BACKGROUND: 14-3-3γ is implicated in neurodegeneration, yet its role in postoperative cognitive dysfunction (POCD) remains unclear. METHODS: We performed CSF proteomic profiling using the SomaScan 7K platform in the Alzheimer's Disease Neuroimaging Initiative cohort (n = 237) to identify biomarkers associated with neurodegeneration-enriched cognitive vulnerability (NECV). A prospective surgical cohort (n = 213) was used to evaluate circulating 14-3-3γ levels in relation to perioperative cognitive outcomes. Mechanistic studies were conducted using a murine surgery model, AAV-mediated gene manipulation, neuronal cultures, pharmacological intervention, and molecular dynamics simulations. RESULTS: CSF proteomics identified 14-3-3γ as a candidate biomarker associated with NECV and neurodegenerative progression. Plasma 14-3-3γ levels were associated with POCD and postoperative delirium. In mice, anesthesia and surgery reduced hippocampal 14-3-3γ expression, accompanied by increased Tau phosphorylation at Thr205 among examined sites, synaptic dysfunction, and cognitive impairment. Neuronal 14-3-3γ overexpression rescued these deficits. Mechanistically, 14-3-3γ interacted with Tau in a phosphorylation-dependent manner and regulated Tau phosphorylation homeostasis. Pharmacological stabilization of the 14-3-3γ-Tau interaction using FC-A reduced Tau Thr205 phosphorylation and improved cognition, whereas TauT205E expression diminished this rescue effect. CONCLUSIONS: 14-3-3γ represents a potential regulator of postoperative cognitive vulnerability and a candidate therapeutic target for POCD.

Beta-amyloid peptide (Aβ)-induced suppression of hippocampal GABAergic interneuron activity drives hyperexcitability, amyloid pathology, and cognitive impairment in Alzheimer's disease (AD), suggesting that enhancing hippocampal inhibition may be protective. However, hippocampal interneurons are highly diverse and differentially regulate inhibition and cognition, making it challenging to identify the affected subtypes and optimally restore hippocampal inhibition in AD. We have previously found that Aβ selectively binds to two of the three major hippocampal nicotinic acetylcholine receptor (nAChR) subtypes, α7- and α4β2-nAChRs, but not α3β4-nAChRs, and inhibits these two receptors in hippocampal inhibitory interneurons to decrease their activity, leading to hyperexcitation in excitatory neurons. Here, we further reveal that α7- and α4β2-nAChRs predominantly control nicotinic cholinergic signaling and neuronal activity in hippocampal parvalbumin-positive (PV+) and somatostatin-positive (SST+) inhibitory interneurons, respectively. We also find that systemic co-stimulation of α7- and α4β2-nAChRs is required to reverse hippocampal hyperexcitability, dysfunction of fear learning-associated hippocampal oscillatory activity, and hippocampus-dependent memory loss, and to reduce Aβ pathology in AD model mice. This suggests that co-stimulation of PV+ and SST+ cells via activation of α7- and α4β2-nAChRs together is required to enhance hippocampal inhibition optimally, which reverses hippocampal dysfunction, reduces amyloid pathology, and ultimately prevents memory loss in AD.

The temporal lobes are key hubs for memory and cognition. Although 40 Hz transcranial alternating current stimulation (tACS) has shown potential cognitive benefits, evidence for accelerated bilateral temporal stimulation remains limited. This study aims to evaluate its cognitive and neural effects. In this randomized, double-blind, controlled trial, 100 Alzheimer's disease (AD) patients were randomized 1:1 to active or sham 40 Hz tACS over the bilateral temporal. Cognitive outcomes at three time points were analyzed using mixed repeated-measures analysis of variance (ANOVA). Resting-state functional near-infrared spectroscopy (fNIRS) data from baseline and Week 4 were analyzed using ANOVA, followed by network-based statistics with family-wise error (FWE) correction. Eighty-five participants completed the trial. Significant Group × Time interactions were observed for Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) total (p = 0.010), memory (p = 0.007), and praxis (p = 0.002), but not for the Mini-Mental State Examination (MMSE) (p = 0.075). The fNIRS analysis revealed a functional network primarily involving the frontal and parietal regions, comprising 38 connections and 18 nodes (p = 0.010). Active-group connectivity changes were associated with ADAS-Cog total, language, praxis, and MMSE variations, but not in the sham group. Accelerated bilateral temporal 40 Hz tACS improved cognition and modulated frontotemporoparietal connectivity. Larger multicenter studies with biomarkers are warranted.

