Alzheimer's disease (AD) is a neurodegenerative disorder with a higher risk incidence in females than in males, and there are also differences in AD pathophysiology between sexes. The role of sex in the pathogenesis of AD may be crucial, yet the cellular and molecular basis remains unclear. Here, we performed a comprehensive analysis using four public transcriptome datasets of AD patients and age-matched control individuals in prefrontal cortex, including bulk transcriptome (295 females and 402 males) and single-nucleus RNA sequencing (snRNA-seq) data (224 females and 219 males). We found that the transcriptomic profile in female control was similar to those in AD. To characterize the key features associated with both the pathogenesis of AD and sex difference, we identified a co-expressed gene module that positively correlated with AD, sex, and aging, and was also enriched with immune-associated pathways. Using snRNA-seq datasets, we found that microglia (MG), a resident immune cell in the brain, demonstrated substantial differences in several aspects between sexes, such as an elevated proportion of activated MG, altered transcriptomic profile and cell-cell interaction between MG and other brain cell types in female control. Additionally, genes upregulated in female MG, such as TLR2, MERTK, SPP1, SLA, ACSL1, and FKBP5, had high confidence to be identified as biomarkers to distinguish AD status, and these genes also interacted with some approved drugs for treatment of AD. These findings underscore the altered immune response in female is associated with sex difference in susceptibility to AD, and the necessity of considering sex factors when developing AD biomarkers and therapeutic strategies, providing a scientific basis for further in-depth studies on sex differences in AD.

Emerging evidence supports the therapeutic potential of cannabinoids in Alzheimer's disease (AD), but the underlying mechanism upon how cannabinoids impact brain cognition and AD pathology remains unclear. Here we show that chronic cannabidiol (CBD) administration significantly mitigates cognitive deficiency and hippocampal β-amyloid (Aβ) pathology in 5×FAD mouse model of AD. CBD achieves its curative effect mainly through potentiating the function of inhibitory extrasynaptic glycine receptor (GlyR) in hippocampal dentate gyrus (DG). Based on the in vitro and in vivo electrophysiological recording and calcium imaging, CBD mediated anti-AD effects via GlyR are mainly accomplished by decreasing neuronal hyperactivity of granule cells in the DG of AD mice. Furthermore, the AAV-mediated ablation of DG GlyRα1, or the GlyRα1S296A mutation that exclusively disrupts CBD binding, significantly intercepts the anti-AD effect of CBD. These findings suggest a GlyR dependent mechanism underlying the therapeutic potential of CBD in the treatment of AD.

A key molecule in cellular metabolism, citrate is essential for lipid biosynthesis, energy production, and epigenetic control. The etiology of Alzheimer's disease (AD), a progressive neurodegenerative illness marked by memory loss and cognitive decline, may be linked to dysregulated citrate transport, according to recent research. Citrate transporters, which help citrate flow both inside and outside of cells, are becoming more and more recognized as possible participants in the molecular processes underlying AD. Citrate synthase (CS), a key enzyme in the tricarboxylic acid (TCA) cycle, supports mitochondrial function and neurotransmitter synthesis, particularly acetylcholine (ACh), essential for cognition. Changes in CS activity affect citrate availability, influencing energy metabolism and neurotransmitter production. Choline, a precursor for ACh, is crucial for neuronal function. Lipid metabolism, oxidative stress reactions, and mitochondrial function can all be affected by aberrant citrate transport, and these changes are linked to dementia. Furthermore, the two main pathogenic characteristics of AD, tau hyperphosphorylation and amyloid-beta (Aβ) aggregation, may be impacted by disturbances in citrate homeostasis. The goal of this review is to clarify the complex function of citrate transporters in AD and provide insight into how they contribute to the development and course of the illness. We aim to provide an in-depth idea of which particular transporters are dysregulated in AD and clarify the functional implications of these dysregulated transporters in brain cells. To reduce neurodegenerative processes and restore metabolic equilibrium, we have also discussed the therapeutic potential of regulating citrate transport. Gaining insight into the relationship between citrate transporters and the pathogenesis of AD may help identify new indicators for early detection and creative targets for treatment. This study offers hope for more potent ways to fight this debilitating illness and is a crucial step in understanding the metabolic foundations of AD.

Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by insidious and gradual onset. Identifying biomarkers associated with the early stages of AD is crucial for delaying its progression. In this study, we aimed to identify AD-related biomarkers in blood and urine by integrating genetic correlation analysis, shared genetic loci identification, and causal inference using linkage disequilibrium score regression (LDSC), conjunction false discovery rate (conjFDR), generalized summary data-based Mendelian randomization (GSMR) and two-sample Mendelian randomization (MR). To enhance robustness and minimize sample bias, we cross-validated findings using different AD GWAS datasets. Across multiple AD GWASs, we consistently observed nominally significant genetic correlations: AD was positively correlated with albumin (ALB) and negatively correlated with cystatin C (CYS) and urea (BUN). MR analysis further suggested that genetic predisposition to higher level of ALB and lower level of non-albumin protein (NAP) can represent risk factors for AD. In reverse MR analysis, a higher genetic risk for AD can predispose individuals to higher levels of ratio of aspartate aminotransferase to alanine aminotransferase (AST2ALT) and estimated glomerular filtration rate (EGFR), as well as lower level of creatinine (CRE). Overall, this study provides insights into the genetic correlations and causal relationships between AD and several biomarkers, offering potential candidates for AD diagnosis and management.

Background/aim: A growing body of evidence suggests a link between dyslipidemias and neurodegenerative diseases, highlighting the crucial role of lipid metabolism in the health of the central nervous system. The aim of our work was to provide an update on this topic, with a focus on clinical practice from an endocrinological point of view. Endocrinologists, being experts in the management of dyslipidemias, can play a key role in the prevention and treatment of neurodegenerative conditions, through precocious and effective lipid profile optimization. Methods: The literature was scanned to identify clinical trials and correlation studies on the association between dyslipidemia, statin therapy, and the following neurodegenerative diseases: Alzheimer's disease (AD), Parkisons's disease (PD), Multiple sclerosis (MS), and Amyotrophic lateral sclerosis (ALS). Results: Impaired lipid homeostasis, such as that frequently observed in patients affected by obesity and diabetes, is related to neurodegenerative diseases, such as AD, PD, and other cognitive deficits related to aging. AD and related dementias are now a real priority health problem. In the United States, there are approximately 7 million subjects aged 65 and older living with AD and related dementias, and this number is projected to grow to 12 million in the coming decades. Lipid-lowering therapy with statins is an effective strategy in reducing serum low-density lipoprotein cholesterol to normal range concentrations and, therefore, cardiovascular disease risk; moreover, statins have been reported to have a positive effect on neurodegenerative diseases. Conclusions: Several pieces of research have found inconsistent information following our review. There was no association between statin use and ALS incidence. More positive evidence has emerged regarding statin use and AD/PD. However, further large-scale prospective randomized control trials are required to properly understand this issue.

