50% (OR: 4.92, 95% CI: 2.31-10.47), and resistive index >0.75 (OR: 3.15, 95% CI: 1.89-5.24) were independently associated with VCI. A combined model incorporating multiple carotid parameters achieved an area under the curve of 0.82 for VCI detection. These findings suggest that carotid ultrasound parameters may help identify cardiovascular patients at elevated risk for cognitive impairment, though external validation is needed before clinical implementation.

OBJECTIVE: This study examined the clinical utility of the long-term memory sign (LTMS), which is defined as self-reported long-term memory loss that is equal to or greater than self-reported short-term memory loss, and hypothesized to be a sign of functional cognitive disorders. METHOD: The LTMS was established using two standardized clinical interview prompts in 568 consecutive patients ( = 64.25,  = 13.03) referred for neuropsychological evaluation. Patients were categorized into five diagnostic groups: dementia ( = 140), mild neurocognitive disorder ( = 245), primary psychiatric diagnosis ( = 100), subjective cognitive complaints with no diagnosis ( = 42), and invalid cognitive presentations ( = 41). The LTMS was analyzed as a marker of functional cognitive disorders using diagnostic accuracy indices. RESULTS: The LTMS demonstrated high specificity (92.2%) but low sensitivity (28.3%) for functional cognitive disorders. It was reported by 82/568 patients (14.4%), with the highest frequency observed in those with invalid cognitive profiles (43.9%), primary psychiatric diagnoses (26.0%), and subjective cognitive complaints (19.0%), with progressively lower rates in mild neurocognitive disorder (9.8%) and dementia (4.3%). CONCLUSIONS: The LTMS is a quickly elicited interview-based clinical sign that may reflect a neurologically unlikely subjective complaint pattern associated with functional cognitive disorders.

BACKGROUND: Medication prescribing in Long-Term Care Facilities (LTCFs) is characterised by widespread polypharmacy and frequent exposure to potentially clinically relevant drug-drug interactions (DDIs). METHODS: Data from the Italian Prescription Day in LTCFs 2024, a national multicentre point-prevalence study conducted in 82 LTCFs, were analysed. Prescriptions were classified using the Anatomical Therapeutic Chemical system, and DDIs were identified using an international consensus list. Resident-level variables were assessed using validated tools, and associations with DDI burden were examined using univariate mixed-effects Poisson regression models. Facility-level organisational characteristics were described by centre-level DDI burden. RESULTS: The analysis included 3,174 residents (mean age 84.8 years; 74.1% women), with a mean of 7.7 prescribed drugs. Drugs acting on the nervous system, alimentary tract and metabolism, and cardiovascular system were most frequently prescribed; furosemide, paracetamol, pantoprazole, quetiapine, and macrogol were the most commonly used active substances. Overall, 42.2% of residents were exposed to at least one potentially clinically relevant DDI, most commonly involving centrally acting drugs, cumulative anticholinergic burden, serotonergic combinations, and potassium-related interactions. Higher DDI burden was associated with greater pharmacological complexity, depression, sleep disorders, cardiopulmonary disease, and behavioural and psychological symptoms of dementia, whereas older age, severe cognitive impairment, malnutrition, and dysphagia were associated with fewer DDIs. Facility-level and staffing characteristics showed limited differentiation, with assisted living facilities under-represented at higher DDI burden. CONCLUSIONS: Potentially clinically relevant DDIs are common in Italian LTCFs and are primarily associated with resident-level clinical complexity, highlighting targets for medication review and deprescribing to improve medication safety.