Cure occupies a prominent place among the goods of medicine, yet its limits raise a fundamental question about medicine's constitutive end. Chronic illness, disability, dementia, frailty, and dying reveal circumstances in which medicine retains substantial obligations despite the absence of cure. These cases invite renewed reflection on what medicine is fundamentally for. This article argues that care constitutes medicine's moral foundation and the broader framework within which cure derives its meaning and purpose. Drawing primarily on Edmund Pellegrino's philosophy of medicine, together with contemporary debates concerning medicine's constitutive aims and scholarship on suffering, vulnerability, and human dignity, the argument proceeds in five stages. First, it examines the relationship between care, cure, and the ends of medicine, situating the argument within competing accounts of medicine's defining aims. Second, it examines the influence of the curative ideal on modern conceptions of medical success. Third, it considers how chronic illness, disability, dementia, aging, and dying expose the limits of cure as an account of medicine's enduring obligations. Fourth, it argues that medical care constitutes a distinct moral practice arising from the fiduciary structure of the clinical encounter, in which professional knowledge and competence respond to patient vulnerability. Fifth, it considers the implications of this account for medicine increasingly shaped by artificial intelligence and digital technologies. The central claim is that medicine exists not because diseases require treatment but because persons seek help in matters concerning health, illness, suffering, and bodily vulnerability. Cure remains one of medicine's greatest goods, but it does not constitute medicine's ultimate end. Cure serves the good of the patient; care names medicine's enduring commitment to that good across changing clinical circumstances. This account preserves the importance of therapeutic intervention while explaining why medicine's obligations persist when cure is unavailable.

Huntington's Disease is a neurodegenerative disorder that progresses over time and can be passed down from parent to child. In uncontrolled motor activities, behavioural problems come into play, as well as progressive mental decline. The CAG triplet in the HTT gene found on chromosome 4 undergoes changes, leading to the production of a mutant protein called huntingtin, which consists of a bigger-than-normal polyglutamine tract that then undergoes misfolding and produces toxic oligomers and fibrillar deposits that can cause dysfunction in normal cell functioning and therefore in nerve cells as well. Although early research linked the pathophysiology of Huntington's disease primarily to mHTT aggregation, more recent research indicates broad protein-protein interaction networks that affect several cellular pathways. Systems biology approaches using tools such as STRING, BioGRID, and Cytoscape have provided evidence of interconnected networks that promote proteostasis, mitochondrial dynamics, energy metabolism, neuroinflammation, synaptic transmission, and transcriptional and epigenetic regulation. Important protein hubs, including HSP70, DRP1, NLRP3, and TFEB, act as central controls that bind those pathways. mHTT-mediated defect in the function of the ubiquitin-proteasome system promotes mitochondrial oxidative stress, which triggers the NLRP3 inflammasome, leading to synaptic dysfunction and specific loss of striatal medium spiny neurons. Investigations using various experimental techniques, which involve R6/2 and YAC128 mouse models, neurons derived from human iPS cells, and multi-omics studies, reveal that faulty neuroplasticity develops before the formation of visible protein aggregates. As for therapeutics targeting central components of neuronal networks, they have all demonstrated certain neuroprotective effects.

Functional ultrasound (fUS), ultrasound localization microscopy (ULM), and functional ULM (fULM) are three emerging brain ultrasound imaging techniques that measure the cerebrovascular structure and function at different spatial scales. Here we establish an awake, longitudinal fUS-ULM-fULM imaging framework to study structural vascularity, microvascular flow velocity, mesoscale hemodynamic responses, and microvascular functional responses in the same animals across 5 months. No significant linear longitudinal trend was detected for any of the ultrasound measurements in control animals, with structural measures showing lower longitudinal variability than functional readouts. Mean flow velocity showed the strongest longitudinal consistency and the lowest pooled within-subject variability. Behavioral testing and GFAP/Iba1 staining further revealed no detectable memory impairment or chronic neuroinflammatory response during the 5-month serial imaging setup. Application of fUS-ULM-fULM in 5xFAD-positive mice revealed a temporally ordered, cross-scale pattern of cerebrovascular dysfunction, with cerebral blood flow velocity declining first followed by impaired stimulus-evoked responses at the microvascular and then mesoscale levels. No vascular structural changes were detected across 5 months. Overall, this study established a stable longitudinal multimodal ultrasound imaging framework for tracking the awake mouse brain and demonstrated the utility for detecting cerebrovascular structural and functional variations in a preclinical Alzheimer's disease mouse model.