Current therapeutic regimens approved to treat Alzheimer's disease (AD) provide symptomatic relief by replenishing the acetylcholine levels in the brain by inhibiting AChE. However, these drugs don't halt or slow down the progression of Alzheimer's disease, which remains a major challenge. Evidence suggests a significant increase in BuChE activity with a decrease in AChE activity as the AD progresses along with the Aβ1-42 aggregation. To address this unmet need, we rationally developed sulfenylated 5-aminopyrazoles (3a-3o) via electro-organic synthesis in good to excellent yields (68-89%) and duly characterized them using spectrophotometric techniques. The compounds were tested for acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibition, with 3b (4-NO2) showing the highest potency. It exhibited IC50 values of 1.634 ± 0.066 μM against AChE and 0.0285 ± 0.019 μM against BuChE, outperforming donepezil and tacrine. Admittedly, 3b effectively inhibited Aβ1-42 aggregation and enhanced working memory, as indicated by the Y-maze test, besides portraying no cytotoxicity. The outcome was further corroborated using in silico techniques, leading to the elucidation of plausible inhibition and metabolism mechanisms.

Tauopathies comprise a range of neurodegenerative conditions characterized by the aberrant accumulation of tau protein clumps in the brain. These aggregates are formed by different tau splicing isoforms. Here, we analyzed the role of a specific intron-derived peptide called the W-Tau peptide on the polymerization-depolymerization of tau filaments. This peptide originates from a new isoform of the tau protein, named W-Tau, which is formed due to the retention of intron 12. AlphaFold3 (AF3)-based in silico investigations suggested that the W-Tau peptide interacts with tau monomers. Our in vitro experiments confirmed these predictions and showed that the W-Tau peptide inhibited tau aggregation. In addition, the W-Tau peptide disrupted preexisting paired helical filaments (PHFs) isolated from postmortem brain samples of patients with Alzheimer's disease, thereby supporting its potential therapeutic value. The effectiveness of the W-Tau peptide was demonstrated by the decrease in tau aggregation observed after cotransfection of the W-Tau peptide and PHF seeds, as demonstrated by analysis involving a fluorescence resonance energy transfer (FRET) cell biosensor. The W-Tau peptide breaks PHFs by selectively attaching to their ends, causing the structures to unwind and convert into circle-like formations. Considering the potential neuroprotective effects against tauopathies, the W-Tau isoform and its peptide are interesting candidates for future therapeutic interventions.

The cerebral accumulation of α-synuclein (α-Syn) and amyloid β-1-42 (Aβ-42) proteins is known to play a key role in the pathology of Parkinson's disease (PD). Currently, levodopa (L-dopa) is the first-line dopamine replacement therapy for treating bradykinetic symptoms (i.e., difficulty initiating physical movements), which become visible in PD patients. Using atomic force microscopy, we evidence at nanometer length scales the differential effects of L-dopa on the morphology of α-Syn and Aβ-42 protein fibrils. L-dopa treatment was observed to reduce the length and diameter of both types of protein fibrils, with a stark reduction mainly observed for Aβ-42 fibrils in physiological buffer solution and human cerebrospinal fluid. The insights gained on Aβ-42 fibril disassembly from the label-free nanoscale imaging experiments are substantiated by using atomic-scale molecular dynamics simulations. Our results indicate L-dopa-driven reversal of amyloidogenic protein aggregation, which might provide leads for designing chemical effector-mediated disassembly of insoluble protein aggregates.

In vitro diagnostics often detects biomarkers in body fluids (such as blood, urine, sputum, and cerebrospinal fluids) to identify life-threatening diseases at an early stage, monitor overall health, or provide information to help cure, treat, or prevent diseases. Most clinically used optical in vitro diagnostic tests utilize dye-labeled biomolecules for biomarker recognition and signal readout, which typically involve complex steps and long processing times. Activatable optical probes (AOPs), which spontaneously activate their optical signals only in the presence of disease biomarkers, offer higher signal-to-background ratios and improved detection specificity. They also have the potential to simplify detection procedures by eliminating multiple washing steps. In this review, we summarize recent advances in the use of AOPs for pre-clinical and clinical body fluid diagnostics across various diseases, including cancer, nephro-urological disorders, infectious diseases, and digestive diseases. We begin by discussing the molecular design strategies of AOPs to achieve different optical signal readouts and biomarker specificity. We then highlight their diagnostic applications in various disease models and body fluids. Finally, we address the challenges and future perspectives of AOPs in enhancing body fluid diagnostics and advancing precision medicine.

Despite decades of research in brain energy metabolism and to what extent different cell types utilize distinct substrates for their energy metabolism, this topic remains a vibrant area of neuroscience research. In this review, we focus on the substrates utilized by the inhibitory GABAergic neurons, which has been less explored than glutamatergic neurons. First, we discuss how GABAergic neurons may utilize both glucose, lactate, or ketone bodies under different functional conditions, and provide some preliminary data suggesting that unlike glutamatergic neurons, GABAergic neurons work well when substrate supply is restricted to lactate. We end by discussing the role of GABAergic neuron energy metabolism in pathologies where failure of inhibitory function play a central role, namely epilepsy, hepatic encephalopathy, and Alzheimer's disease.

Histamine H3 receptor (H3R) antagonists regulate histamine release that modulates neuronal activity and cognitive function. Although H3R is elevated in Alzheimer's disease (AD) patients, whether H3R antagonists can rescue AD-associated neural impairments and cognitive deficits remains unknown. Pitolisant is a clinically approved H3R antagonist/inverse agonist that treats narcolepsy. Here, we find that pitolisant reverses AD-like pathophysiology and cognitive impairments in an AD mouse model. Behavioral assays and in vivo wide-field Ca2+ imaging revealed that recognition memory, learning flexibility, and slow-wave impairment were all improved following the 15-day pitolisant treatment. Improved recognition memory was tightly correlated with slow-wave coherence, suggesting slow waves serve as a biomarker for treatment response and for AD drug screening. Furthermore, pitolisant reduced amyloid-β deposition and dystrophic neurites surrounding plaques, and enhanced neuronal lysosomal activity, inhibiting which blocked cognitive and slow-wave restoration. Our findings identify pitolisant as a potential therapeutic agent for AD treatments.

Sleep disturbances and cognitive decline are intricately connected, and both are prevalent in aging populations and individuals with neurodegenerative disorders such as Alzheimer's disease (AD) and other dementias. Sleep is vital for cognitive functions including memory consolidation, executive function, and attention. Disruption in these processes is associated with cognitive decline, although causal evidence is mixed. This review delves into the bidirectional relationship between alterations in sleep and cognitive impairment, exploring key mechanisms such as amyloid-β accumulation, tau pathology, synaptic homeostasis, neurotransmitter dysregulation, oxidative stress, and vascular contributions. Evidence from both experimental research and population-based studies underscores the necessity of early interventions targeting sleep to mitigate risks of neurodegenerative diseases. A deeper understanding of the interplay between sleep and cognitive health may pave the way for innovative strategies to prevent or reduce cognitive decline through improved sleep management.