BACKGROUND: The normal functioning of gamma rhythms is crucial for maintaining brain health, while their abnormalities are closely associated with various neurological disorders, particularly Alzheimer's disease. Gamma stimulation modalities including auditory, visual, electrical, and strong magnetic approaches have all demonstrated potential therapeutic effects for AD, with substantial research findings continuously emerging. However, 40 Hz gamma low field magnetic stimulation(gamma-LFMS) remains unexplored. METHODS: To investigate this question, we applied pulsed magnetic fields with a magnetic field strength of 10 mT and frequency of 40 Hz (2 × 30 min/day) to 9-month-old APP/PS1 double transgenic AD model mice for 18 consecutive days, and evaluated changes in spatial memory capacity, hippocampal neural network characteristics, and amyloid protein 42 content in AD mice. RESULTS: Gamma-LFMS significantly enhanced spatial memory performance in AD mice, increased theta-gamma phase-amplitude coupling and gamma band power in the hippocampal CA1 region, showed a trend toward desynchronization in low gamma, and effectively reduced hippocampal β-amyloid42 burden. CONCLUSIONS: This study demonstrates for the first time that gamma-LFMS effectively ameliorates pathophysiological alterations and spatial memory deficits in AD mice. These findings address a critical knowledge gap regarding the effects of gamma-LFMS on AD pathology and provide a theoretical foundation for developing cost-effective home-based prevention and treatment devices applicable throughout the lifespan.

The relationships between exogenous hormones and dementia, as well as cognitive function in females, remains debated. This study aimed to investigate the associations of exogenous hormone exposure (oral contraceptives [OC] and hormone replacement therapy [HRT]) with incident dementia risk, cognitive function and changes in brain structures. Multivariate Cox proportional hazard regression models were used to assess the associations between exogenous hormone exposure and dementia incidence. Linear regression models were employed to explore the relationships of exogenous hormone exposure and cognitive performances. Mediation models were conducted to explore the underlying mechanisms driven by brain structures. A total of 233,896 female participants from the UK Biobank were included. In fully adjusted models, OC use was associated with reduced risks of all-cause dementia (ACD) (HR [95% CI], 0.806 [0.724-0.897]), Alzheimer's disease (AD) (HR [95%CI], 0.767 [0.659-0.893]) and vascular dementia (VaD) (HR [95%CI], 0.735 [0.578-0.934]). HRT was associated with decreased risks of ACD (HR [95%CI], 0.897 [0.811-0.992]) and AD (HR [95%CI], 0.804 [0.696-0.928]). Duration of OC use showed a non-linear (J-shaped) association with the risks of ACD and AD. In addition, brain structures, including the bilateral pallidum and left thalamus proper were identified as potential mediators in the relationships between the duration of OC use and cognitive performance. To summarize, exogenous hormone use is associated with reduced dementia risk and better cognitive function, with pallidum and thalamus possibly mediating the associations.

BACKGROUND: While omega-3 fatty acid supplementation is widely used for cognitive protection, its efficacy remains controversial, and its impact on core Alzheimer's disease (AD) pathologies in humans is not well-established. METHODS: This longitudinal study utilized data from the Alzheimer's Disease Neuroimaging Initiative (ADNI). We employed linear mixed-effects models to assess the association between omega-3 supplementation and longitudinal cognitive decline, and mediation analyses to examine whether this relationship was mediated by core AD pathologies (Aβ-PET, tau-PET, T1-MRI, FDG-PET). RESULTS: Omega-3 supplementation was associated with significantly accelerated cognitive decline, as evidenced by a faster decrease in MMSE scores (β = -0.266, p < 0.001) and a faster increase in both ADAS-Cog13 (β = 0.823, p < 0.001) and CDR-SB scores (β = 0.205, p < 0.001). This association was not mediated by Aβ deposition, tau pathology, or gray matter atrophy. Instead, longitudinal FDG hypometabolism within AD-vulnerable regions served as a significant mediating pathway, accounting for 30.8%, 40.8%, and 19.0% of the total effect on the decline in MMSE, ADAS-Cog13, and CDR-SB, respectively. CONCLUSIONS: Omega-3 supplementation may be associated with accelerated cognitive decline in older adults, potentially through adverse effects on cerebral synaptic function rather than classical AD proteinopathies. These findings challenge the prevailing view of omega-3 as uniformly beneficial and highlight the need for a cautious reassessment of its widespread use for cognitive protection.