Electroencephalography (EEG) has been investigated as a noninvasive approach for characterizing brain activity in neurodegenerative conditions. This study evaluated whether multidomain EEG biomarkers could distinguish Alzheimer's disease (AD), frontotemporal dementia (FTD), and healthy controls (HC). The publicly available dataset contained resting-state, eyes-closed EEG recordings from 88 participants, including 36 with AD, 23 with FTD, and 29 healthy controls. Multidomain EEG biomarkers and demographic features were extracted for machine learning classification. The EEG-derived features included root-mean-square (RMS), power spectral density (PSD), and entropy measures. A Random Forest classifier was trained using the combined feature set and interpreted using explainable artificial intelligence. Feature-stability and Cohen's d effect-size analyses were performed to evaluate feature contributions, followed by an ablation analysis. Entropy-based features showed the lowest contribution to classification. The complete multidomain model achieved 96% training accuracy and 92% test accuracy. After the removal of the entropy features, test accuracy increased to 94%. These results describe the classification performance of the selected multidomain EEG and demographic features within the Random Forest framework.

Alzheimer's disease (AD) is the leading cause of dementia worldwide, disproportionately affecting individuals over 65 years of age and imposing a rapidly escalating burden on healthcare systems and caregivers globally. For decades, management relied on symptomatic agents-cholinesterase inhibitors and memantine-that provide modest cognitive benefits without altering disease progression. The recent approvals of the anti-amyloid monoclonal antibodies lecanemab (2023) and donanemab (2024) represent a paradigm shift, offering the first therapies that modestly but significantly slow clinical decline by targeting the underlying amyloid-β pathology. However, these advances are accompanied by important safety concerns, particularly amyloid-related imaging abnormalities, substantial costs, and unresolved questions regarding long-term clinical meaningfulness and equitable access. This comprehensive review synthesizes current knowledge across the full spectrum of AD, encompassing molecular pathophysiology (amyloid cascade, tau hyperphosphorylation, and neuroinflammation), genetic architecture (familial mutations and APOE-mediated risk), evolving biomarker-based diagnostic frameworks, established symptomatic treatments, and newly approved disease-modifying agents. We further examine emerging therapeutic strategies, including tau-targeted therapies, neuroinflammation-directed approaches, multi-target and combination strategies, drug delivery innovations, and prevention trials in preclinical populations. Throughout, we critically evaluate the evidence, acknowledging controversies and limitations while identifying promising future directions. Importantly, integrating these diagnostic and genetic advances into geriatric care settings presents unique implementation challenges, as aging populations often face comorbidities, polypharmacy, and limited access to specialized diagnostic infrastructure. As AD therapeutics enter a new era, integrating pharmacological interventions with biomarker-guided patient selection, rigorous safety monitoring, and modifiable risk factor management will be essential for optimizing outcomes in aging populations.

Neurodegenerative diseases are characterized by cognitive or motor impairments resulting from the progressive degeneration of neurons or myelin sheaths. Currently, the majority of these disorders remain incurable, leading to significant detriments in patients' quality of life and imposing substantial economic burdens. Exosomes are a type of extracellular vesicles secreted by cells into the extracellular space, typically range from 30 to 150 nanometers in diameter. These vesicles have been identified in a variety of cell types and can participate in various physiological and pathological processes, including intercellular transport of biomolecules, signal transduction, immune modulation, tissue repair, facilitation of tumor metastasis, and evasion of immune surveillance by cancer cells. In recent years, the potential applications of exosomes in neurodegenerative diseases have garnered increasing attention. Their roles encompass early diagnostic biomarker functions, vehicles for drug delivery and therapeutic agents, mediators in the propagation of pathogenic proteins, and regulators of neuroinflammatory responses. In this review, we try to aims to synthesize recent progress in exosome isolation techniques, elucidate the pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), and examine the diagnostic and therapeutic applications of exosomes within these conditions. Furthermore, it addresses current limitations in exosome-based applications and explores potential strategies to overcome these challenges. The insights of this review may provide the research directions and guidance for future related researchers in these fields.