In the innate immune system, the CD33 receptor modulates microglial activity. Its downregulation promises to slow Alzheimer's disease, and it is already targeted in blood cancers. The mechanism underlying CD33 signaling is unresolved. Starting from the available crystal structure of its extracellular IgV-IgC1 domains, we have assembled a model of the human CD33 receptor by characterizing the oligomerization and structure of IgC1, transmembrane, and cytosolic domains in solution. IgC1 homodimerizes via intermolecular β-strand pairing and packing. In contrast, the 21-residue transmembrane helix of CD33 appears monomeric and straight, with a conserved thin neck and thick belly appearance followed by a positively charged cytosolic patch. The cytosolic domain is dynamically unstructured. Sequence alignment and AlphaFold models indicate that IgC domains in the family of human Siglecs, to which CD33 belongs, are surprisingly variable. Only Siglec-6 is identified to analogously dimerize via IgC1. Our CD33 structural model suggests that the receptor is not signaling via a monomer-dimer shift. Rather, we propose that, aided but also constrained by dimerization, multivalent ligands may concentrate the receptor transmembrane and cytosolic domains sufficiently to trigger colocalization with an activating kinase.

Thrombosis, the formation of blood clots in arteries or veins, poses a significant health risk by disrupting the blood flow. It can potentially lead to major cardiovascular complications such as acute myocardial infarction or ischemic stroke (arterial thrombosis) and deep vein thrombosis or pulmonary embolism (venous thrombosis). Nevertheless, over the course of several decades, researchers have observed an association between different cardiovascular events and neurodegenerative diseases, which progressively harm and impair parts of the nervous system, particularly the brain. Furthermore, thrombotic complications have been identified in numerous clinical instances of neurodegenerative diseases, particularly Alzheimer's disease, Parkinson's disease, multiple sclerosis, and Huntington's disease. Substantial research indicates that endothelial dysfunction, vascular inflammation, coagulation abnormalities, and platelet hyperactivation are commonly observed in these conditions, collectively contributing to an increased risk of thrombosis. Thrombosis can, in turn, contribute to the onset, pathogenesis, and severity of these neurological disorders. Hence, this concise review comprehensively explores the correlation between cardiovascular diseases and neurodegenerative diseases, elucidating the cellular and molecular mechanisms of thrombosis in these neurodegenerative diseases. Additionally, a detailed discussion is provided on the commonly employed antithrombotic medications in the context of these neuronal diseases.

BackgroundAlzheimer's disease (AD) causes cognitive function disorder and has become the preeminent cause of dementia. Glucagon-like peptide-1 (GLP-1) receptor agonists, semaglutide, have shown positive effects on promoting the cognitive function. However, research about the mechanism of semaglutide as a therapeutic intervention in AD is sparse.ObjectiveThis study was to investigate the therapeutic efficacy of semaglutide in a transgenic mouse model of AD pathology and explored the detailed mechanism by semaglutide modulated neuroinflammatory processes.MethodsMale amyloid precursor protein/presenilin 1 (APP/PS1) transgenic mice were treated with semaglutide or vehicle for 8 weeks. Morris water maze test was used to assess the therapeutic efficacy of semaglutide on recognition function. Pathology analysis was performed to detect the deposition of amyloid plaques. High-throughput sequencing analysis was applied to specify the mechanism. Microglia and astrocyte activation were assessed with immunofluorescent staining. Inflammation cytokine levels were evaluated with enzyme-linked immunosorbent assay (ELISA). Related proteins and pathway were evaluated with western blot.ResultsSemaglutide treatment attenuated Aβ accumulation and enhanced cognitive function in APP/PS1 transgenic mice. Through transcriptomic profiling, immunohistochemical staining, and ELISA, semaglutide was substantiated to inhibit the overactivation of microglia and astrocytes, as well as to curtail the secretion of inflammatory mediators. Furthermore, semaglutide robustly activated AMP-activated protein kinase (AMPK) and suppressed the toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB) signaling cascade, thus reducing the Aβ deposition and dampening the inflammatory cascade.ConclusionsThe results demonstrated that semaglutide mitigated neuroinflammation and decelerated the advance of AD in APP/PS1 transgenic mice.

Stroke remains a predominant cause of death and long-term disability among adults worldwide. Emerging evidence suggests that proteinopathies, characterized by the aggregation and accumulation of misfolded proteins, may play a significant role in the aftermath of stroke and the progression of neurodegenerative disorders. In this review, we explore preclinical and clinical research on key proteinopathies associated with stroke, including tau, Aβ (amyloid-β), TDP-43 (TAR DNA-binding protein 43), α-synuclein, and UCH-L1 (ubiquitin C-terminal hydrolase-L1). We focus on their potential as biomarkers for recovery management and as novel treatment targets that may enhance neuronal repair and mitigate secondary neurodegeneration. The involvement of these proteinopathies in various aspects of stroke, including neuroinflammation, oxidative stress, neuronal damage, and vascular dysfunction, underscores their potential. However, further investigations are essential to validate the clinical utility of these biomarkers, elucidate the mechanisms connecting proteinopathies to poststroke neurodegeneration, and develop targeted interventions. Identifying specific protein signatures associated with stroke outcomes could facilitate the advancement of precision medicine tailored to individual patient needs, significantly enhancing the quality of life for stroke survivors.

We employed Stereo-seq combined with single-nucleus RNA sequencing (snRNA-seq) to investigate the gene expression and cell composition changes in human hippocampus with or without Alzheimer's disease (AD). The transcriptomic map, with single-cell precision, unveiled AD-associated alterations with spatial specificity, which include the following: (1) elevated synapse pruning gene expression in the fimbria of AD, with disrupted microglia-astrocyte communication likely leading to disorganized synaptic structure; (2) a globally increased energy generation in the cornu ammonis (CA) region, with varying degrees across its subregions; (3) a significant reduction in the number of CA1 neurons in AD, while CA4 neurons remained largely unaffected, potentially due to gene alterations in CA4 conferring resilience to AD; and (4) aggravated amyloid-beta (Aβ) plaques in CA1 and stratum lucidum, radiatum, and moleculare (SLRM), and integration of Stereo-seq map with Aβ staining revealed a sequential enrichment of microglia and astrocytes around Aβ plaques. Finally, reduced brain-derived extracellular vesicles carrying cholecystokinin (CCK) and peripheral myelin protein 2 (PMP2) in AD plasma highlighted their diagnostic potential for clinical applications.