BACKGROUND: Early differentiation between Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD) is a prerequisite for secondary prevention and targeted trial enrollment, yet remains challenging at disease onset. We investigated whether automated speech analysis could serve as a digital biomarker for early etiological stratification across clinically heterogeneous presentations. METHODS: In this prospective biomarker-confirmed prognostic study, 172 participants (108 patients with biomarker-confirmed AD or FTLD and 64 controls) completed a standardized speech protocol at initial clinical assessment. Acoustic, temporal, and phonatory features were automatically extracted. Machine learning models and a stacking ensemble were trained using stratified, repeated 5-fold cross-validation to discriminate between AD and FTLD pathology, with exploratory analysis extending to atypical and rare phenotypes crossed with physiopathology, including primary progressive aphasia (PPA) variants. RESULTS: Speech-based models achieved high sensitivity and specificity in distinguishing physiopathology independently (mean area under the curve (AUC)=0.986) and crossed phenotype and physiopathological diagnostic association (mean AUC=0.966).The ensemble identified 82% of cases with clinicopathological discordance. Interpretability analyses revealed distinct speech signatures: AD was associated with global speech slowing and phonatory instability, while FTLD was characterized by reduced verbal output and acoustic hypo-expressivity. CONCLUSIONS: Automated speech analysis provides a promising non-invasive digital biomarker for the early etiological stratification of AD and FTLD, including atypical phenotypes, with high accuracy in a monocentric biomarker-confirmed cohort. These findings support the feasibility of speech-based etiological stratification and its potential to complement existing biomarker frameworks, particularly in cases of clinicopathological discordance. External validation is required before clinical deployment can be considered.

BACKGROUND: Hydromethylthionine mesylate (HMTM) targets tau pathology and also has tau-independent symptomatic activity. A traditional randomised placebo-controlled trial (RCT) was precluded by loss of blinding due to urinary colouration and therapeutic activity at the minimum dose required to maintain blinding. OBJECTIVE: To evaluate the efficacy of HMTM in participants with mild cognitive impairment (MCI) and mild to moderate dementia due to Alzheimer's disease (AD). METHODS: Because a traditional RCT was not feasible without loss of blinding, we compared HMTM 16 mg/day in TRx-237-039 with propensity score matched true placebo controls from the FDA-sponsored Critical Path for AD (CPAD) database with the same inclusion/exclusion criteria (protocol TRx-237-080). We also compared HMTM 16 mg/day with matched natural history controls from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and with a meta-analysis of placebo arms from trials in comparable populations in analyses specified prior to the 104-week database lock of TRx-237-039. PARTICIPANTS: Propensity score matching yielded 127 pairs (HMTM n = 127; CPAD placebo n = 127) in the CPAD comparison, and 189 pairs in the ADNI comparison. A total of 218 receiving HMTM 16 mg/day were compared with meta-analytic controls (n = 1805-8567). INTERVENTION: HMTM 16mg/day MEASUREMENTS: Primary outcomes in TRx-237-080 were change from baseline to 78 weeks in ADAS-Cog and whole brain volume (WBV). CDR-Sum of Boxes (CDR-SB) and CDR-Global were analysed at 104 weeks. ADAS-cog and WBV were analysed in ADNI comparisons, and ADAS-cog, ADCS-ADL, CDR-SB and WBV were analysed in meta-analytic comparisons. RESULTS: Compared with matched CPAD placebo, HMTM 16 mg/day produced statistically significant differences in change on ADAS-Cog (p < 0.0001) and WBV at 78 (primary; p < 0.0001) and 104 weeks (p < 0.0001), and CDR-SB differed significantly overall (104-weeks; p < 0.001) and in MCI (p = 0.007). The odds of progressing to a more advanced CDR-Global stage were lower with HMTM (overall OR 0.31) and particularly in MCI (OR 0.15) versus CPAD placebo. Clinical and brain atrophy outcomes were similarly statistically significant in comparisons with ADNI case-matched natural history data and in meta-analytic comparisons. CONCLUSION: Comparisons of HMTM treatment with CPAD, ADNI, and meta-analytic controls provide evidence consistent with clinical benefit HMTM. It has the potential to offer an accessible oral treatment option which could be delivered with minimal patient/physician burden.