Tuberculosis (TB), caused by (Mtb), is one of the most threatening infectious disease worldwide. Selenium, an essential micronutrient, is incorporated into selenoproteins such as glutathione peroxidase, which modulate lipid peroxidation and immune responses, thus playing pivotal roles in host defense against infection and control of Mtb dissemination. As an emerging class of selenium-based medicines, selenium nanoparticles (SeNPs) have demonstrated attractive anti-tuberculosis potential based on their favorable bioactivity, lower toxicity compared, high drug-loading capacity, sustained-release kinetics, and enhanced targeting specificity. Beyond their anti-TB potential, SeNPs have shown significant promise in various biomedical applications, including the treatment of diabetes, liver disease, Alzheimer's disease, and cancer, owing to their ability to modulate oxidative stress, inflammation, and apoptotic pathways. This review explores the relationship between selenium and the occurrence and development of tuberculosis, evaluates the potential of serum selenium as an auxiliary diagnostic biomarker, and outlines common preparation methods for SeNPs, including physical, chemical, and biological synthesis approaches. Furthermore, this review systematically summarizes the anti-tuberculosis functions of SeNPs, detailing multiple mechanisms such as accelerating Mtb-lysosome fusion, modulating intracellular ROS levels, driving M1 macrophage polarization, and inhibiting the PI3K/AKT/mTOR signaling pathway to collectively trigger autophagy and apoptosis in Mtb-infected macrophages. These insights may support the development of new anti-tuberculosis technologies based on SeNPs. Furthermore, we also address the key challenges hindering the clinical translation of SeNPs: the long-term in vivo tissue accumulation patterns of SeNPs have not been fully elucidated, long-term systemic nanotoxicity data remain scarce, almost all anti-tuberculosis studies are restricted to in vitro cell experiments and animal models, and the translational pathway from laboratory studies to clinical practice remains ambiguous.

INTRODUCTION: Visual impairment is associated with dementia risk, but the role of severity and longitudinal change remains unclear. We examined whether visual impairment severity and its progression were associated with incident dementia. METHODS: This territory-wide cohort study followed 15,576 community-dwelling older adults without dementia at baseline for 16 years. Incident dementia was ascertained using International Classification of Diseases, Tenth Revision diagnoses or Clinical Dementia Rating scores of 1 to 3. Visual acuity was measured using the Snellen chart. Cox models estimated hazard ratios, excluding dementia cases occurring within the first 6 years to minimize reverse causation and adjusting for demographic, comorbidity, and lifestyle factors. RESULTS: Moderate to severe visual impairment and faster visual acuity decline were associated with increased dementia risk. Severe visual impairment was associated with dementia onset 2.1 years earlier than normal vision. DISCUSSION: These findings strengthen the evidence for visual impairment as a dementia risk factor, supporting incorporation of visual assessment into dementia risk stratification. TRIAL REGISTRATION: The Chinese Clinical Trial Registry: ChiCTR1900023536.

OBJECTIVES: The Alzheimer's Association has reported a 746% increase in dementia-related deaths in Asian American populations between 2000 and 2018, the most significant rise compared to all other racial groups. Asian Americans face a unique myriad of obstacles and factors contributing to significant health disparities, including those in dementia. Our aim is to compare determinants and outcomes of dementia between US-born and foreign-born Asian Americans. METHODS: Data from the 2019-2022 National Health Interview Survey was analyzed to examine the relationship between nativity and dementia. Other life course risk factors and outcomes of having dementia were also included in the analysis. The study sample included 16,331 US-born and 126,978 foreign-born Asian Americans. RESULTS: Foreign-born Asian Americans were found to have a higher proportion of dementia compared to US-born Asian Americans (1.1%>0.4%, p = 0.0140). Risk factors that were found to significantly explain the relationship between nativity and dementia included age > 65, ever being married, having some college education, and having Medicaid coverage. Foreign-born Asian Americans with dementia are more likely to suffer from depression (p < 0.001) and experience/have difficulty in social involvement (p < 0.001) compared to US-born Asian Americans with dementia. CONCLUSION: Our findings reaffirm that nativity contributes to the heterogeneous risk and outcomes of dementia in Asian Americans and the likelihood of having dementia is further impacted by life course factors. Interventions to support Asian American immigrants are needed to reduce the burden of dementia. More studies that identify nativity variations are also recommended to address health disparities that disproportionately affect older immigrants.