Traumatic brain injury (TBI) is a modifiable risk factor for Alzheimer's disease (AD). TBI and AD share several histopathological hallmarks: namely, beta-amyloid aggregation, tau hyperphosphorylation, and plasma protein infiltration. The relative contributions of these proteinopathies and their interplay in the pathogenesis of both conditions remains unclear although important differences are emerging. This review synthesises emerging evidence for the critical role of the neurovascular unit in mediating protein accumulation and neurotoxicity in both TBI and AD. We propose a shared pathogenic cascade centred on a neurovascular unit, in which increased blood-brain barrier permeability induces a series of noxious mechanisms leading to neuronal loss, synaptic dysfunction and ultimately cognitive dysfunction in both conditions. We explore the application of this hypothesis to outstanding research questions and potential treatments for TBI and AD, as well as other neurodegenerative and neuroinflammatory conditions. Limitations of this hypothesis, including the challenges of establishing a causal relationship between neurovascular damage and proteinopathies, are also discussed.

Protein aggregation is a critical factor in the development and progression of several human diseases, including Alzheimer's disease (AD), Huntington's disease, Parkinson's disease, and type 2 diabetes. Among these conditions, AD is recognized as the most prevalent progressive neurodegenerative disorder, characterized by the accumulation of amyloid-beta (Aβ) peptides. Neuronal toxicity is likely driven by soluble oligomeric intermediates of the Aβ peptide, which are thought to play a central role in the cascade leading to neuronal dysfunction and cognitive decline. In response, numerous therapeutic strategies have been developed to inhibit Aβ oligomerization, as this is believed to delay the formation of Aβ protofibrils. Traditional research has focused on discovering small molecules or peptides that antagonize Aβ oligomerization. However, recent studies have explored an alternative approach-developing ligands that stabilize the Aβ peptide in its α-helical conformation. This stabilization is thought to alter the peptide's natural aggregation kinetics, shifting it away from toxic oligomer formation and toward less harmful states. Crucially, by maintaining Aβ in this α-helical form, these ligands have been shown to rescue the peptide's associated cytotoxicity, offering a promising mechanism to mitigate the detrimental effects of Aβ in AD. While challenges remain, including treatment costs and side effects like ARIA (amyloid-related imaging abnormalities), anti-Aβ drug development represents a major advancement in Alzheimer's research and therapeutic options. This brief review aims to highlight the development and potential of these α-helix-stabilizing ligands as antagonists of Aβ aggregation, focusing on their interactions with Aβ and how these compounds induce and maintain secondary structural changes in the Aβ peptide. Notably, this innovative strategy holds promise beyond Aβ-related pathology, as the fundamental principles could be applied to other amyloidogenic proteins implicated in various amyloid-related diseases, potentially broadening the scope of therapeutic intervention for multiple neurodegenerative conditions.

Neurodegenerative diseases (NDs), such as Alzheimer disease, Parkinson disease, Huntington disease, amyotrophic lateral sclerosis, and frontotemporal dementia, are well known to pose formidable challenges for their treatment due to their intricate pathogenesis and substantial variability among patients, including differences in environmental exposures and genetic predispositions. One of the defining characteristics of NDs is widely reported to be the buildup of misfolded proteins. For example, Alzheimer disease is marked by amyloid beta and hyperphosphorylated Tau aggregates, whereas Parkinson disease exhibits α-synuclein aggregates. Amyotrophic lateral sclerosis and frontotemporal dementia exhibit TAR DNA-binding protein 43, superoxide dismutase 1, and fused-in sarcoma protein aggregates, and Huntington disease involves mutant huntingtin and polyglutamine aggregates. These misfolded proteins are the key biomarkers of NDs and also serve as potential therapeutic targets, as they can be addressed through autophagy, a process that removes excess cellular inclusions to maintain homeostasis. Various forms of autophagy, including macroautophagy, chaperone-mediated autophagy, and microautophagy, hold a promise in eliminating toxic proteins implicated in NDs. In this review, we focus on elucidating the regulatory connections between autophagy and toxic proteins in NDs, summarizing the cause of the aggregates, exploring their impact on autophagy mechanisms, and discussing how autophagy can regulate toxic protein aggregation. Moreover, we underscore the activation of autophagy as a potential therapeutic strategy across different NDs and small molecules capable of activating autophagy pathways, such as rapamycin targeting the mTOR pathway to clear α-synuclein and Sertraline targeting the AMPK/mTOR/RPS6KB1 pathway to clear Tau, to further illustrate their potential in NDs' therapeutic intervention. Together, these findings would provide new insights into current research trends and propose small-molecule drugs targeting autophagy as promising potential strategies for the future ND therapies. SIGNIFICANCE STATEMENT: This review provides an in-depth overview of the potential of activating autophagy to eliminate toxic protein aggregates in the treatment of neurodegenerative diseases. It also elucidates the fascinating interrelationships between toxic proteins and the process of autophagy of "chasing and escaping" phenomenon. Moreover, the review further discusses the progress utilizing small molecules to activate autophagy to improve the efficacy of therapies for neurodegenerative diseases by removing toxic protein aggregates.

Diet can impact cognitive aging, but comprehensive data from human studies is lacking and the underlying biological mechanisms are still not fully understood.

To investigate the associations between two dietary patterns consistently linked to inflammation and brain health [the Mediterranean diet (MDS) and inflammatory potential of diet (EDII)] and five blood-based biomarkers of Alzheimer´s disease (AD) in a sample of dementia-free community-dwelling older adults.

We used cross-sectional data from the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K).

Participants who were institutionalized, had dementia or Parkinson's disease, or had missing data on diet and/or biomarkers were excluded. Our study sample consisted of 1907 adults ≥60 years old.

Adherence to the MDS and EDII was assessed using a validated food frequency questionnaire. T-tau, p-tau181, Aβ 42/40, NfL, and GFAP were measured in serum. Associations were estimated through quantile regression models at the 25th, 50th, and 75th percentiles of the biomarkers' levels, and were adjusted for potential confounders and stratified by sex, age, and APOE-e4 genotype.

In the whole sample, higher adherence to the MDS was associated with lower levels of p-tau181 at the 50th and 75th percentiles [β (95% CI) per 1-SD increment = -0.028 (-0.053, -0.002) and -0.036 (-0.072, -0.001), respectively], while higher adherence to the EDII was associated with higher levels of NfL at the 75th percentile [β (95% CI) per 1-SD increment =0.031 (0.008, 0.053)]. Associations with other biomarkers were only apparent at lower levels of their distribution. Subgroup analyses showed: 1) a stronger inverse association between the MDS and p-tau181 in APOE-e4 carriers than non-carriers, and 2) an inverse association of the MDS with GFAP only in participants ≥78 years.