Alzheimer's disease (AD) is a chronic neurodegenerative disorder characterized by progressive cognitive and memory decline. An imbalance in the excitatory/inhibitory (E/I) neurotransmitter systems is hypothesized to play a significant role in the pathological mechanisms underlying this cognitive failure. As therapies targeting the excitatory side of this E/I balance provide only mild symptomatic relief, modulating inhibitory GABAergic neurotransmission has emerged as a potential therapeutic strategy for AD. α5 GABA type A receptors (α5-GABAARs) are of particular interest given their high expression in the hippocampus and involvement in learning and memory processes. Positive and negative allosteric modulators of α5-GABAARs have been developed with the converging aim of cognitive enhancement. This perspective explores the current literature on positive and negative allosteric modulators of α5-GABAARs in AD and proposes a model where two drug classes with opposing mechanisms can both offer therapeutic potential. Current evidence suggests that α5-GABAAR modulation may play divergent, circuit-dependent roles, such that negative allosteric modulators could enhance cognition in conditions of excessive inhibition, while positive allosteric modulators may be beneficial in hyperexcitable circuits. Ultimately, the successful clinical translation of α5-GABAAR positive and negative allosteric modulators will require careful phenotyping of neuronal activity and E/I balance to align pharmacological strategies with circuit state.

In a recent study, Sauvé et al. identified hypothalamic tanycytes as a route for tau transport from cerebrospinal fluid to blood and suggested that disruption of this pathway contributes to Alzheimer's disease pathology. The work broadens current models of tau clearance and raises new questions about how tanycytic dysfunction contributes to neurodegeneration.

OBJECTIVES: Explore treatment patterns of Canadian patients with AAD to understand variability in clinical management. DESIGN: This retrospective study used public claims data from Ontario and New Brunswick in IQVIA databases. SETTING: Inferred patients with AAD were identified through claims for cognitive enhancers and medications used off-label to treat AAD, i.e., antipsychotics (AP), anticonvulsants (AC), antidepressants (ADT), benzodiazepines (benzo). PARTICIPANTS: Patients (≥55 years) were identified between 2011-2018, indexed on their first AP/AC/AD/benzo and followed until the earlier of their fourth line (4L) of therapy or September 30, 2023. An all-history lookback to 2003 was used to ensure no prior claims for these therapies. MEASUREMENTS: Descriptive analyses explored treatment utilization patterns. RESULTS: 23,732 patients with AAD were identified, mostly from Ontario (98.7%). Patients with AAD tended to move to long-term care, with these increasing with more treatment trials from 24% (1 L therapy) to 54% (4 L therapy). Patients received between 500 and 2000 unique combinations across therapy lines. Citalopram, escitalopram, gabapentin, lorazepam, mirtazapine, pregabalin, quetiapine, risperidone, sertraline, and trazodone ranked in the top 10 therapies. Risperidone accounted for 7.2% of claims and ranked as the 6th most common 1 L therapy. Although trazodone remained the most common therapy for patients with AAD, it had one of the lowest persistence rates. Most patients remained on their 3 L - 4 L therapy, and ≥ 80% were adherent across all therapy lines. Average daily doses were lower than those described in the product monographs. CONCLUSIONS: AAD treatment varies widely, underscoring the need for approved treatments and enhanced clinical education. CLINICAL TRIAL NUMBER: Not applicable.