RATIONALE AND OBJECTIVES: This study aimed to efficiently denoise short 7 T MRI acquisitions to achieve the image quality of longer scans using a generative Artificial Intelligence (AI) model. MATERIALS AND METHODS: A 7T Conditional Diffusion Model (7TCDM) was trained on an in-house 7T dataset of 11 examinations consisting of multi-repetition 2D T2-weighted gradient-echo acquisitions. The model utilized native single-acquisition 2D reconstructions, using multi-repetition images as a reference to guide denoising and enhance signal-to-noise ratio and contrast. Performance was compared to the same single-acquisition reconstruction either unprocessed or enhanced by a similarly trained convolutional neural network, vision transformer, and generative adversarial network, using Mean Squared Error (MSE), Peak Signal-to-Noise Ratio (PSNR), Structural Similarity Index Measure (SSIM), and comprehensive neuroradiologic ratings. RESULTS: 7TCDM was tested on 2D T2-weighted gradient-echo images from 19 participants: eight healthy controls, six individuals with mild cognitive impairment, and five with Alzheimer's disease. Referencing the multi-repetition reference standard, 7TCDM improved the single-acquisition original image by 31.7% in MSE, 4.9% in PSNR, and 7.5% in SSIM, outperforming all other models in all metrics (P < 0.001). Expert rater evaluations confirmed superior image quality, with significantly enhanced detail (P < 0.001) and contrast preservation (P < 0.001) for the hippocampi, for white matter lesions, and for small cortical veins. CONCLUSIONS: Generative AI denoising provides high-quality denoised images from shorter scans, increasing the feasibility of scanning patients in shorter times while preserving essential anatomical and pathological details.

In healthy liver, large macromolecules pass freely into the space of Disse through liver sinusoidal endothelial cell (LSEC) fenestration. In aging, LSEC fenestration is largely lost (pseudocapillarization). We hypothesized that restoring aged LSECs' fenestration would enhance passage into the space of Disse of large-diameter (>50 nm) triglyceride-rich lipoproteins to which the majority of circulating amyloid-beta is bound and permit hepatocyte uptake of amyloid-beta: in aged rats, two weeks of the soluble guanylate cyclase activator cinaciguat restored fenestration; circulating amyloid-beta 40 levels halved, returning to levels found in young rats. Surprisingly, cinaciguat also reversed age-related increases in LDL (a smaller, 20-30 nm diameter lipoprotein), which crosses the sinusoidal endothelial barrier even when LSECs are defenestrated. We therefore investigated additional mechanisms by which LSECs promote hepatocyte clearance. Whereas primary hepatocytes had minimal uptake of amyloid-beta 40 or LDL, hepatocytes cultured in young rat LSEC conditioned medium retained their uptake function. Aged rat LSEC conditioned medium did not facilitate hepatocyte amyloid-beta 40 and LDL uptake but treating aged rats with cinaciguat restored aged rat LSECs paracrine signaling. We discovered that heparin-binding epidermal growth factor-like growth factor (HB-EGF) mediates this LSEC-hepatocyte interaction and that HB-EGF is synthesized but not secreted by aged rat LSECs; cinaciguat treatment restores aged LSECs' HB-EGF secretion. Treatment reversed age-associated loss of LDLR and LRP1 surface expression in rat hepatocytes. This study identifies a candidate therapy to address age-related increases in circulating amyloid-beta and LDL and elucidates an intercellular crosstalk mechanism that governs these phenomena.