Diet seems to be associated with biomarkers of AD pathology in cognitively intact older adults. Some associations were more apparent in the presence of genetic predisposition for AD or advanced age.

Tau PET quantitation methods have been used in research settings and clinical trials to measure tau burden for diagnostic, staging, and prognostic purposes. However, these methods require specialized software, skilled analysts, and advanced image processing. We developed a novel 18F-flortaucipir PET (FTP, or Tauvid) visual read method enabling stratification of patients with Alzheimer disease (AD) according to the tau level without the need for quantitation. An independent reader study (I7E-AV-A26) was conducted to test this method against a quantitation-based high-tau standard of truth. Methods: A total of 140 baseline or screening FTP scans were randomly selected from the TRAILBLAZER-ALZ 2 phase 3 trial (NCT04437511). Five qualified imaging physicians were trained for the FTP visual stratification method, using previously identified thresholds and cortical regions of interest thought to optimally stratify high-tau and non-high-tau scans. Positive and negative percent agreement (PPA and NPA, respectively) between visual stratifications and quantitation-based high tau (AD-signature SUV ratio > 1.46) were calculated. Predefined success criteria were met if the lower bounds of a 2-sided 95% CI for PPA and NPA were 50% or greater for at least 3 of the 5 readers. Inter- and intrareader reliability were assessed using Fleiss κ (n = 140) and Cohen κ (n = 20 test-retest scans) metrics. Results: The median PPA and NPA were 83.4% and 88.9%, respectively, with lower bounds of 2-sided 95% CIs being 50% or greater for all readers. The Fleiss κ-point estimate was 0.8882 (95% CI, 0.8356-0.9409) and the Cohen κ-point estimate was 0.9599 (95% CI, 0.9049-1.000) for all readers, indicating almost perfect inter- and intrareader agreement. Study I7E-AV-A26 successfully validated the feasibility of the FTP visual stratification method, possibly supporting AD staging and prognosis with high inter- and intrareader agreements, confirming the reliability of the method. Conclusion: Future investigations may include expanding the validation dataset, including real-world clinical data from diverse populations, using autopsy confirmation, exploring alternative regions and thresholds for other tau PET stratifications, and assessing differences in treatment response among visually stratified participants enrolled in disease-modifying therapy trials.

Alzheimer's disease (AD) arises from complex multilevel interactions between genetic, epigenetic, and environmental factors. Recent studies suggest that exposure to the environmental and occupational toxicant formaldehyde (FA) may play a significant role in AD development. However, the effects of FA exposure on Aβ and tau pathologies in human neural cell 3D culture systems remain unexplored. To investigate FA's role in AD initiation, we differentiated 3D-cultured immortalized human neural progenitor ReN cells (ReNcell VM) into neurons and glial cells, followed by FA treatment. FA exposure for 12 weeks resulted in a dose-dependent increase in Aβ40, Aβ42, and phosphorylated tau levels. To further examine FA's role in AD progression, we established a 3D human neural cell culture AD model by transfecting ReN cells with AD-related mutant genes, including mutant APP and PSEN1, which recapitulate key AD pathological events. Our findings demonstrate that FA exposure significantly elevated Aβ40, Aβ42, and phosphorylated tau levels in this 3D-cultured AD model. These results suggest that FA exposure contributes to the initiation and progression of AD pathology in 3D-cultured human neural cells.

While hallmarked by the accumulation of β-amyloid plaques (Aβ) and neurofibrillary tangles (tau) in the brain, Alzheimer's disease (AD) is a multifactorial disorder that involves additional pathological events, including neuroinflammation, neurodegeneration and synaptic dysfunction. AD-associated biomolecular changes seem to be attenuated in carriers of the functionally advantageous variant of the KLOTHO gene (KL-VSHET). Independently, better cardiorespiratory fitness (CRF) is associated with better health outcomes, both in general and specifically with regard to AD pathology. Here we investigate whether the relationships between CRF (peak oxygen consumption (VO2peak)) and cerebrospinal fluid (CSF) core AD biomarkers and those of neuroinflammation, neurodegeneration, and synaptic dysfunction differ for KL-VSHET compared to non-carriers (KL-VSNC).

The cohort, enriched for AD risk, consisted of cognitively unimpaired adults (N=136; MeanAGE(SD)=62.5(6.7)) from the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center. Covariate-adjusted (age, sex, parental AD history, APOE4+ status, and age difference between CSF sampling and exercise test) linear models examined the interaction between VO2peak and KLOTHO genotype on core AD biomarker levels in CSF [phosphorylated tau 181 (pTau181), Aβ42/Aβ40, pTau181/Aβ42]. Analyses were repeated for CSF biomarkers of neurodegeneration [total tau (tTau), α-synuclein (α-syn), neurofilament light polypeptide (NfL)], synaptic dysfunction [neurogranin (Ng)], and neuroinflammation [glial fibrillary acidic protein (GFAP), soluble triggering receptor expressed in myeloid cells (sTREM2), chitinase-3-like protein 1 (YKL-40), interleukin 6 (IL-6), S100 calcium-binding protein B (S100B)].

The interaction between VO2peak and KL-VSHET was significant for tTau (P=0.05), pTau181 (P=0.03), Ng (P=0.02), sTREM2 (P=0.03), and YKL-40 (P=0.03), such that lower levels of each biomarker were observed for KL-VSHET who were more fit. No significant KL-VSxVO2peak interactions were observed for Aβ42/Aβ40, pTau181/Aβ42, α-syn, NfL, GFAP, IL-6 or S100B (all Ps>0.09).

We report a synergistic relationship between KL-VSHET and CRF with regard to pTau181, tTau, Ng, sTREM2 and YKL-40, suggesting a protective role for both KL-VSHET and better cardiovascular fitness against unfavorable AD-related changes. Their potentially shared biological mechanisms will require future investigations.

Alzheimer's disease is the most common age-related dementia. Recent compelling evidence from previous retrospective electronic health record (EHRs) studies suggests that herpes simplex virus (HSV) infections may be a risk factor for developing dementia. However, no age and propensity score matched studies have been published in a United States general population cohort study to date.

We aimed to identify whether HSV infection shows a significantly increased risk of the development of dementia in a sizable and heterogeneous cohort. We investigated whether herpes simplex virus type 1 (HSV1), herpes simplex virus type 2 (HSV2), or coinfections with both serotypes pose a greater risk of developing dementia across different biological sexes and racial groups.

EHRs from patients with a history of HSV or specific serotypes (HSV1 or HSV2) infection were selected for analysis. These records were compared to a propensity-matched control group and analyzed for hazard and odds ratios through TriNetX.

There was a significant difference in dementia incidence in the HSV-infected group versus the control. Individuals with a history of HSV, HSV1, HSV2, and coinfection all showed a significant risk of developing dementia compared to controls. Males with HSV2 are at a higher risk of dementia outcome than females with HSV2.