Growing evidence suggests that exposure to fine particulate matter (PM) may accelerate cognitive decline and increase dementia risk, but the roles of individual PM components, particularly when accounting for exposure measurement error, remain unclear. We followed 12,824 participants in the Nurses' Health Study cognition substudy (2000-2008). One-year average PM component concentrations preceding each participant's first cognitive assessment were assigned based on residential address. A global cognitive score was calculated as the mean of z-scores from six tests, and individual rates of cognitive decline were estimated using linear mixed models with random intercepts and slopes. Using information on the relationships of personal exposures and nearest-monitor PM components from a prior validation study, we employed double/debiased machine learning (DML) method to estimate associations between PM components and cognitive decline while accommodating high-dimensional multi-pollutant exposures and accounting for exposure measurement error. Higher exposure to several PM components were associated with changes in rates of cognitive decline. In multi-pollutant models without measurement error correction, each doubling of chloride (Cl) concentration was associated with a 0.0003 (95% CI: 0.0000, 0.0005) standard unit slower annual rate of cognitive decline, while each doubling in silicon (Si) was associated with a -0.0025 (95% CI: -0.0050, 0.0000) faster rate of decline. After correction for measurement error, associations generally strengthened: higher bromine (Br), manganese (Mn), and lead (Pb) were significantly associated with faster cognitive decline. In contrast, higher strontium (Sr) and vanadium (V) were associated with slower decline. Our findings suggest that long-term exposure to certain PM components, and their sources, may be more detrimental to cognitive aging than others, and highlight the critical need to correct for measurement error when assessing the health impacts of PM and its components. More research is needed to confirm these findings, ideally with access to larger validation studies of component exposures.

Structural characterization of proteins is essential for understanding their function, stability, and role in disease. Butyrylcholinesterase (BChE), expressed in the brain and localized within amyloid-β plaques, may generate an extended 69-amino acid, cysteine-rich signal peptide capable of self-aggregation and iron binding. In this study, we investigated the structure and aggregation of the BChE signal peptide using far-UV circular dichroism (CD) spectroscopy combined with in silico modelling via AlphaFold and coarse-grained replica-exchange molecular dynamics simulations with the UNRES force field. CD spectra revealed a predominance of β-sheet structure, with additional α-helices and statistical coil contributions. These experimental results were qualitatively consistent with AlphaFold and UNRES predictions, which revealed mixed α and β secondary structure in oligomeric assemblies. UNRES also predicted a substantial statistical coil content. Thermal CD analyses revealed marked differences in stability between variants. The p.C31Y signal peptide showed no significant spectral changes after heating, indicating exceptional resistance to thermal unfolding. In contrast, the wild-type peptide exhibited partial structural change under identical conditions. To refine structural interpretation, three short fragments of the BChE signal sequence (P1-P3) were analyzed by far-UV CD. P1 and P3 were largely disordered, whereas P2 displayed mixed secondary structure. An equimolar mixture of all three fragments produced an approximately additive CD spectrum, suggesting minimal conformational interference. Notably, P1 and P2 improved the solubility of the hydrophobic P3 fragment. Overall, these findings support a stable, aggregation-prone architecture for the extended BChE signal peptide and provide molecular insights into its potential role in promoting Alzheimer's pathology.

Tauopathies encompass a diverse group of neurodegenerative disorders characterized by abnormal TAU accumulation, synaptic dysfunction, neuroinflammation, and progressive neuronal loss. Beyond its role as a pathological hallmark, increasing evidence indicates that TAU actively drives neurodegeneration by disrupting mitochondrial function, promoting oxidative stress, and triggering maladaptive innate immune responses. In this context, pyroptosis, a highly inflammatory form of programmed cell death mediated by inflammasome activation and GASDERMIN pore formation, has emerged as a critical mechanism linking TAU pathology to chronic neuroinflammation and neuronal damage. This review summarizes current advances on the molecular crosstalk between TAU pathology, redox imbalance, inflammasome signaling, and pyroptotic cell death across primary and secondary tauopathies, including Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD). We discuss how pathological TAU induces mitochondrial dysfunction and reactive oxygen species generation, providing key priming and activation signals for inflammasomes, particularly NLRP3, in microglia and other brain cells. Pyroptosis is highlighted as a downstream effector that amplifies neuroinflammation through the release of pro-inflammatory cytokines and danger-associated molecular patterns, thereby sustaining TAU propagation and neurodegeneration. Special attention is paid to the redox-sensitive transcription factor NRF2 as a central regulatory node capable of counteracting oxidative stress, inflammasome activation, and pyroptosis. Finally, we examine emerging therapeutic strategies targeting pyroptotic and redox pathways, discussing their translational potential and current limitations. Overall, this review positions pyroptosis-driven redox-immune dysregulation as a promising yet underexplored therapeutic target in TAU-driven neurodegenerative diseases.