Polyamines (PAs) are evolutionarily conserved metabolites that connect protein quality control with lysosomal, mitochondrial, and redox homeostasis. Their metabolism is situated at a critical intersection of cell-sustaining and neurodegenerative pathways. Here, we synthesize evidence across Alzheimer's disease, Parkinson's disease, polyglutamine repeat disorders, amyotrophic lateral sclerosis, and multiple system atrophy, each of which differ in vulnerability to changes in PA metabolism. Although previous reviews have investigated polyamines in individual neurodegenerative disorders, few have compared their roles across the broader spectrum of neurodegenerative proteinopathies. Here, we address this gap by synthesizing evidence across multiple diseases to examine how PAs influence disease-associated protein aggregation and clearance, and how these effects depend on PA species, concentration, cellular context, disease stage, subcellular localization, redox state, and lysosomal and mitochondrial capacity. Human tissue and biofluid studies report disease-associated changes in PA metabolites, pathway enzymes, and transporter remodeling, as a function of neurodegenerative disorders. Mechanistic studies reveal that spermidine and spermine can alter the assembly, condensation, compartmentalization, and clearance of various neurotoxic proteins, whereas the effects of putrescine are more system- and concentration-dependent. These effects engage both shared pathways and distinct mechanisms, depending on protein identity, cell type, and subcellular location. Curiously, PA manipulation may be protective in one context yet harmful in another. The framework that we propose can distinguish adaptive remodeling from pathogenic dysregulation and can guide disease-relevant therapeutic strategies.

The reduction of Cu(II) to Cu(I) in oxidative extracellular environments contributes to oxidative stress because the reoxidation of Cu(I) back to Cu(II) generates reactive oxygen species. Monoamine neurotransmitters such as serotonin (5-HT) and dopamine (DA) possess Cu(II)-reducing ability and coexist with copper ions near the synapse, suggesting that they may serve as potential mediators of oxidative stress. The neurotoxicity of aggregated amyloid-β peptide (Aβ) observed in the brains of Alzheimer's disease patients is thought to arise from oxidative stress induced by complex formation of Aβ with redox-active metal ions. However, the absence of apparent Cu(II)-reducing activity in Aβ suggests the involvement of other reducing agents in the generation of oxidative stress. In this study, we examined the effects of Aβ on the redox reactions between copper and monoamine neurotransmitters 5-HT and DA. The Cu(II)-reducing activities of both neurotransmitters, together with the accompanying production of hydrogen peroxide, were inhibited by either unfibrillized Aβ or non-amyloidogenic Aβ, whereas fibrillized Aβ enhanced them. Canonical small-molecule Cu(II) ligands, such as L-histidine, diminished these activities, whereas Cu(I) chelators exerted an enhancing effect. These findings suggest that the activation of monoamine-mediated copper reduction by fibrillized Aβ may be attributable to the Cu(I)-binding capability that is absent in the monomeric form. This study provides a partial mechanistic basis for the causal link between Aβ aggregation and the onset of Alzheimer's disease.

Chronic cerebral hypoperfusion (CCH) is a major risk factor for neurodegenerative diseases, including vascular dementia (VD). It is well documented that sex differences account for variability in progression and outcomes in cerebrovascular pathophysiology and dementia risk. Despite extensive study of VD, most mechanistic and preclinical work has been conducted in male animals, leaving the molecular and cellular consequences of CCH in the female brain largely unexplored. To address this critical gap in knowledge, we investigated the effects of short-term CCH on pathology and gene expression changes in 6-7-month-old female C57BL/6 J mice using the bilateral common carotid artery stenosis (BCAS) mouse model. Thirty days following BCAS surgery, the mice exhibited early pathological changes such as pyknotic nuclei and moderate white matter damage, cellular changes such as astrocytic activation and clusters of degenerating neurons in the cortex and hippocampus, and gene expression alterations primarily related to extracellular matrix remodeling and mRNA splicing, with no significant changes in hippocampal-dependent spatial working memory. Together, our study demonstrates that pathological changes in the female brain begin to emerge as early as 30-35 days of continuous CCH.

BACKGROUND: Epilepsy is a relevant comorbidity of dementia due to Alzheimer's Disease (AD) and probably directly related to its pathology. We aimed to generate hypotheses how interictal epileptiform discharges (IEDs) may be associated with pathological levels of AD markers from cerebrospinal fluid (CSF). OBJECTIVE: To perform bivariate analyses between IEDs or EEG background slowing to CSF AD markers including amyloid-β42 to amyloid-β40 ratio (Aβ ratio), total tau and phospho-tau. METHODS: In this retrospective cross-sectional study, we identified 26 clinical AD patients who presented with at least one of three pathological neurodegeneration markers in the CSF (Aβ ratio ≤0.5, total tau ≥370 pg/ml, phospho-tau ≥66 pg/ml) and received at least one routine EEG. RESULTS: IEDs and EEG background slowing were present in 5/26 and 14/26 patients, respectively. We observed that patients with IEDs or EEG background slowing had significantly lower phospho-tau levels than patients without (Cohen's d=0.91, P = 0.044 and Cohen's d=1.33, P = 0.005, respectively). Consistent with this, a positive history of seizures tended to be associated with lower phospho-tau levels (Cohen's d=0.79, P = 0.059). Moreover, phospho-tau levels were significantly correlated to dominant posterior EEG frequencies (Spearman's ρ=0.524, P = 0.006), and Aβ ratios were significantly lower in patients with normal EEG background frequencies than in those with EEG slowing (Cohen's d=1.31, P = 0.017). CONCLUSIONS: Our bivariate analyses revealed the unexpected observation that the presence of IEDs was associated with lower rather than higher phospho-tau levels in clinical AD patients. This finding awaits further confirmation in a larger cohort.