While consistent with previous reports, these findings are the first to establish a higher risk of developing dementia in patients who have any HSV diagnosis using a nationwide, population-based matched cohort study in the United States.

The small nucleolar RNA (snoRNA) SNORD116 is a small non-coding RNA of interest across multiple biomedical fields of research. Much of the investigation into SNORD116 has been undertaken in the context of the congenital disease Prader-Willi syndrome, wherein SNORD116 expression is lost. However, emerging evidence indicates wider roles in various disease and tissue contexts such as cellular growth, metabolism and signalling. Nevertheless, a conclusive mechanism of action for SNORD116 remains to be established. Here, we review the key findings from these investigations, with the aim of identifying common elements from which to elucidate potential targets and mechanisms of SNORD116. A key recurring element identified is disruption to the insulin/IGF-1 and PI3K/mTOR signalling pathways, contributing to many of the phenotypes associated with SNORD116 modulation explored in this review.

Neurodegenerative diseases are defined by specific protein accumulation and anatomic vulnerability leading to neuronal loss. Some studies have shown that lutein may have an effect on neurodegenerative diseases. As most of the neurodegenerative diseases don't have certain cure and therapies focus on symptom control, Lutein may be a complementary treatment. Due to controversies in studies investigating lutein effect on neurodegenerative diseases, we decided to perform a systematic review on these studies.

A systematic search was carried out in the available databases. We used all MeSH terms and relevant keywords. Studies that reported relationship between lutein and any neurodegenerative disease were included.

We found 278 studies. After removing duplicates, screening by titles and abstracts and excluding irrelevant papers, 17 articles were included in this study. Fourteen studies investigated Alzheimer's disease, 2 studies Parkinson's disease and 1 study Amyotrophic lateral sclerosis. 1/17 study found that high serum levels of lutein at baseline were associated with a lower risk of AD mortality and lutein effect on lipid profile have been investigated in 2/17 studies. Also, 1/17 study has been shown that high intake of lutein may reduce the risk of ALS progression.

4/17 studies confirm that lutein can improve cognitive function. 8/17 studies demonstrate a reduction in the progression of AD, and 2/17 studies indicate an improvement in lipid profiles. However, some studies did not find any significant associations. Additionally, there is a limited number of studies investigating the effects of lutein on other neurodegenerative diseases.

Comorbid conditions associated with Alzheimer's disease (AD) are poorly understood regarding timing and potential impact on disease onset and progression.

Medical Information Mart for Intensive Care-IV electronic health records from 2008 to 2019 were examined. The study identified 2527 AD patients (34.9% male, mean age 80.27 years) among 299,712 patients. We examined the timing of 12 cardiovascular and metabolic diseases relative to AD diagnosis. Data from the National Alzheimer's Coordinating Center validated the findings.

Hypertension was the most common comorbidity, diagnosed 1.09 years before AD. Depression was the only comorbidity diagnosed after AD start, 0.16 years on average. AD patients had greater rates of hypertension, hypercholesterolemia, and depression compared to the general population.

The findings emphasize early detection and therapy of AD-related comorbidities, notably cardiovascular and metabolic diseases. The temporal link between these diseases and AD suggests opportunities for preventive strategies and improved care pathways.

Temporal analysis of comorbidities: The study reveals hypertension and hyperlipidemia as leading precursors to AD, typically diagnosed 1 to 1.3 years prior to AD onset, while depression emerges predominantly after diagnosis. Unique data integration: Large-scale datasets from MIMIC-IV (n = 299,712) and NACC (n = 51,836) were leveraged to identify chronological patterns in 12 key comorbid conditions relative to AD diagnosis. Sex- and age-specific insights: AD prevalence peaks at 80 to 86 years, with females exhibiting higher rates of LOAD compared to males. Depression as a post-diagnostic marker: Unlike other comorbidities, depression's post-diagnostic mean onset (0.16 years after AD diagnosis) highlights the need for targeted mental health interventions in AD patients. Implications for early detection: Findings suggest that managing hypertension, hyperlipidemia, and other modifiable conditions in midlife may delay or reduce the risk of AD development. Comorbidity variability across cohorts: Hypertension and hypercholesterolemia showed significantly higher prevalence in the NACC cohort compared to MIMIC-IV, reflecting potential dataset-specific biases or regional healthcare differences. Future research directions: Advocates for longitudinal, multiethnic, and global studies to refine early diagnostic criteria and explore preventive strategies tailored to comorbid conditions.

Alzheimer's Disease (AD) is a debilitating neurocognitive disorder with an unclear underlying mechanism. Recent studies have implicated gut microbiota dysbiosis with the onset and progression of AD. The connection between gut microbiota and AD can significantly affect the prevention and treatment of AD patients. This systematic review summarizes primary outcomes of human and mouse AD models concerning gut microbiota alterations. A systematic literature search in February through March 2023 was conducted on PubMed, Embase, and Web of Science. We identified 711 as potential manuscripts of which 672 were excluded because of irrelevance to the identified search criteria. Primary outcomes include microbiota compositions of control and AD models in humans and mice. In total, 39 studies were included (19 mouse and 20 human studies), published between 2017 and 2023. We included studies involving well-established mice models of AD (5xFAD, 3xTg-AD, APP/PS1, Tg2576, and APPPS2) which harbor mutations and genes that drive the formation of Aß plaques. All human studies were included on those with AD or mild cognitive impairment. Among alterations in gut microbiota, most studies found a decreased abundance of the phyla Firmicutes and Bifidobacteria, a genus of the phylum Actinomycetota. An increased abundance of the phyla Bacteroidetes and Proteobacteria were identified in animal and human studies. Studies indicated that gut microbiota alter the pathogenesis of AD through its impact on neuroinflammation and permeability of the gastrointestinal tract. The ensuing increase in blood-brain barrier permeability may accelerate Aβ penetrance and formation of neuritic plaques that align with the amyloid hypothesis of AD pathogenesis. Further studies should assess the relationship between gut microbiota and AD progression and therapy preserving beneficial gut microbiota.

Alzheimer's disease (AD) is the leading cause of dementia, and the early detection of the disease-associated changes allows early interventions. The locus coeruleus (LC) has been reported to be the first brain region to develop tau pathology in AD. However, the functional brain network of the LC in both healthy aging and AD pathology is largely unknown due to technical difficulties associated with the small size of the LC. In this study, we used the measurement of spontaneous pupil constriction/dilation as a surrogate for LC activity to study LC brain network changes during healthy aging.

Thirty-seven healthy younger and thirty-nine healthy older adults were included from the Emory Healthy Brain Study and underwent resting-state functional MRI while simultaneously tracking pupil diameter. The measurements of pupil diameter dynamics were used as reference signals in brain connectivity analysis. The connectivity of the identified networks was then compared between younger and older participants. Correlations of the identified regions with neuropsychological assessments and cerebrospinal fluid (CSF) biomarkers were also evaluated.