ETHNOPHARMACOLOGICAL RELEVANCE: Ginkgo biloba L., a 'living fossil' with an evolutionary history spanning over 200 million years, occupies a prominent place in traditional medicine systems. Historical records, including the Chinese pharmacopoeia Ben Cao Gang Mu, document its use for treating various ailments related to the respiratory, circulatory, and cognitive systems. Modern pharmacological research has validated these traditional applications, identifying Ginkgo biloba extract (GBE) as a valuable phytomedicine for neurodegenerative, cardiovascular, and metabolic diseases. AIM OF STUDY: This comprehensive review aims to synthesize recent advances in GBE research, with a primary focus on literature from the past three years in GBE research, critically evaluating four key areas: 1) innovations in green extraction and purification technologies; 2) novel organelle-level mechanisms of action; 3) the development and application of nano-delivery systems for targeted therapy; and 4) clinical evidence and toxicological studies supporting GBE's therapeutic use and safety profile. MATERIALS AND METHODS: This holistic review was conducted through a systematic literature search (covering 2003.8.15-2026.2.22) in databases including PubMed, Web of Science, and Scopus, using keywords related to GBE's extraction technologies, nano-delivery systems, organelle-level mechanisms, and clinical applications. The retrieved literature was screened and critically evaluated to synthesize recent advances, with a focus on identifying emerging trends, convergent evidence, and knowledge gaps across the four key areas outlined in the review's aim. RESULTS: Significant improvements in the sustainability and efficiency of GBE extraction have been achieved through recent technological innovations. DESs have emerged as tunable platforms for the selective and efficient extraction of bioactive compounds, while physical field-assisted methods enhance yields. Mechanistic studies reveal that GBE orchestrates cellular homeostasis by synchronously modulating mitochondrial bioenergetics, endoplasmic reticulum stress, and autophagic-lysosomal activity. Nano-delivery systems, such as liposomal nanoparticles and chitosan-coated carriers, effectively enhance the bioavailability and targeting precision of GBE's bioactive components, including quercetin. Clinically, standardized formulations like Ginkgo Diterpene Lactone Meglumine Injection (GDLI) show promise in improving cognitive outcomes in ischemic stroke and Alzheimer's disease, and in managing cardiovascular diseases. However, potential toxic side effects, primarily from ginkgolic acids (GA) and 4'-O-methylpyridoxine (MPN), necessitate rigorous quality control, with advanced methods like enzymatic degradation being developed for detoxification. CONCLUSION: GBE represents a promising, multifaceted therapeutic agent that effectively bridges traditional medicine and modern scientific innovation. Its broad-spectrum efficacy stems from the synergistic interactions of its bioactive constituents and their system-level regulatory mechanisms. To fully harness GBE's potential as a precision therapeutic agent, future research should focus on a coordinated technological strategy: employing green extraction methods such as DES to ensure sustainable and efficient compound isolation; developing standardized nano-formulations to overcome key pharmacokinetic limitations like low bioavailability and poor targeting; and applying multi-omics approaches to elucidate its organelle-level mechanisms of action. Validating these integrated innovations in large-scale clinical trials will be essential. Ultimately, the convergence of green chemistry, nanomedicine, and systems biology is key to translating GBE's multifaceted bioactivity into targeted and reliable clinical therapies.