Alzheimer's disease (AD) has emerged as an increasingly prevalent and burdensome public health challenge with global aging, underscoring the urgent need to clarify the key factors involved in its pathogenesis for effective prevention and management. Mounting evidence suggests that disrupted crosstalk between the intestine and brain may contribute to aging-related neurodegeneration, including AD. Acting as a peripheral modulatory hub of the intestine-brain axis, the intestine releases a variety of bioactive substances that regulate brain function. This narrative review synthesizes current evidence on intestine-derived signaling molecules and immune mediators implicated in AD pathogenesis, with a focus on two primary communication routes: the vagus nerve and systemic circulation. In addition, intestine-targeted interventions-including dietary modification, probiotic supplementation, and fecal microbiota transplantation-are summarized. Notably, metagenomics-based intestinal microbiota aging clocks represent an emerging non-invasive strategy for AD risk prediction. Although preclinical findings are encouraging, the translational limitations and heterogeneity of current intestine-brain research remain noteworthy. In summary, this narrative review integrates substantial evidence on the correlation between intestine-derived mediators and AD and provides potential insights for the development of intestine-targeted preventive strategies.

BACKGROUND: Pregnancies complicated by fetal growth restriction (FGR) and preeclampsia are associated with increased long-term chronic disease risk. A blood test could possibly identify those at risk, opening the door to early interventions soon after delivery. Prior work in non-pregnant people have identified protein signatures associated with 18 different health parameters, called SomaSignal Tests. METHODS: This study applied SomaSignal tests to plasma samples collected in pregnancy from two independent cohorts to assess the 18 health parameters in those who later developed FGR and preeclampsia. SomaScan Assay measured ∼7000 modified aptamers in plasma from two independent cohorts. Plasma samples (Melbourne, Australia) were collected at 36 weeks' gestation from women who later delivered an FGR infant (<3rd birthweight centile, n = 118), preeclampsia at term (n = 92) or did not develop either condition (n = 177). The second cohort (Cambridge, UK) were plasma samples collected at 36 weeks' gestation from women who later delivered an FGR infant (n = 80), and those who did not (n = 172). FINDINGS: In the Australian cohort, women who later delivered growth-restricted infants had composite protein signatures associated with reduced cardiac function (p = 0.001), increased cardiovascular events (p = 7.6 × 10), mid-life dementia (p = 1.5 × 10), and higher visceral fat (p = 4.06 × 10), compared to pregnancies without complications. Findings were largely consistent in both Australian and UK sample sets. Those who developed preeclampsia had protein signatures signifying cardiovascular (p = 5.54 × 10), hepatic (p = 0.001), and renal (p = 0.0007) disease risks, compared to pregnancies without complications. INTERPRETATION: Since signatures were more pronounced in pregnancies that were later diagnosed with FGR and preeclampsia, underlying physiological changes may have been present before diagnosis. These changes result in protein signatures concordant with those associated with poor long-term health outcomes in non-pregnant populations. These associations require validation in large, longitudinal cohorts investigating pregnancy, with long-term maternal follow-up. FUNDING: Stillbirth CRE, Mercy Hospital Foundation and National Health and Medical Research Council, Royal Australian and New Zealand College of Obstetricians and Gynaecologists, Taylor Hammond Scholarship, National Health and Medical Research Council Fellowships and Australian Research Council Future Fellowships.