A brain network of 20 clusters associated with pupil diameter dynamics was identified, including the LC as well as brain regions functionally connected to the LC. The pupil diameter network was found to positively correlate with the salience network and negatively correlate with the central executive network. Functional connectivity decreased within the pupil diameter network with healthy aging. The pupil diameter connectivity was associated with memory, executive, and visuospatial functioning. CSF total tau closely correlated with pupil diameter network.

Pupil diameter dynamics provide valuable insights into LC-related processes. While they are not solely influenced by LC activity, spontaneous pupil constrictor/dilatory activity shows promise as a non-invasive approach to probe the LC network and warrants further studies to evaluate its value as an early biomarker of AD.

Psychiatric inpatients face an increased risk of deep vein thrombosis (DVT) due to their psychiatric conditions and pharmacological treatments. However, research focusing on this population remains limited.

This study analyzed 17,434 psychiatric inpatients at Huzhou Third Municipal Hospital, incorporating data on demographics, psychiatric diagnoses, physical illnesses, laboratory results, and medication use. Predictive models for DVT were developed using logistic regression, random forest, support vector machine (SVM), and XGBoost (Extreme Gradient Boosting). Feature importance was assessed using the random forest model.

The DVT incidence among psychiatric inpatients was 1.6%. Predictive model performance, measured by the area under the curve (AUC), showed logistic regression (0.900), random forest (0.885), SVM (0.890), and XGBoost (0.889) performed well. Logistic regression and random forest models exhibited optimal overall performance, while XGBoost excelled in recall. Significant predictors of DVT included elevated D-dimer levels, age, Alzheimer's disease, and Madopar use.

Psychiatric inpatients require vigilance for DVT risk, with factors like D-dimer levels and age serving as critical indicators. Machine learning models effectively predict DVT risk, enabling early detection and personalized prevention strategies in clinical practice.

Alzheimer's disease (AD), the most prevalent form of dementia, disproportionately affects the elderly population. While aging is widely recognized as a major risk factor for AD, the precise mechanisms by which aging contributes to the pathogenesis of AD remain poorly understood. In our previous work, the neuropathological changes in the brains of aged cynomolgus monkeys (≥18 years old) following parenchymal cerebral injection of amyloid-β oligomers (AβOs) have been characterized. Here, we extend our investigation to middle-aged cynomolgus monkeys (≤15 years old) to establish an AD model. Surprisingly, immunohistochemical analysis reveals no detectable AD-related pathology in the brains of middle-aged monkeys, even after AβOs injection. In a comprehensive pathological analysis of 38 monkeys, we observe that the amyloid-β (Aβ) burden increases significantly with advancing age. Notably, the density of Aβ plaques is markedly higher in the ventral regions compared to the dorsal regions of aged monkey brains. Furthermore, we demonstrate that tau phosphorylation coincides with the accumulation of extensive Aβ plaques and exhibits a positive correlation with Aβ burden in aged monkeys. Collectively, these findings underscore the critical role of the aged brain in providing the necessary conditions for AβO-induced AD pathologies in cynomolgus monkeys.

The fluorescent imaging of pathologically accumulated β-amyloid (Aβ) proteins is of significant importance to the diagnosis of Alzheimer's disease (AD). In the paper, we prepare two new NIR probes, NIR-1 and NIR-2, through hydrophilic modification of introducing water-soluble bioactive groups such as polyethylene glycol (PEG) and morpholine to tune in vivo pharmacokinetics for specific detection of soluble and insoluble Aβ species. The in vitro assessments confirm that both NIR-1 and NIR-2 display strong near-infrared (NIR) fluorescence (FL) enhancement upon interaction with Aβ42 monomers, oligomers or aggregates (λem>670 nm) and show highly sensitive, rapid and selective response towards Aβ42 species. After i. v. injection, each probe showed fast blood-brain barrier (BBB) penetration and immediately produced intense FL signals in the brain of APP/PS1 AD model mice at 10 min. Moreover, compared with NIR-2, NIR-1 bearing a hydrophilic PEG chain displayed not only more rapid clearance but also lower background signal to efficiently distinguish APP/PS1 mice and wild-type mice with higher signal-to-background ratio, which was further validated by ex vivo histological staining of brain tissues. Therefore, due to its excellent pharmacokinetics, NIR-1 shows great promise as an effective NIR probe for specific detection of Aβ species.

Erythrocytes, or red blood cells, are essential components of vertebrate blood, comprising approximately 45% of human blood volume. Their distinctive features, including small size, biconcave shape, extended lifespan (∼115 days), and lack of a nucleus or other membrane-bound organelles, make them unique among mammalian cell types. Traditionally regarded as passive carriers of oxygen and carbon dioxide, erythrocytes were long thought to function merely as hemoglobin-filled sacs, incapable of gene expression or roles beyond gas transport. However, advancements in molecular biology have revealed a more complex picture. Recent studies have identified various RNA types within erythrocytes, demonstrated globin mRNA translation, and uncovered miRNA-mediated defenses against Plasmodium infection. Beyond gas exchange, erythrocytes play critical roles in regulating regional blood flow via nitric oxide, contribute to innate immunity through toll-like receptors, transport amino acids between tissues, and maintain water homeostasis. Furthermore, emerging technologies have repurposed erythrocytes as drug-delivery vehicles, opening new avenues for therapeutic applications. This review highlights these recent discoveries and explores the expanding functional landscape of erythrocytes, shedding light on their multifaceted roles in physiology and medicine.

Messenger RNA (mRNA) therapy is an innovative approach that delivers specific protein-coding information. By promoting the ribosomal synthesis of target proteins within cells, it supplements functional or antigenic proteins to treat diseases. Unlike traditional gene therapy, mRNA does not need to enter the cell nucleus, reducing the risks associated with gene integration. Moreover, protein expression levels can be regulated by adjusting the dosage and degradation rates of mRNA. As a new generation gene therapy strategy, mRNA therapy represents the latest advancements and trends in the field. It offers advantages such as precision, safety, and ease of modification. It has been widely used in the prevention of COVID-19. Unlike acute conditions such as cerebral hemorrhage and stroke that often require immediate surgical or interventional treatments, neurodegenerative diseases (NDs) and brain tumors progress relatively slowly and face challenges such as the blood-brain barrier and complex pathogenesis. These characteristics make them particularly suitable for mRNA therapy. With continued research, mRNA-based therapeutics are expected to play a significant role in the prevention and treatment of NDs and brain tumors. This paper reviews the preparation and delivery of mRNA drugs and summarizes the research progress of mRNA gene therapy in treating NDs and brain tumors. It also discusses the current challenges, providing a theoretical basis and reference for future research in this field.