ETHNOPHARMACOLOGICAL RELEVANCE: As a progressive neurological degenerative disorder, Alzheimer's disease (AD) remains a significant concern, with the lack of effective cures burdening healthcare resources and posing ongoing obstacles for scientific research in neuroscience. Tianwang Buxin Pills (TWBXP) is a traditional Chinese medicinal formula long employed for treating amnesia and cognitive decline, and has shown promising potential in AD treatment. Nevertheless, the detailed mechanisms responsible for these effects warrant further investigation. AIM OF THE STUDY: This study seeks to systematically evaluate the impact of TWBXP on cognition, neuronal damage, and synaptic plasticity in AD mice, while clarifying its underlying therapeutic mechanisms. MATERIALS AND METHODS: HPLC-UV was employed to ensure the quality of TWBXP. APP/PS1 mice were administered TWBXP (0.43, 0.85, 1.70 g/kg) for 8 weeks, and cognitive performance was assessed using behavioral tests. AD-related pathology was evaluated by Immunohistochemistry (IHC), Western blotting, ELISA, Transmission electron microscopy (TEM), and Immunofluorescence (IF). The integration of Network Pharmacology and Proteomics was conducted for the exploration of potential mechanisms. RESULTS: TWBXP markedly improved cognitive performance and reduced cerebral Aβ burden. It promoted microglial polarization toward an M2 phenotype, dampened neuroinflammation, and enhanced microglia-associated Aβ clearance. TWBXP also exerted marked neuroprotective and synaptic protective effects by increasing NeuN, MAP2, and MBP levels, restoring synaptic proteins (PSD95, SYP) and neurotrophic factors (BDNF, NGF), reducing neuronal loss and functional impairment, and improving synaptic plasticity. Such effects might be associated with the enhanced activity of the cAMP/PKA/NR2B/CaMKⅡ signaling axis. CONCLUSIONS: TWBXP significantly ameliorated cognitive impairment and AD-related pathological changes in APP/PS1 mice, accompanied by improvements in neuronal injury and synaptic plasticity. Its therapeutic effects may be associated with the regulation of microglial function and the cAMP/PKA/NR2B/CaMKII signaling axis.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with a growing global impact. Early and accurate diagnosis is crucial for effective management and therapeutic development. Cerebrospinal fluid (CSF) biomarkers have revolutionized AD diagnostics, reflecting core pathological hallmarks such as amyloid plaques and neurofibrillary tangles. Core CSF biomarkers, including amyloid-beta 42 (Aβ42), total tau (T-tau), and phosphorylated tau (p-tau), demonstrate high diagnostic accuracy, identifying AD even in early stages and predicting the conversion from mild cognitive impairment (MCI) to dementia. These biomarkers are invaluable not only for diagnosis but also for monitoring therapeutic responses in clinical trials and assessing the biochemical effects of disease-modifying treatments. This narrative review synthesizes the evolving role of CSF biomarkers in AD, focusing on their strategic application in enhancing diagnostic precision, enabling therapeutic monitoring, and facilitating clinical implementation. We explore the established utility of core CSF biomarkers, the development of novel markers, and the ongoing efforts to standardize assays and integrate these tools into routine clinical practice, ultimately aiming to improve patient outcomes and accelerate the development of effective AD interventions.

While both high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) are known to benefit physical health, their comparative effects on cognitive function in Alzheimer's disease (AD) remain unclear. Here, using equal number 3.5 months old male (28 ± 2 g) and female (24.0 ± 1.1 g) 5 × FAD transgenic mice, we demonstrate that HIIT and MICT improve AD pathology and cognitive performance, as evidenced by reduced amyloid-β deposition and enhanced hippocampal synaptic plasticity. Both exercise modalities significantly elevated lactate levels in the blood and hippocampus of AD mice. The functional consequences of this increase, however, were not linear. We found that while low lactate (2 mM) universally enhanced excitatory postsynaptic potentials in the hippocampus, high lactate (7 mM) was inhibitory, with no significant effects observed at intermediate concentrations (4 and 6 mM), an effect independent of genotype. To mechanistically link lactate dynamics to functional benefits, we performed lactylation-based proteomics. This revealed that HIIT and MICT differentially modulated protein lactylation-both reduced lactylation of glutamatergic synaptic proteins, but HIIT specifically upregulated lactylation of necroptosis-related proteins (CypA/Cyp40), while MICT downregulated proteasome-related proteins (Psmc1/Psmα7). Our findings suggest that exercise-induced lactate dynamically regulates brain function via protein lactylation, offering a novel therapeutic avenue for AD.