BACKGROUND: Apathy is a multidimensional neuropsychiatric syndrome involving cognitive, emotional, and behavioral domains. Cognitive impairment and apathy are both associated with reduced social functioning, but how specific apathy dimensions relate cognition to social functioning across neurodegenerative diseases remains unclear. OBJECTIVE: This study compared multidimensional apathy profiles across Parkinson's disease (PD), Alzheimer's disease-like mild cognitive impairment (AD-like MCI), and normal controls (NC), and investigated whether specific apathy dimensions mediate the association between cognitive function and social functioning. METHODS: A total of 297 participants were enrolled, comprising 96 PD, 66 AD-like MCI, and 135 NC. All participants provided demographic information and underwent neuropsychological tests, a multidimensional apathy measure, and a social functioning measure. Depressive symptoms, sex, age, and education were included as covariates. Mediation analyses were conducted using PROCESS Model 4 with bootstrapping. RESULTS: A coherent triadic association among cognitive function, apathy, and social functioning was observed exclusively in the PD group. Hierarchical regression showed that cognitive and social motivation (CSM) independently predicted social functioning beyond executive function and covariates. Mediation analysis demonstrated that mental shifting was indirectly associated with social functioning through CSM (indirect effect = -.014, 95% CI [-.033, -.002]), with a non-significant direct effect. This pattern was not observed in the AD-like MCI or NC groups. CONCLUSIONS: These findings reveal a PD-specific pattern of associations among impaired mental shifting, CSM, and reduced social functioning. Its absence in AD-like MCI suggests distinct apathy mechanisms across neurodegenerative diseases and highlights CSM as a potential intervention target.

BACKGROUND: Perioperative neurocognitive disorders (PND) and Alzheimer's disease (AD) are both important aging related cognitive disorders. Accumulating evidence suggests that they share common pathological mechanisms involving Aβ deposition, neuroinflammation, and immunometabolic imbalance. However, the key regulatory molecules linking these two conditions remain unclear. FKBP prolyl isomerase 51 (FKBP51) is an immune regulatory molecule widely involved in inflammation control and metabolic homeostasis maintenance, but its role in PND and AD is still unknown. This study aimed to investigate whether FKBP51 participates in the shared pathological processes of PND and AD by regulating microglial immunometabolism. METHODS: This study integrated transcriptomic data from PND and AD brain tissues to screen for commonly abnormally expressed metabolism related genes and analyzed key hub genes in relation to clinical cognitive scores. The Brain RNA-seq database, single cell RNA sequencing data, and immunofluorescence staining were used to determine the cellular localization and expression characteristics of FKBP51. Primary microglia were stimulated with oligomeric Aβ, and Fkbp5 expression was knocked down using siRNA to evaluate its effects on microglial inflammatory responses and Aβ phagocytosis. Furthermore, single gene GSEA, Seahorse metabolic analysis, and ROS and JC-1 detection were combined to investigate the regulatory role of FKBP51 on microglial mitochondrial function and oxidative phosphorylation. RESULTS: Bioinformatics analysis identified FKBP51 as a key metabolism related hub gene that was commonly abnormally elevated in both PND and AD brain tissues, and its expression level was significantly correlated with cognitive decline in AD patients. Further studies revealed that FKBP51 was enriched in microglia and was significantly upregulated in brain tissues from AD patients and model mice. Aβ stimulation markedly induced FKBP51 expression in microglia. Functional experiments demonstrated that Fkbp5 knockdown enhanced microglial phagocytic capacity for Aβ and reduced the expression and secretion of proinflammatory factors. Mechanistic studies showed that FKBP51 was closely associated with pathways related to fatty acid oxidation and oxidative phosphorylation. Following FKBP51 inhibition, maximal respiration capacity and ATP production in microglia were significantly increased, mitochondrial membrane potential was improved, and ROS accumulation was markedly reduced. These metabolic improvements were accompanied by restoration of microglial phagocytic function and alleviation of the inflammatory state. CONCLUSIONS: This study reveals that FKBP51 is an important immunometabolic regulatory molecule linking the shared pathological processes of PND and AD. Abnormal upregulation of FKBP51 promotes microglial functional imbalance by inhibiting mitochondrial oxidative phosphorylation and inducing oxidative stress, thereby exacerbating Aβ related neuroinflammation and cognitive impairment. Targeting FKBP51 mediated microglial metabolic reprogramming may provide a novel intervention strategy for aging related cognitive disorders such as PND and AD.