Alzheimer's disease (AD) is a distinctive form of dementia characterized by age-related cognitive decline and memory impairment. A key hallmark of AD is the irreversible overaccumulation of beta-amyloid (Aβ) in the brain, associated with neuroinflammation and neuronal death. Although Aβ clearance and immunoregulation have been the major therapeutic strategies for AD, highly selective transport across the blood-brain barrier (BBB) negatively affects the delivery efficacy of the drugs without the ability to cross the BBB. In this review, we discuss the potential of lipid-based nanoparticles (LBNs) as promising vehicles for drug delivery in AD treatment. LBNs, composed of phospholipid mono- or bilayer, have attracted attention due to their exceptional cellular penetration capabilities and drug loading capabilities, which also facilitate cargo transcytosis across the BBB. Recent advances in the development and engineering of LBNs overcome the existing limitations of the current clinical approaches for AD treatment by addressing off-target effects and low therapeutic efficacy. Here, we review the transport pathways across the BBB, as well as various types of LBNs for AD therapy, including exosomes, liposomes, solid lipid nanoparticles (SLNs), and nanostructured lipid carriers (NLCs), to elucidate their distinctive properties, preparation methodologies, and therapeutic efficacy, thereby offering innovative avenues for novel drug development for clinical translation in AD therapy.

To evaluate the association between cardiorespiratory fitness (CRF) and cognition in a large sample of older adults, and to examine clinical and demographic factors that might moderate these associations.

CRF was measured with a graded exercise test performed on a motorised treadmill. A confirmatory factor analysis was conducted using data from a comprehensive neuropsychological battery to obtain latent factors reflecting core cognitive domains. Linear regression models evaluated the association between CRF and each of the cognitive composites, and potential moderators including demographic factors (age, sex, education), apolipoprotein E ε4 (APOE4) carriage, beta-blocker use and components of maximal effort criteria during CRF testing.

The sample consisted of 648 adults (mean (SD) age 69.88 (3.75)), including 461 women (71.1%). The highest oxygen consumption obtained during testing (VO2max) was mean (SD) = 21.68 (5.06) mL/kg/min. We derived a five-factor model composed of episodic memory, processing speed, working memory, executive function/attentional control and visuospatial function. Higher CRF was associated with better performance across all five cognitive domains after controlling for covariates. Age and APOE4 carriage did not moderate observed associations. The relationship between CRF and cognitive performance was greater in women, those with fewer years of education and those taking beta-blockers in the domains of processing speed (sex: β=-0.447; p=0.015; education: β=-0.863; p=0.018) and executive function/attentional control (sex: β=-0.417; p=0.022; education β=-0.759; p=0.034; beta-blocker use: β=0.305; p=0.047).

Higher CRF in older adulthood is associated with better cognitive performance across multiple domains susceptible to age-related cognitive decline. Sex, education and use of beta-blockers moderated observed associations within select cognitive domains.

Systemic inflammation with alterations in inflammatory markers is involved in ageing and Alzheimer's disease. However, few studies have investigated the longitudinal trajectories of systemic inflammatory markers during ageing and Alzheimer's disease, and specific markers contributing to Alzheimer's disease remain undetermined. In this study, a longitudinal cohort (cohort 1: n = 290; controls, 136; preclinical Alzheimer's disease, 154) and a cross-sectional cohort (cohort 2: n = 351; controls, 62; Alzheimer's disease, 63; vascular dementia, 58; Parkinson's disease dementia, 56; behavioural variant frontotemporal dementia, 57; dementia with Lewy bodies, 55) were included. Plasma levels of inflammatory markers were measured every 2 years during a 10-year follow-up in the longitudinal cohort and once in the cross-sectional cohort. The study demonstrated that the inflammatory markers significantly altered during both ageing and the development of Alzheimer's disease. However, only complement C3, interleukin-1β and interleukin-6 exhibited significant changes in participants with preclinical Alzheimer's disease, and their longitudinal changes were significantly associated with the development of Alzheimer's disease compared to controls over the 10-year follow-up. In the cross-sectional cohort, complement C3 demonstrated specificity to Alzheimer's disease, while interleukin-1β and interleukin-6 were also altered in other dementias. The study provides a new perspective on the involvement of inflammatory markers in the ageing process and the development of Alzheimer's disease, implying that regulating inflammation may have a pivotal role in promoting successful ageing and in the prevention and treatment of Alzheimer's disease.

Both sleep alterations and epileptiform activity are associated with the accumulation of amyloid-β and tau pathology and are currently investigated for potential therapeutic interventions in Alzheimer's disease. However, a bidirectional intertwining relationship between sleep and neuronal hyperexcitability might modulate the effects of Alzheimer's disease pathology on the corresponding associations. To investigate this, we performed multiple day simultaneous foramen ovale (FO) plus scalp EEG and polysomnography recordings and acquired 18F-MK6240 tau PET-MR in three patients in the prodromal stage of Alzheimer's disease and in two patients with mild and moderate dementia due to Alzheimer's disease, respectively. As an eligibility criterion for the present study, subjects either had a history of a recent seizure (n = 2) or subclinical epileptiform activity (SEA) on a previous scalp EEG taken in a research context (n = 3). The 18F-MK6240 standard uptake value ratio (SUVR) and asymmetry index (AI) were calculated in a priori-defined volumes of interest. Linear mixed-effects models were used to study associations between interictal epileptiform discharges (IEDs), polysomnography parameters and 18F-MK6240 SUVR. Epileptiform activity was bilateral but asymmetrically present on FO electrodes in all patients and ≥95% of IEDs were not visible on scalp EEG. In one patient, two focal seizures were detected on FO electrodes, both without visual scalp EEG correlate. We observed lateralized periodic discharges, brief potentially ictal rhythmic discharges and lateralized rhythmic delta activity on FO electrodes in four patients. Unlike scalp EEG, intracranial electrodes showed a lateralization of epileptiform activity. Although the amount of IEDs on intracranial electrodes was not associated to the 18F-MK6240 SUVR binding in different volumes of interest, there was a congruent asymmetry of the 18F-MK6240 binding towards the most epileptic hemisphere for the mesial (P = 0.007) and lateral temporal cortex (P = 0.006). IEDs on intracranial electrodes were most abundant during slow wave sleep (SWS) (92/h) and non-REM sleep 2 (N2, 81/h), followed by non-REM sleep 1 (N1, 33/h) and least frequent during wakefulness (17/h) and REM sleep (9/h). The extent of IEDs during sleep was not reflected in the relative time in each sleep stage spent [REM% (P = 0.415), N1% (P = 0.668), N2% (P = 0.442), SWS% (P = 0.988)], and not associated with the arousal index (P = 0.317), apnoea-hypopnoea index (P = 0.846) or oxygen desaturation index (P = 0.746). Together, our observations suggest a multi-directional interaction between sleep, epileptiform activity and tau pathology in Alzheimer's disease.