Although life expectancy has increased, the proportion of years lived without disability has not improved at the same rate. This has contributed to the rising prevalence of dementia, which currently affects over 55 million people worldwide. In the absence of curative treatments, non-pharmacological strategies such as exercise and diet have attracted interest as a means of preserving cognitive function in older adults. This systematic review and meta-analysis evaluated the effectiveness of combined exercise and dietary or nutritional supplementation interventions on global cognitive function in healthy older adults or those with mild cognitive impairment. Following PRISMA guidelines (PROSPERO ID: CRD42024528600), we searched the following databases up to 1 May 2025: PubMed, Scopus, Web of Science and SportDiscus. Fourteen randomised controlled trials involving 4,013 participants aged 65 years or over (mean age: 71.4) without diagnosed dementia were included. Global cognition was assessed using validated tools. The methodological quality was assessed using the PEDro scale and the risk of bias using Cochrane's RoB 2 tool. A random-effects meta-analysis was conducted using the DerSimonian-Laird method, with heterogeneity estimated via the I² statistic. A combined exercise and nutritional intervention significantly improved global cognitive function compared to the control group (SMD: 0.15; 95% CI: 0.07-0.24; I²: 50%). A sensitivity analysis that excluded multi-domain interventions confirmed this effect (d = 0.12; 95% CI: 0.02-0.22; I² = 0%). However, no significant improvements were found in specific domains, such as executive function or visual-perceptual ability. Variability in methodological protocols, follow-up durations, cognitive tools and adherence measurement limits comparability. While the observed effect size was modest, these findings, in the context of healthy ageing, suggest the potential for these combined interventions to attenuate cognitive decline and preserve functional autonomy, thereby highlighting their role in dementia prevention strategies.

Spontaneous memory replay during sleep is crucial for cognition but challenging to capture because distinct sleep rhythms hinder the generalization of wake-trained electroencephalogram (EEG) decoders. To address this, we developed the Sleep Interpreter (SI), which uses neural contrastive learning to isolate shared semantic content from background rhythms. We collected a dataset of 135 participants undergoing targeted reactivation of 15 semantic categories, yielding approximately 1,000 h of overnight sleep and 400 h of wake EEG. During non-rapid eye movement (NREM) sleep, SI achieved high decoding accuracy for cue-evoked semantic responses, with accuracy peaking during slow oscillation and spindle coupling at 40.02% top-1 accuracy on unseen participants (chance 6.7%). We demonstrated SI generalizability in two independent nap experiments involving targeted and spontaneous reactivation, where decoded reactivations correlated with post-sleep memory performance. Finally, we implemented SI for real-time sleep staging and stage-specific NREM and REM decoding. The dataset and codebase are shared as open resources for future clinical applications.

People with dementia can live alone successfully even when they do not have support from family or friends. This requires professionals to be able to provide timely and effective support. This study aims to identify professional perspectives on the challenges and strategies in supporting people with dementia who live alone and have no informal support. Semi-structured qualitative interviews were conducted with twenty-two professionals working in dementia-related roles across various sectors in England. Interviews were analysed using Reflexive Thematic Analysis. Themes were finalised through support of the study advisory team, including people with lived experience of dementia. Six themes were identified, reflecting stages of the 'dementia care pathway', from identification of patients to discharge. Professionals reported experiencing barriers around identifying clients, communicating with them, gathering information, engaging with them, managing risks, and setting up continuity of care. They shared strategies for each of these challenges. This study identified some key strategies that a variety of professionals can deploy to promote access and use of services for an especially vulnerable population to be able to live independently for as long as possible. These strategies would need to be embedded and consistently implemented across different sectors. This would ensure that people are identified and supported in a timely fashion and could, in turn, prevent more costly long-term care and contribute to cost-containment.